88 results on '"Marini FC"'
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2. Production and culture of HSVtk transduced suicidal lymphocytes induces variable changes in the lymphocyte subset composition
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Marini, FC, primary and Kornblau, SM, additional
- Published
- 1999
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3. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement.
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Dominici, M, Le Blanc, K, Mueller, I, Slaper-Cortenbach, I, Marini, Fc, Krause, Ds, Deans, Rj, Keating, A, Prockop, Dj, and Horwitz, Em
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CELLULAR therapy ,STEM cells ,CELL differentiation ,FAT cells ,CHONDROBLASTOMA - Abstract
The considerable therapeutic potential of human multipotent mesenchymal stromal cells (MSC) has generated markedly increasing interest in a wide variety of biomedical disciplines. However, investigators report studies of MSC using different methods of isolation and expansion, and different approaches to characterizing the cells. Thus it is increasingly difficult to compare and contrast study outcomes, which hinders progress in the field. To begin to address this issue, the Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC. First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR surface molecules. Third, MSC must differentiate to osteoblasts, adipocytes and chondroblasts in vitro . While these criteria will probably require modification as new knowledge unfolds, we believe this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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4. Fibroblasts Isolated from Common Sites of Breast Cancer Metastasis Enhance Cancer Cell Growth Rates and Invasiveness in an Interleukin-6–Dependent Manner
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Gianluca Storci, Pasquale Sansone, Thomas J. Rosol, Tim H M Huang, Michael W.Y. Chan, Simona Tavolari, A. Kate Sasser, Massimiliano Bonafè, Jillian L. Werbeck, Frank C. Marini, Adam W. Studebaker, Brett Hall, Studebaker AW., Storci G., Werbeck JL., Sansone P., Sasser AK., Tavolari S., Huang T., Chan MW., Marini FC., Rosol TJ., Bonafé M., and Hall BM.
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STAT3 Transcription Factor ,CA15-3 ,Cancer Research ,Pathology ,medicine.medical_specialty ,CA 15-3 ,Estrogen receptor ,Breast Neoplasms ,Biology ,Breast cancer ,Cell Line, Tumor ,medicine ,Humans ,Immunoprecipitation ,Neoplasm Invasiveness ,Neoplasm Metastasis ,Phosphorylation ,Fibroblast ,Interleukin 6 ,INTERLEUCHINA 6 ,Interleukin-6 ,Cancer ,Fibroblasts ,medicine.disease ,medicine.anatomical_structure ,CANCRO MAMMARIO ,Oncology ,INFIAMMAZIONE ,Culture Media, Conditioned ,Cancer cell ,biology.protein ,Cancer research ,RNA Interference ,Cell Division - Abstract
Common sites of breast cancer metastasis include the lung, liver, and bone, and of these secondary metastatic sites, estrogen receptor α (ERα)–positive breast cancer often favors bone. Within secondary organs, cancer cells would predictably encounter tissue-specific fibroblasts or their soluble factors, yet our understanding of how tissue-specific fibroblasts directly affect cancer cell growth rates and survival remains largely unknown. Therefore, we tested the hypothesis that mesenchymal fibroblasts isolated from common sites of breast cancer metastasis provide a more favorable microenvironment with respect to tumor growth rates. We found a direct correlation between the ability of breast, lung, and bone fibroblasts to enhance ERα-positive breast cancer cell growth and the level of soluble interleukin-6 (IL-6) produced by each organ-specific fibroblast, and fibroblast-mediated growth enhancement was inhibited by the removal or inhibition of IL-6. Interestingly, mice coinjected with MCF-7 breast tumor cells and senescent skin fibroblasts, which secrete IL-6, developed tumors, whereas mice coinjected with presenescent skin fibroblasts that produce little to no IL-6 failed to form xenograft tumors. We subsequently determined that IL-6 promoted growth and invasion of breast cancer cells through signal transducer and activator of transcription 3–dependent up-regulation of Notch-3, Jagged-1, and carbonic anhydrase IX. These data suggest that tissue-specific fibroblasts and the factors they produce can promote breast cancer disease progression and may represent attractive targets for development of new therapeutics. [Cancer Res 2008;68(21):9087–95]
- Published
- 2008
5. Traditional postpartum rituals among immigrant and non-immigrant Chinese women.
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Dennis CL, Brennenstuhl S, Brown HK, Grigoriadis S, Vigod SN, Marini FC, and Fung K
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- Female, Humans, Canada, China, Longitudinal Studies, Asian People, Ceremonial Behavior, Emigrants and Immigrants, Postpartum Period psychology
- Abstract
Due to cultural and systemic factors, Chinese-Canadians tend to use mental health services less or when mental health problems are more severe. Services need to be more culturally responsive in their treatment of mental illness. Around important life events, when there may be heightened vulnerability to mental illness, this is especially important. In this study, postpartum cultural practices were examined among recent immigrant, longer-term immigrant, and Canadian-born Chinese women. We conducted a longitudinal cohort study of 493 women in Toronto, Ontario, with livebirths in 2011-2014. Participants completed a demographic survey and Postpartum Rituals Questionnaire. Most women (82.2%) practiced at least one postpartum ritual. Younger age (OR 0.93; 95% CI 0.87-0.99) and greater participation in the heritage culture (OR 1.28; 95% CI 1.02-1.61) were associated with ritual practice. From among five types of postpartum rituals identified (i.e., avoidance of homeostatic disturbances, dietary practices, wind avoidance, organized support, and cold avoidance), dietary practices were most commonly undertaken and cold avoidance was least commonly undertaken. There were differences in postpartum ritual patterns by immigration status, with immigrant women being more likely to undertake a greater number of rituals, to attribute these rituals to Chinese culture, and to ascribe health benefits to these rituals and being less likely to feel forced into performing these rituals. Our findings underscore the importance of clinicians becoming more aware of Chinese postpartum rituals to provide women with culturally competent and patient-centered care., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
- Published
- 2024
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6. Development of a novel air-liquid interface airway tissue equivalent model for in vitro respiratory modeling studies.
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Leach T, Gandhi U, Reeves KD, Stumpf K, Okuda K, Marini FC, Walker SJ, Boucher R, Chan J, Cox LA, Atala A, and Murphy SV
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- Humans, Cells, Cultured, Phenotype, Extracellular Matrix Proteins metabolism, Hydrogels metabolism, Lung, Epithelial Cells metabolism
- Abstract
The human airways are complex structures with important interactions between cells, extracellular matrix (ECM) proteins and the biomechanical microenvironment. A robust, well-differentiated in vitro culture system that accurately models these interactions would provide a useful tool for studying normal and pathological airway biology. Here, we report the development and characterization of a physiologically relevant air-liquid interface (ALI) 3D airway 'organ tissue equivalent' (OTE) model with three novel features: native pulmonary fibroblasts, solubilized lung ECM, and hydrogel substrate with tunable stiffness and porosity. We demonstrate the versatility of the OTE model by evaluating the impact of these features on human bronchial epithelial (HBE) cell phenotype. Variations of this model were analyzed during 28 days of ALI culture by evaluating epithelial confluence, trans-epithelial electrical resistance, and epithelial phenotype via multispectral immuno-histochemistry and next-generation sequencing. Cultures that included both solubilized lung ECM and native pulmonary fibroblasts within the hydrogel substrate formed well-differentiated ALI cultures that maintained a barrier function and expressed mature epithelial markers relating to goblet, club, and ciliated cells. Modulation of hydrogel stiffness did not negatively impact HBE differentiation and could be a valuable variable to alter epithelial phenotype. This study highlights the feasibility and versatility of a 3D airway OTE model to model the multiple components of the human airway 3D microenvironment., (© 2023. The Author(s).)
- Published
- 2023
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7. Preconception risk factors and health care needs of pregnancy-planning women and men with a lifetime history or current mental illness: A nationwide survey.
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Dennis CL, Brown HK, Brennenstuhl S, Vigod S, Miller A, Castro RA, Marini FC, and Birken C
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- Anxiety Disorders, Child, Chronic Disease, Delivery of Health Care, Female, Humans, Male, Preconception Care, Pregnancy, Risk Factors, Mental Disorders epidemiology
- Abstract
Objectives: While depression and anxiety are common in women and men of reproductive age, preconception interventions to optimize the health of individuals with mental illness before pregnancy is limited and focuses primarily on psychotropic medication management. Comparing individuals with depression, anxiety, and comorbidity to those with neither condition, we identified areas of preconception care optimization related to psychosocial risk factors, general physical health, medication use, and uptake of high-risk health behaviours. We also investigated differences in preconception health care use, attitudes, and knowledge., Method: We conducted a nationwide survey of 621 women (n = 529) and men (n = 92) across Canada who were planning a pregnancy within five years, including those with lifetime or current depression (n = 38), anxiety (n = 55), and comorbidity (n = 104) and those without mental illness (n = 413). Individuals with depression, anxiety, and comorbidity were compared to individuals without mental illness using logistic regression, adjusted for age, sex, and education level., Results: Individuals with a lifetime or current mental illness were significantly more likely to have several risk factors for suboptimal reproductive and perinatal outcomes, including increased rates of obesity, stress, fatigue, loneliness, number of chronic health conditions, and medication use. Further, they were more likely to have high-risk health behaviours including increased substance use, internet addiction, poorer eating habits, and decreased physical activity. By assessing depression, anxiety, or both separately, we also determined there was variation in risk factors by mental illness type., Conclusion: Our nationwide study is one of the first and largest to examine the preconception care needs of women and men with a lifetime or current mental illness who are pregnancy-planning. We found this population has many important reproductive and perinatal risk factors that are modifiable via preconception interventions which could have a significant positive impact on their health trajectories and those of their future children., Competing Interests: The authors have no conflicts of interest to declare.
- Published
- 2022
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8. Bioreactor design and validation for manufacturing strategies in tissue engineering.
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Lim D, Renteria ES, Sime DS, Ju YM, Kim JH, Criswell T, Shupe TD, Atala A, Marini FC, Gurcan MN, Soker S, Hunsberger J, and Yoo JJ
- Abstract
The fields of regenerative medicine and tissue engineering offer new therapeutic options to restore, maintain or improve tissue function following disease or injury. To maximize the biological function of a tissue-engineered clinical product, specific conditions must be maintained within a bioreactor to allow the maturation of the product in preparation for implantation. Specifically, the bioreactor should be designed to mimic the mechanical, electrochemical and biochemical environment that the product will be exposed to in vivo. Real-time monitoring of the functional capacity of tissue-engineered products during manufacturing is a critical component of the quality management process. The present review provides a brief overview of bioreactor engineering considerations. In addition, strategies for bioreactor automation, in-line product monitoring and quality assurance are discussed., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest.
- Published
- 2022
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9. Polycarbonate Urethane Mesh: A New Material for Pelvic Reconstruction.
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Bickhaus JA, Fraser MO, Weidner AC, Jayes FL, Amundsen CL, Gall K, Miller AT, Marini FC, Robboy SJ, and Siddiqui NY
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- Animals, Collagen Type I metabolism, Collagen Type III metabolism, Cytokines metabolism, Female, Hysterectomy, Macrophages metabolism, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Models, Animal, Ovariectomy, Polycarboxylate Cement, Rats, Sprague-Dawley, Urethane, Vagina metabolism, Rats, Surgical Mesh
- Abstract
Objective: Polycarbonate urethane (PCU) is a new biomaterial, and its mechanical properties can be tailored to match that of vaginal tissue. We aimed to determine whether vaginal host immune and extracellular matrix responses differ after PCU versus lightweight polypropylene (PP) mesh implantation., Methods: Hysterectomy and ovariectomy were performed on 24 Sprague-Dawley rats. Animals were divided into 3 groups: (1) PCU vaginal mesh, (2) PP vaginal mesh, and (3) sham controls. Vagina-mesh complexes or vaginas (controls) were excised 90 days after surgery. We quantified responses by comparing: (1) histomorphologic scoring of hematoxylin and eosin- and Masson trichrome-stained slides, (2) macrophage subsets (immunolabeling), (3) pro-inflammatory and anti-inflammatory cytokines (Luminex panel), (4) matrix metalloproteinase (MMP)-2 and -9 using an enzyme-linked immunosorbent assay, and (5) type I/III collagen using picrosirius red staining., Results: There was no difference in histomorphologic score between PCU and PP (P = 0.211). Although the histomorphologic response was low surrounding all mesh fibers, groups with PCU and PP mesh had a higher histomorphologic score than the control group (P < 0.005 and P < 0.002, respectively). There were no differences between groups in terms of macrophage subsets, pro-inflammatory cytokines, anti-inflammatory cytokines, MMP-2 and MMP-9, or collagen ratio., Conclusions: Polycarbonate urethane, an elastomer with material properties similar to those of vaginal tissue, elicits minimal host inflammatory responses in a rat model. Because its implantation does not elicit more inflammation than currently used lightweight PP, using PCU for prolapse mesh warrants further investigation with larger animal models., Competing Interests: N.Y.S. has a research grant with Medtronic Inc. The other authors report no conflict of interest., (Copyright © 2020 American Urogynecologic Society. All rights reserved.)
- Published
- 2021
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10. Evaluation of Host Immune Cellular and Extracellular Matrix Responses to Prolapse Mesh With and Without Tension in a Rat Model.
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Bickhaus JA, Fraser MO, Weidner AC, Jayes FL, Amundsen CL, Gall K, Marini FC, Robboy SJ, and Siddiqui NY
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- Animals, Collagen Type I metabolism, Collagen Type III metabolism, Cytokines metabolism, Female, Hysterectomy, Macrophages metabolism, Matrix Metalloproteinase 2 metabolism, Matrix Metalloproteinase 9 metabolism, Models, Animal, Ovariectomy, Polypropylenes, Rats, Sprague-Dawley, Rats, Surgical Mesh, Vagina metabolism, Vagina pathology
- Abstract
Objectives: We sought to determine whether vaginal host immune cellular and extracellular matrix responses are altered in a rat sacrocolpopexy model when lightweight polypropylene mesh is attached on tension versus without tension., Methods: We performed hysterectomy and ovariectomy in 32 Sprague-Dawley rats. Animals were assigned to 4 groups (n = 8/group): (1) controls with sham operation only (control), (2) mesh sutured only on the vagina (vaginal mesh), (3) sacrocolpopexy without tension, and (4) sacrocolpopexy with tension. Ninety days later, we excised vagina-mesh complexes. A histomorphologic scoring system of hematoxylin/eosin and Masson trichrome stained slides was used to assess host inflammatory responses. The cellular inflammatory response was further quantified using (1) identification of M1 and M2 macrophage subsets and (2) quantification of proinflammatory and anti-inflammatory cytokines. The extracellular matrix response was evaluated by measuring (1) matrix metalloproteinase-2 and matrix metalloproteinase-9 levels and (2) type I/III collagen., Results: Histomorphological tissue responses were greater in all groups with mesh compared with sham controls. Both sacrocolpopexy groups had similar scores, but each group scored significantly higher than the vaginal mesh group. Among the 4 groups, there were no statistically significant differences in M1 or M2 macrophage subsets, proinflammatory or anti-inflammatory cytokines, or extracellular matrix remodeling responses., Conclusions: Attachment of prolapse mesh resulted in an increased histologic inflammatory response independent of tension. Other markers of cellular inflammation and extracellular matrix remodeling showed no differences among experimental groups. Tension on lightweight polypropylene mesh did not significantly alter the host response in this rat sacrocolpopexy model., Competing Interests: N.Y.S. has a research grant with Medtronic Inc. The other authors report no conflict of interest., (Copyright © 2020 American Urogynecologic Society. All rights reserved.)
- Published
- 2021
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11. Fertility preservation for pediatric male cancer patients: illustrating contemporary and future options; a case report.
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Abdelaal O, Deebel NA, Zarandi NP, Kogan S, Marini FC, Pranikoff T, Stogner-Underwood K, McLean TW, Atala A, and Sadri-Ardekani H
- Abstract
The main aim of current pediatric male fertility preservation programs is storing spermatogonia stem cell (SSC) prior to starting cancer treatment. From July 1st, 2014 to May 1st, 2020; 170 patients have been recruited in Wake Forest Testicular Tissue Banking Program. The existence of multiple testis biopsies in different time points and detailed histological analyses of a unique cancer patient, provided an educational opportunity to investigate testis condition in different phases of cancer management. A pediatric male cancer patient with B-cell acute lymphoblastic leukemia (ALL) had multiple testicular leukemia recurrences and went through several testicular biopsies, to identify leukemic infiltration as well as considering fertility preservation. Infiltration of leukemia cells into both testes was identified. Neither elongated spermatid nor sperm were detected, but germ cells including SSC, spermatocyte and round spermatid could be identified in the stored tissue even after initial cancer treatment. Different germ cells were identified by hematoxylin and eosin (H&E) staining and specific immunohistochemical (IHC) markers including PGP9.5/UCHL1 or MAGE-A4 (spermatogonia), SYCP3 (spermatocyte) and PRM1 (round spermatid). This emphasizes the importance of offering testicular biopsy to pediatric cancer patients at risk of infertility regardless to the stage of cancer treatment, although earlier biopsy is preferred. Promising research on in vitro spermatogenesis and auto-transplantation support the practice of SSC preservation. In addition, finding and storing round spermatids isolated from testicular biopsy provides a currently available option of round spermatid injection (ROSI). Given the complexity of managing cancer while considering fertility preservation, a multidisciplinary collaboration is important to achieve optimal overall outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tau-20-908). The authors have no conflicts of interest to declare., (2021 Translational Andrology and Urology. All rights reserved.)
- Published
- 2021
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12. Imaging of Fibroblast Activation Protein Alpha Expression in a Preclinical Mouse Model of Glioma Using Positron Emission Tomography.
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Pandya DN, Sinha A, Yuan H, Mutkus L, Stumpf K, Marini FC, and Wadas TJ
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- Animals, Cell Line, Tumor, Endopeptidases, Female, Humans, Mice, Mice, Nude, Central Nervous System Neoplasms diagnostic imaging, Central Nervous System Neoplasms metabolism, Gelatinases biosynthesis, Gene Expression Regulation, Neoplastic, Glioblastoma diagnostic imaging, Glioblastoma metabolism, Membrane Proteins biosynthesis, Neoplasm Proteins biosynthesis, Neoplasms, Experimental diagnostic imaging, Neoplasms, Experimental metabolism, Positron-Emission Tomography, Serine Endopeptidases biosynthesis
- Abstract
Glioblastoma multiforme (GBM) is the most aggressive glioma of the primary central nervous system. Due to the lack of effective treatment options, the prognosis for patients remains bleak. Fibroblast activation protein alpha (FAP), a 170 kDa type II transmembrane serine protease was observed to be expressed on glioma cells and within the glioma tumor microenvironment. To understand the utility of targeting FAP in this tumor type, the immuno-PET radiopharmaceutical [
89 Zr]Zr-Df-Bz-F19 mAb was prepared and Lindmo analysis was used for its in vitro evaluation using the U87MG cell line, which expresses FAP endogenously. Lindmo analysis revealed an association constant (Ka ) of 10-8 M-1 and an immunoreactivity of 52%. Biodistribution studies in U87MG tumor-bearing mice revealed increasing radiotracer retention in tumors over time, leading to average tumor-to-muscle ratios of 3.1, 7.3, 7.2, and 8.3 at 2, 24, 48 and 72 h, respectively. Small animal PET corroborated the biodistribution studies; tumor-to-muscle ratios at 2, 24, 48, and 72 h were 2.0, 5.0, 6.1 and 7.8, respectively. Autoradiography demonstrated accumulated activity throughout the interior of FAP+ tumors, while sequential tumor sections stained positively for FAP expression. Conversely, FAP- tissues retained minimal radioactivity and were negative for FAP expression by immunohistochemistry. These results demonstrate FAP as a promising biomarker that may be exploited to diagnose and potentially treat GBM and other neuroepithelial cancers.- Published
- 2020
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13. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model.
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Gu X, Thakker PU, Matz EL, Terlecki RP, Marini FC, Allickson JG, Lue TF, Lin G, Atala A, Yoo JJ, Zhang Y, and Jackson JD
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- Animals, Disease Models, Animal, Endothelial Cells metabolism, Female, Humans, Hypogastric Plexus metabolism, Male, Pelvis pathology, Penile Erection physiology, Pregnancy, Prostatectomy adverse effects, Rats, Rats, Nude, Recovery of Function, Erectile Dysfunction physiopathology, Placenta cytology, Stem Cell Transplantation methods, Trauma, Nervous System complications
- Abstract
Introduction: The human placenta provides a bountiful and noncontroversial source of stem cells which have the potential for regeneration of injured tissue. These cells may restore erectile function after neurovascular tissue injury such as that seen in radical pelvic surgeries and pelvic trauma., Aim: To determine the effect of human placenta-derived stem cells on erectile function recovery and histological changes at various time points in a cavernous nerve injury rat model and to study the fate of injected stem cells throughout the regenerative process., Methods: Human placental stem cells (PSCs) were dual labeled with monomeric Katushka far red fluorescent protein (mKATE)-renLUC using a lentivirus vector. A pelvic neurovascular injury-induced erectile dysfunction model was established in male, athymic rats by crushing the cavernous nerves and ligating the internal pudendal neurovascular bundles, bilaterally. At the time of defect creation, nonlabeled PSCs were injected into the corpus cavernosum at a concentration of 2.5 × 10
6 cells/0.2 mL. The phosphate-buffered saline-treated group served as the negative control group, and age-matched rats (age-matched controls) were used as the control group. Erectile function, histomorphological analyses, and Western blot were assessed at 1, 6, and 12 weeks after model creation. The distribution of implanted, dual-labeled PSCs was monitored using an in vivo imaging system (IVIS). Implanted cells were further tracked by detection of mKATE fluorescence in histological sections., Main Outcome Measure: The main outcome measure includes intracavernous pressure/mean arterial pressure ratio, neural, endothelial, smooth muscle cell regeneration, mKATE fluorescence, and IVIS imaging., Results: The ratio of intracavernous pressure to mean arterial pressure significantly increased in PSC-injected rats compared with phosphate-buffered saline controls (P < 0.05) at the 6- and 12-week time points, reaching 72% and 68% of the age-matched control group, respectively. Immunofluorescence staining and Western blot analysis showed significant increases in markers of neurons (84.3%), endothelial cells (70.2%), and smooth muscle cells (70.3%) by 6 weeks in treatment groups compared with negative controls. These results were maintained through 12 weeks. IVIS analysis showed luminescence of implanted PSCs in the injected corpora immediately after injection and migration of cells to the sites of injury, including the incision site and periprostatic vasculature by day 1. mKATE fluorescence data revealed the presence of PSCs in the penile corpora and major pelvic ganglion at 1 and 3 days postoperatively. At 7 days, immunofluorescence of penile PSCs had disappeared and was diminished in the major pelvic ganglion., Clinical Implications: Placenta-derived stem cells may represent a future "off-the-shelf" treatment to mitigate against development of erectile dysfunction after radical prostatectomy or other forms of pelvic injury., Strength & Limitations: Single dose injection of PSCs after injury resulted in maximal functional recovery and tissue regeneration at 6 weeks, and the results were maintained through 12 weeks. Strategies to optimize adult stem cell therapy might achieve more effective outcomes for human clinical trials., Conclusion: Human PSC therapy effectively restores the erectile tissue and function in this animal model. Thus, PSC therapy may provide an attractive modality to lessen the incidence of erectile dysfunction after pelvic neurovascular injury. Further improvement in tissue regeneration and functional recovery may be possible using multiple injections or systemic introduction of stem cells. Gu X, Thakker PU, Matz EL, et al. Dynamic Changes in Erectile Function and Histological Architecture After Intracorporal Injection of Human Placental Stem Cells in a Pelvic Neurovascular Injury Rat Model. J Sex Med 2020;17:400-411., (Copyright © 2019 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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14. Trajectory and Predictors of Fatigue Among Chinese Immigrant and Chinese Canadian-Born Women in the Postpartum Period.
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Dennis CL, Brown HK, Brennenstuhl S, Haddad S, Marini FC, and Stremler R
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- Adult, China ethnology, Cohort Studies, Emigrants and Immigrants statistics & numerical data, Fatigue psychology, Female, Humans, Longitudinal Studies, Ontario, Pregnancy, Prospective Studies, Risk Factors, Surveys and Questionnaires, Emigrants and Immigrants psychology, Fatigue etiology, Postpartum Period
- Abstract
Objective: To describe the proportion of women with improving or worsening symptoms of fatigue at 1, 3, 6, and 12 months after birth; to model the trajectory of fatigue across the first year after birth and identify baseline predictors (e.g., immigrant status) and time-varying predictors; and to describe the degree to which fatigue interferes with activities of daily living across the first year after birth among a cohort of Chinese immigrant and Chinese Canadian-born women., Design: Prospective cohort study., Setting: Toronto, Ontario, Canada., Participants: Chinese women who were recent immigrants (n = 244), nonrecent immigrants (n = 247), or Canadian born (n = 100)., Methods: Women completed surveys at 1, 3, 6, and 12 months after birth. We measured fatigue with the use of the Multidimensional Assessment of Fatigue scale. Fatigue predictor variables were classified as baseline (e.g., immigrant status) or time varying (e.g., depression). We used latent growth curve modeling to examine fatigue trajectories and identify predictors over time., Results: Fatigue followed a nonlinear pattern: it improved from 1 to 6 months after birth and then worsened from 6 to 12 months after birth. Depression, anxiety, infant sleep characteristics, and breastfeeding problems, but not immigrant status, significantly increased risk for fatigue. Several daily activities were significantly influenced by fatigue, particularly early in the postpartum period as well as later, which showed a U-shaped relationship between fatigue and activities of daily living., Conclusion: Fatigue is common and persistent across the postpartum period. Modifiable risk factors related to mental health, infant sleep, and breastfeeding difficulties suggest that preventive strategies for maternal fatigue warrant further investigation., (Copyright © 2020. Published by Elsevier Inc.)
- Published
- 2020
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15. Prevalence and Predictors of Postpartum Maternal and Infant Bed-Sharing Among Chinese-Canadian Women.
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Dennis CL, Brown HK, Brennenstuhl S, Haddad S, Marini FC, and Stremler R
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- Adult, Female, Humans, Infant, Infant, Newborn, Middle Aged, Young Adult, Asian People, Beds, Canada, Longitudinal Studies, Prevalence, Infant Care methods, Mother-Child Relations psychology, Postpartum Period psychology
- Abstract
Objective/Background : Our primary objective was to describe and identify predictors of any and predominant bed-sharing at 4 and 12 weeks postpartum among Chinese-Canadian mothers. Participants : We conducted a longitudinal study of 570 Chinese immigrant and Canadian-born women in Toronto, Ontario. Methods : Any bed-sharing, defined as sharing a bed or mattress for any part of the night on any night in the previous week, and predominant bed-sharing, defined as sharing a bed or mattress for most of the night, on more than half the nights of the previous week, were evaluated at 4 and 12 weeks postpartum. Predictors of bed-sharing, evaluated in multivariable logistic regression models, were background (age, parity, education, household size, delivery mode, social support), cultural (immigrant status, acculturative stress, acculturation, postpartum ritual uptake), and postpartum variables (mental health, breastfeeding problems, fatigue, sleep knowledge, plans for bed-sharing, perceptions of infant sleep problems, cognitions about infant sleep). Results : One in five women (20.7%) reported bed-sharing as the predominant sleep location for their infant at 4 weeks postpartum, with nearly half (45.6%) reporting any bed-sharing at this time. The prevalence of any bed-sharing remained relatively stable at 12 weeks postpartum (46.5%), while predominant bed-sharing increased to 30.1%. The most consistent predictors of any and predominant bed-sharing at 4 and 12 weeks postpartum were lower education level, greater acculturative stress, and predelivery plans to bed-share. Conclusions : These findings have implications for the development of clinical recommendations given to expectant and new parents to promote infant sleep practices that are consistent with American Academy of Pediatrics recommendations.
- Published
- 2020
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16. Osteoblasts are "educated" by crosstalk with metastatic breast cancer cells in the bone tumor microenvironment.
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Kolb AD, Shupp AB, Mukhopadhyay D, Marini FC, and Bussard KM
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- Animals, Bone Matrix cytology, Bone Matrix diagnostic imaging, Bone Matrix pathology, Bone Neoplasms diagnostic imaging, Bone Neoplasms secondary, Breast cytology, Breast pathology, Cell Line, Tumor, Cell Proliferation, Culture Media, Conditioned, Female, Humans, Intravital Microscopy, Mice, Mice, Nude, NIH 3T3 Cells, Primary Cell Culture, Xenograft Model Antitumor Assays, Bone Neoplasms pathology, Breast Neoplasms pathology, Cell Communication, Osteoblasts pathology, Tumor Microenvironment
- Abstract
Introduction: In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are diverted from laying down bone matrix to producing cytokines that facilitate breast cancer cell maintenance in late-stage disease. Here, we have new evidence to suggest that there are subpopulations of osteoblasts in the tumor niche as evidenced by their protein marker expression that have distinct roles in tumor progression in the bone., Methods: Tumor-bearing tibia of mice was interrogated by immunofluorescent staining for the presence of osteoblasts and alterations in niche protein expression. De-identified tissue from patients with bone metastatic breast cancer was analyzed for osteoblast subpopulations via multi-plex immunofluorescent staining. Effects of breast cancer cells on osteoblasts were recapitulated in vitro by osteoblast exposure to breast cancer-conditioned medium. Triple-negative and estrogen receptor-positive breast cancer proliferation, cell cycle, and p21 expression were assessed upon contact with "educated" osteoblasts., Results: A subpopulation of osteoblasts was identified in the bone tumor microenvironment in vivo of both humans and mice with bone metastatic breast cancer that express RUNX2/OCN/OPN but is negative for IL-6 and alpha-smooth muscle actin. These tumor "educated" osteoblasts (EOs) have altered properties compared to "uneducated" osteoblasts and suppress both triple-negative and estrogen receptor-positive breast cancer cell proliferation and increase cancer cell p21 expression. EO effects on breast cancer proliferation were mediated by NOV and decorin. Importantly, the presence of EO cells in the tibia of mice bearing tumors led to increased amounts of alkaline phosphatase and suppressed the expression of inflammatory cytokines in vivo., Conclusions: Our work reveals that there is a subpopulation of osteoblasts in the bone tumor microenvironment that demonstrate a functional role in retarding breast cancer cell growth.
- Published
- 2019
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17. A comprehensively revised strategy that improves the specific activity and long-term stability of clinically relevant 89 Zr-immuno-PET agents.
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Bhatt NB, Pandya DN, Rideout-Danner S, Gage HD, Marini FC, and Wadas TJ
- Abstract
Zirconium-89 is currently being used in numerous clinical trials involving monoclonal antibodies and positron emission tomography. This report describes a revised strategy that reduces preparation time while increasing the specific activity of clinically relevant immuno-PET agents. Additionally, it demonstrates that n-acetyl-l-cysteine acts as a superior radioprotective agent that improves long-term stability without compromising antigen affinity in vivo.
- Published
- 2018
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18. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction.
- Author
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Allen JK, Armaiz-Pena GN, Nagaraja AS, Sadaoui NC, Ortiz T, Dood R, Ozcan M, Herder DM, Haemmerle M, Gharpure KM, Rupaimoole R, Previs RA, Wu SY, Pradeep S, Xu X, Han HD, Zand B, Dalton HJ, Taylor M, Hu W, Bottsford-Miller J, Moreno-Smith M, Kang Y, Mangala LS, Rodriguez-Aguayo C, Sehgal V, Spaeth EL, Ram PT, Wong STC, Marini FC, Lopez-Berestein G, Cole SW, Lutgendorf SK, De Biasi M, and Sood AK
- Subjects
- Animals, Cell Line, Tumor, Cyclic AMP metabolism, Female, Guanine Nucleotide Exchange Factors metabolism, Humans, Membrane Glycoproteins metabolism, Mice, Neoplasms mortality, Peripheral Nerves metabolism, Peripheral Nerves pathology, Receptor, trkB metabolism, Signal Transduction, Tumor Microenvironment physiology, Xenograft Model Antitumor Assays, Brain-Derived Neurotrophic Factor metabolism, Feedback, Physiological, Neoplasms pathology, Norepinephrine metabolism, Receptors, Adrenergic, beta-3 metabolism
- Abstract
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233-42. ©2018 AACR ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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19. Unique trajectories of anxiety among Chinese-Canadian women across the first postpartum year: A longitudinal cohort study.
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Dennis CL, Brennenstuhl S, Wanigaratne S, Brown HK, Grigoriadis S, Marini FC, and Vigod SN
- Subjects
- Adult, Canada, China ethnology, Fatigue psychology, Female, Humans, Longitudinal Studies, Pregnancy, Risk Factors, Social Support, Young Adult, Anxiety psychology, Depression, Postpartum psychology, Emigrants and Immigrants psychology, Postpartum Period psychology
- Abstract
Background: Our objectives were to identify subtypes of Chinese-Canadian women with unique trajectories of anxiety symptomatology over the first postpartum year, investigate covariates associated with group membership, and determine if mental healthcare utilization varies by group membership., Methods: This was a longitudinal cohort study of 570 Chinese immigrant and Canadian-born women in Toronto, Canada with live births in 2010-2014. Covariates were age, immigrant status, income, fatigue, social support, acculturative stress, and depression. Mental healthcare utilization included visits at 4-24 weeks postpartum. Anxiety symptomatology was measured using the State-Trait Anxiety Inventory-State. Growth mixture modeling was used to identify latent classes corresponding to trajectories of anxiety symptomology at 4-52 weeks., Results: Three groups were identified: "consistently non-anxious" (74%, stable low levels of anxiety), "consistently anxious" (19.5%, clinically meaningful anxiety at baseline and across time), and "anxious-improving" (6.5%, high anxiety at baseline followed by decline). Compared to consistently non-anxious women, consistently anxious women were more likely to report baseline fatigue, depression, and acculturative stress; anxious-improving women were more likely to report baseline fatigue, depression, and history of depression before pregnancy. At 12-24 weeks, 13.8% of anxious-improving women sought mental healthcare compared to 8.6% of consistently-anxious women and 4.7% of non-anxious women (p = .06)., Limitations: Our sample comprised Chinese immigrant and Canadian-born women; results should be replicated in other groups., Conclusions: We identified three subtypes of postpartum anxiety trajectories. These groups of women may respond differently to interventions due to exposure to various combinations of risk factors., (Copyright © 2018 Elsevier B.V. All rights reserved.)
- Published
- 2018
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20. Practical Guidelines for Cerenkov Luminescence Imaging with Clinically Relevant Isotopes.
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Bhatt NB, Pandya DN, Dezarn WA, Marini FC, Zhao D, Gmeiner WH, Triozzi PL, and Wadas TJ
- Subjects
- Animals, Humans, Mice, Neoplasms diagnostic imaging, Neoplasms metabolism, Practice Guidelines as Topic, Luminescent Measurements methods, Multimodal Imaging methods, Neoplasms pathology, Phantoms, Imaging, Radiopharmaceuticals metabolism
- Abstract
Cerenkov luminescence imaging (CLI) is a relatively new imaging modality that utilizes conventional optical imaging instrumentation to detect Cerenkov radiation derived from standard and often clinically approved radiotracers. Its research versatility, low cost, and ease of use have increased its popularity within the molecular imaging community and at institutions that are interested in conducting radiotracer-based molecular imaging research, but that lack the necessary resources and infrastructure. Here, we provide a description of the materials and procedures necessary to conduct a Cerenkov luminescence imaging experiment using a variety of imaging instrumentation, radionuclides, and animal models.
- Published
- 2018
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21. Identifying women at risk for sustained postpartum anxiety.
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Dennis CL, Brown HK, Falah-Hassani K, Marini FC, and Vigod SN
- Subjects
- Adolescent, Adult, Canada epidemiology, Female, Humans, Models, Psychological, Personality Inventory, Prevalence, Risk Factors, Social Support, Young Adult, Anxiety epidemiology, Mothers psychology, Postpartum Period psychology
- Abstract
Introduction: To describe the prevalence of sustained postpartum anxiety and to develop a multifactorial predictive model to assist in targeted screening procedures., Methods: In a population-based cohort in a health region near Vancouver, Canada, 522 mothers completed a mailed questionnaire at 1, 4, and 8 weeks postpartum measuring socio-demographic, biological, pregnancy-related, life stressor, social support, obstetric, and maternal adjustment factors. We undertook a sequential logistic regression analysis to develop a multifactorial predictive model of sustained postpartum anxiety, as measured by a State Trait Anxiety Inventory (STAI) score >40 at 1 week and/or 4 weeks, and 8 weeks postpartum., Results: The prevalence of sustained postpartum anxiety was 12.6% (95% CI 9.6-16.2). In the multivariable model, predictors of sustained anxiety in the postpartum period were perceived stress at 1 week (1 SD increase; aOR 3.74, 95% CI 2.17-6.44) and partner social support at 1 week (1 SD increase; aOR 0.59, 95% CI 0.40-0.85). Depression symptomatology at 1 week, child care stress, and maternal self-esteem were non-significant., Limitations: Single women and women from ethnic minority backgrounds were underrepresented in the sample., Conclusions: A large proportion of women experience sustained postpartum anxiety. High perceived stress and low partner social support can be used to facilitate early identification of women likely to experience persistent anxiety in the postpartum period and suggest the need for urgent access to psychotherapeutic services for these women. These factors may also be potential targets for individual or couples therapy to treat postpartum anxiety., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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22. Novel Peripherally Derived Neural-Like Stem Cells as Therapeutic Carriers for Treating Glioblastomas.
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Birbrair A, Sattiraju A, Zhu D, Zulato G, Batista I, Nguyen VT, Messi ML, Solingapuram Sai KK, Marini FC, Delbono O, and Mintz A
- Subjects
- Animals, Antigens metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Differentiation, Cell Line, Tumor, Cell Lineage, Cell Movement, Cell Separation, Coculture Techniques, Genetic Therapy adverse effects, Glioblastoma genetics, Glioblastoma metabolism, Glioblastoma pathology, Human Umbilical Vein Endothelial Cells metabolism, Humans, Male, Mice, Inbred C57BL, Mice, Nude, Mice, Transgenic, Neovascularization, Physiologic, Neural Stem Cells metabolism, Pericytes metabolism, Phenotype, Proteoglycans metabolism, Stem Cell Transplantation adverse effects, TNF-Related Apoptosis-Inducing Ligand metabolism, Xenograft Model Antitumor Assays, Brain Neoplasms therapy, Genetic Therapy methods, Glioblastoma therapy, Muscle, Skeletal cytology, Neural Stem Cells transplantation, Pericytes transplantation, Stem Cell Transplantation methods, TNF-Related Apoptosis-Inducing Ligand genetics
- Abstract
Glioblastoma (GBM), an aggressive grade IV astrocytoma, is the most common primary malignant adult brain tumor characterized by extensive invasiveness, heterogeneity, and angiogenesis. Standard treatment options such as radiation and chemotherapy have proven to be only marginally effective in treating GBM because of its invasive nature. Therefore, extensive efforts have been put forth to develop tumor-tropic stem cells as viable therapeutic vehicles with potential to treat even the most invasive tumor cells that are harbored within areas of normal brain. To this end, we discovered a newly described NG2-expressing cell that we isolated from a distinct pericyte subtype found abundantly in cultures derived from peripheral muscle. In this work, we show the translational significance of these peripherally derived neural-like stem cells (NLSC) and their potential to migrate toward tumors and act as therapeutic carriers. We demonstrate that these NLSCs exhibit in vitro and in vivo GBM tropism. Furthermore, NLSCs did not promote angiogenesis or transform into tumor-associated stromal cells, which are concerns raised when using other common stem cells, such as mesenchymal stem cells and induced neural stem cells, as therapeutic carriers. We also demonstrate the potential of NLSCs to express a prototype therapeutic, tumor necrosis factor α-related apoptosis-inducing ligand and kill GBM cells in vitro. These data demonstrate the therapeutic potential of our newly characterized NLSC against GBM. Stem Cells Translational Medicine 2017;6:471-481., (© 2016 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)
- Published
- 2017
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23. Selection of a Novel Aptamer Against Vitronectin Using Capillary Electrophoresis and Next Generation Sequencing.
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Stuart CH, Riley KR, Boyacioglu O, Herpai DM, Debinski W, Qasem S, Marini FC, Colyer CL, and Gmeiner WH
- Abstract
Breast cancer (BC) results in ~40,000 deaths each year in the United States and even among survivors treatment of the disease may have devastating consequences, including increased risk for heart disease and cognitive impairment resulting from the toxic effects of chemotherapy. Aptamer-mediated drug delivery can contribute to improved treatment outcomes through the selective delivery of chemotherapy to BC cells, provided suitable cancer-specific antigens can be identified. We report here the use of capillary electrophoresis in conjunction with next generation sequencing to develop the first vitronectin (VN) binding aptamer (VBA-01; Kd 405 nmol/l, the first aptamer to vitronectin (VN; K
d = 405 nmol/l) , a protein that plays an important role in wound healing and that is present at elevated levels in BC tissue and in the blood of BC patients relative to the corresponding nonmalignant tissues. We used VBA-01 to develop DVBA-01, a dimeric aptamer complex, and conjugated doxorubicin (Dox) to DVBA-01 (7:1 ratio) using pH-sensitive, covalent linkages. Dox conjugation enhanced the thermal stability of the complex (60.2 versus 46.5° C) and did not decrease affinity for the VN target. The resulting DVBA-01-Dox complex displayed increased cytotoxicity to MDA-MB-231 BC cells that were cultured on plasticware coated with VN (1.8 × 10-6 mol/l) relative to uncoated plates (2.4 × 10-6 mol/l), or plates coated with the related protein fibronectin (2.1 × 10-6 mol/l). The VBA-01 aptamer was evaluated for binding to human BC tissue using immunohistochemistry and displayed tissue specific binding and apparent association with BC cells. In contrast, a monoclonal antibody that preferentially binds to multimeric VN primarily stained extracellular matrix and vessel walls of BC tissue. Our results indicate a strong potential for using VN-targeting aptamers to improve drug delivery to treat BC.- Published
- 2016
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24. Near Infrared Fluorescent Nanoparticles Derived from Hyaluronic Acid Improve Tumor Contrast for Image-Guided Surgery.
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Hill TK, Kelkar SS, Wojtynek NE, Souchek JJ, Payne WM, Stumpf K, Marini FC, and Mohs AM
- Subjects
- Animals, Breast Neoplasms surgery, Disease Models, Animal, Heterografts, Humans, Mice, Inbred BALB C, Mice, Nude, Breast Neoplasms diagnostic imaging, Contrast Media administration & dosage, Hyaluronic Acid administration & dosage, Infrared Rays, Nanoparticles administration & dosage, Optical Imaging methods, Surgery, Computer-Assisted methods
- Abstract
Tumor tissue that remains undetected at the primary surgical site can cause tumor recurrence, repeat surgery, and treatment strategy alterations that impose a significant patient and healthcare burden. Intraoperative near infrared fluorescence (NIRF) imaging is one potential method to identify remaining tumor by visualization of NIR fluorophores that are preferentially localized to the tumor. This requires development of fluorophores that consistently identify tumor tissue in different patients and tumor types. In this study we examined a panel of NIRF contrast agents consisting of polymeric nanoparticle (NP) formulations derived from hyaluronic acid (HA), with either physically entrapped indocyanine green (ICG) or covalently conjugated Cy7.5. Using orthotopic human breast cancer MDA-MB-231 xenografts in nude mice we identified two lead formulations. One, NanoICG
PBA , with physicochemically entrapped ICG, showed 2.3-fold greater tumor contrast than ICG alone at 24 h (p < 0.01), and another, NanoCy7.5100-H , with covalently conjugated Cy7.5, showed 74-fold greater tumor contrast than Cy7.5 alone at 24 h (p < 0.0001). These two lead formulations were then tested in immune competent BALB/c mice bearing orthotopic 4T1 breast cancer tumors. NanoICGPBA showed 2.2-fold greater contrast than ICG alone (p < 0.0001), and NanoCy7.5100-H showed 14.8-fold greater contrast than Cy7.5 alone (p < 0.0001). Furthermore, both NanoICGPBA and NanoCy7.5100-H provided strong tumor enhancement using image-guided surgery in mice bearing 4T1 tumors. These studies demonstrate the efficacy of a panel of HA-derived NPs in delineating tumors in vivo , and identifies promising formulations that can be used for future in vivo tumor removal efficacy studies., Competing Interests: The authors have declared that no competing interest exists.- Published
- 2016
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25. Tumor-associated stromal cells as key contributors to the tumor microenvironment.
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Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, and Marini FC
- Subjects
- Adipocytes pathology, Biomarkers, Breast Neoplasms etiology, Breast Neoplasms therapy, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Drug Resistance, Neoplasm, Endothelial Cells metabolism, Endothelial Cells pathology, Exosomes metabolism, Female, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs genetics, Phenotype, Signal Transduction, Breast Neoplasms metabolism, Breast Neoplasms pathology, Stromal Cells metabolism, Stromal Cells pathology, Tumor Microenvironment genetics, Tumor Microenvironment immunology
- Abstract
The tumor microenvironment is a heterogeneous population of cells consisting of the tumor bulk plus supporting cells. It is becoming increasingly evident that these supporting cells are recruited by cancer cells from nearby endogenous host stroma and promote events such as tumor angiogenesis, proliferation, invasion, and metastasis, as well as mediate mechanisms of therapeutic resistance. In addition, recruited stromal cells range in type and include vascular endothelial cells, pericytes, adipocytes, fibroblasts, and bone-marrow mesenchymal stromal cells. During normal wound healing and inflammatory processes, local stromal cells change their phenotype to become that of reactive stroma. Under certain conditions, however, tumor cells can co-opt these reactive stromal cells and further transition them into tumor-associated stromal cells (TASCs). These TASCs express higher levels of proteins, including alpha-smooth muscle actin, fibroblast activating protein, and matrix metalloproteinases, compared with their normal, non-reactive counterparts. TASCs are also known to secrete many pro-tumorigenic factors, including IL-6, IL-8, stromal-derived factor-1 alpha, vascular endothelial growth factor, tenascin-C, and matrix metalloproteinases, among others, which recruit additional tumor and pro-tumorigenic cells to the developing microenvironment. Here, we review the current literature pertaining to the origins of recruited host stroma, contributions toward tumor progression, tumor-associated stromal cells, and mechanisms of crosstalk between endogenous host stroma and tumor cells.
- Published
- 2016
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26. Near infrared fluorescent nanoparticles based on hyaluronic acid: Self-assembly, optical properties, and cell interaction.
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Kelkar SS, Hill TK, Marini FC, and Mohs AM
- Subjects
- Cell Line, Tumor, Female, Humans, Male, Nanoparticles ultrastructure, Fluorescence, Hyaluronic Acid chemistry, Infrared Rays, Materials Testing, Nanoparticles chemistry
- Abstract
Unlabelled: Fluorescent imaging agents that can specifically highlight tumor cells could have a significant impact on image-guided tumor removal. Here, fluorescent nanoparticles (NPs) derived from hyaluronic acid (HA) are investigated. HA is a ligand for the receptor CD44, which is a common biomarker present on many primary tumor cells, cancer-initiating cells, and tumor-associated fibroblasts. In addition, a family of enzymes that degrade HA, called hyaluronidases (HYALs), are also overexpressed with increased activity in many tumors. We report the design and development of a panel of targeted imaging agents using the near-infrared (NIR) dye, Cy7.5, that was directly conjugated to hydrophobically-modified HA. Two different molecular weights of HA, 10kDa and 100kDa, and three different degrees of hydrophobic moiety conjugation (0, 10, and 30mol%) were utilized to develop a panel of NPs with variable size that ranged from 50 to 400nm hydrodynamic diameter (HD) depending HA molecular weight, extent of fluorescence quenching (25-50%), kinetics of cellular uptake, and targeting to CD44+ cells. The kinetics and energy-dependence of cellular uptake in breast and prostate cancer cell lines, MDA-MB 231 and PC-3 cells, respectively, showed increased uptake with longer incubation times (at 4 and 8h compared to 1h), as well as uptake at 37°C but not 4°C, which indicated energy-dependent endocytosis. NP uptake studies in the presence of excess free HA showed that pre-treatment of cells with excess high molecular weight (MW) free HA decreased NP uptake by up to 50%, while no such trend was observed with low MW HA. These data lay the foundation for selection of optimized HA-derived NPs for image-guided surgery., Statement of Significance: Here, hyaluronic acid (HA), a well-studied biomacromolecule, is modified with a near infrared fluorophore and a hydrophobic moiety. The significance of this work, especially for imaging applications, is that the impact of HA molecular weight and the hydrophobic moiety conjugation degree on fluorescence and cell interaction can be predicted. With respect to existing literature, the eventual use of these HA-based NPs is image-guided surgery; thus, we focus on the dye, Cy7.5, for conjugation, which is more NIR than most existing HA literature. Furthermore, HA is a ligand for CD44, which is associated with cancer and tumor microenvironment cells. Systematic studies in this work highlight that HA can be tuned to maximize or minimize CD44 binding., (Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2016
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27. Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas.
- Author
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Cortes-Santiago N, Hossain MB, Gabrusiewicz K, Fan X, Gumin J, Marini FC, Alonso MM, Lang F, Yung WK, Fueyo J, and Gomez-Manzano C
- Subjects
- Angiogenesis Inhibitors adverse effects, Angiopoietin-2 metabolism, Animals, Brain Neoplasms metabolism, Cell Line, Tumor, Chemotaxis, Leukocyte, Glioma metabolism, Humans, Mice, Mice, Nude, Monocytes metabolism, Monocytes pathology, Neoplasm Recurrence, Local metabolism, Tumor Microenvironment, Brain Neoplasms pathology, Glioma pathology, Neoplasm Recurrence, Local pathology, Receptor, TIE-2 metabolism
- Abstract
Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.
- Published
- 2016
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28. Mesenchymal Stem Cells Isolated From Human Gliomas Increase Proliferation and Maintain Stemness of Glioma Stem Cells Through the IL-6/gp130/STAT3 Pathway.
- Author
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Hossain A, Gumin J, Gao F, Figueroa J, Shinojima N, Takezaki T, Priebe W, Villarreal D, Kang SG, Joyce C, Sulman E, Wang Q, Marini FC, Andreeff M, Colman H, and Lang FF
- Subjects
- Female, Glioma pathology, Humans, Male, Mesenchymal Stem Cells pathology, Cell Proliferation, Cytokine Receptor gp130 metabolism, Glioma metabolism, Interleukin-6 metabolism, Mesenchymal Stem Cells metabolism, STAT3 Transcription Factor metabolism, Signal Transduction
- Abstract
Although mesenchymal stem cells (MSCs) have been implicated as stromal components of several cancers, their ultimate contribution to tumorigenesis and their potential to drive cancer stem cells, particularly in the unique microenvironment of human brain tumors, remain largely undefined. Consequently, using established criteria, we isolated glioma-associated-human MSCs (GA-hMSCs) from fresh human glioma surgical specimens for the first time. We show that these GA-hMSCs are nontumorigenic stromal cells that are phenotypically similar to prototypical bone marrow-MSCs. Low-passage genomic sequencing analyses comparing GA-hMSCs with matched tumor-initiating glioma stem cells (GSCs) suggest that most GA-hMSCs (60%) are normal cells recruited to the tumor (group 1 GA-hMSCs), although, rarely (10%), GA-hMSCs may differentiate directly from GSCs (group 2 GA-hMSCs) or display genetic patterns intermediate between these groups (group 3 GA-hMSCs). Importantly, GA-hMSCs increase proliferation and self-renewal of GSCs in vitro and enhance GSC tumorigenicity and mesenchymal features in vivo, confirming their functional significance within the GSC niche. These effects are mediated by GA-hMSC-secreted interleukin-6, which activates STAT3 in GSCs. Our results establish GA-hMSCs as a potentially new stromal component of gliomas that drives the aggressiveness of GSCs, and point to GA-hMSCs as a novel therapeutic target within gliomas., (© 2015 AlphaMed Press.)
- Published
- 2015
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29. Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model.
- Author
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Gabrusiewicz K, Hossain MB, Cortes-Santiago N, Fan X, Kaminska B, Marini FC, Fueyo J, and Gomez-Manzano C
- Subjects
- Animals, Apoptosis physiology, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Line, Tumor, Glioma metabolism, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Monocytes metabolism, Monocytes pathology, fas Receptor metabolism, Glioma pathology, Macrophages pathology
- Abstract
Monocytes/macrophages are an influential component of the glioma microenvironment. However, understanding their diversity and plasticity constitute one of the most challenging areas of research due to the paucity of models to study these cells' inherent complexity. Herein, we analyzed the role of monocytes/macrophages in glioma growth by using a transgenic model that allows for conditional ablation of this cell population. We modeled glioma using intracranial GL261-bearing CSF-1R-GFP(+) macrophage Fas-induced apoptosis (MAFIA) transgenic mice. Conditional macrophage ablation was achieved by exposure to the dimerizer AP20187. Double immunofluorescence was used to characterize M1- and M2-like monocytes/macrophages during tumor growth and after conditional ablation. During glioma growth, the monocyte/macrophage population consisted predominantly of M2 macrophages. Conditional temporal depletion of macrophages reduced the number of GFP(+) cells, targeting mainly the repopulation of M2-polarized cells, and altered the appearance of M1-like monocytes/macrophages, which suggested a shift in the M1/M2 macrophage balance. Of interest, compared with control-treated mice, macrophage-depleted mice had a lower tumor mitotic index, microvascular density, and reduced tumor growth. These results demonstrated the possibility of studying in vivo the role and phenotype of macrophages in gliomas and suggested that transitory depletion of CSF-1R(+) population influences the reconstitutive phenotypic pool of these cells, ultimately suppressing tumor growth. The MAFIA model provides a much needed advance in defining the role of macrophages in gliomas., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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30. Indocyanine green-loaded nanoparticles for image-guided tumor surgery.
- Author
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Hill TK, Abdulahad A, Kelkar SS, Marini FC, Long TE, Provenzale JM, and Mohs AM
- Subjects
- Animals, Breast pathology, Breast surgery, Cell Line, Tumor, Female, Humans, Hyaluronic Acid chemistry, Mice, Mice, Nude, Breast Neoplasms diagnosis, Breast Neoplasms surgery, Fluorescent Dyes administration & dosage, Indocyanine Green administration & dosage, Nanoparticles chemistry, Optical Imaging methods, Surgery, Computer-Assisted methods
- Abstract
Detecting positive tumor margins and local malignant masses during surgery is critical for long-term patient survival. The use of image-guided surgery for tumor removal, particularly with near-infrared fluorescent imaging, is a potential method to facilitate removing all neoplastic tissue at the surgical site. In this study we demonstrate a series of hyaluronic acid (HLA)-derived nanoparticles that entrap the near-infrared dye indocyanine green, termed NanoICG, for improved delivery of the dye to tumors. Self-assembly of the nanoparticles was driven by conjugation of one of three hydrophobic moieties: aminopropyl-1-pyrenebutanamide (PBA), aminopropyl-5β-cholanamide (5βCA), or octadecylamine (ODA). Nanoparticle self-assembly, dye loading, and optical properties were characterized. NanoICG exhibited quenched fluorescence that could be activated by disassembly in a mixed solvent. NanoICG was found to be nontoxic at physiologically relevant concentrations and exposure was not found to inhibit cell growth. Using an MDA-MB-231 tumor xenograft model in mice, strong fluorescence enhancement in tumors was observed with NanoICG using a fluorescence image-guided surgery system and a whole-animal imaging system. Tumor contrast with NanoICG was significantly higher than with ICG alone.
- Published
- 2015
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31. Lineage of origin in rhabdomyosarcoma informs pharmacological response.
- Author
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Abraham J, Nuñez-Álvarez Y, Hettmer S, Carrió E, Chen HI, Nishijo K, Huang ET, Prajapati SI, Walker RL, Davis S, Rebeles J, Wiebush H, McCleish AT, Hampton ST, Bjornson CR, Brack AS, Wagers AJ, Rando TA, Capecchi MR, Marini FC, Ehler BR, Zarzabal LA, Goros MW, Michalek JE, Meltzer PS, Langenau DM, LeGallo RD, Mansoor A, Chen Y, Suelves M, Rubin BP, and Keller C
- Subjects
- Animals, Cell Line, Tumor, Cell Lineage, Disease Models, Animal, Epigenesis, Genetic drug effects, Forkhead Box Protein O1, Forkhead Transcription Factors metabolism, Gene Expression Regulation, Neoplastic drug effects, Humans, Mice, PAX3 Transcription Factor, Paired Box Transcription Factors metabolism, Tumor Suppressor Protein p53 metabolism, Antineoplastic Agents pharmacology, Benzamides pharmacology, Pyridines pharmacology, Rhabdomyosarcoma, Alveolar pathology
- Abstract
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1., (© 2014 Abraham et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2014
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32. Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes.
- Author
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Gabrusiewicz K, Liu D, Cortes-Santiago N, Hossain MB, Conrad CA, Aldape KD, Fuller GN, Marini FC, Alonso MM, Idoate MA, Gilbert MR, Fueyo J, and Gomez-Manzano C
- Subjects
- Angiogenesis Inhibitors therapeutic use, Animals, Antibodies, Monoclonal, Humanized therapeutic use, Bevacizumab, Brain Neoplasms drug therapy, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Fluorescent Antibody Technique, Glioma drug therapy, Humans, Immunohistochemistry, Matrix Metalloproteinase 9 biosynthesis, Mice, Mice, Nude, Microscopy, Confocal, Monocytes metabolism, Neoplasm Invasiveness pathology, Receptor, TIE-2 metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors, Xenograft Model Antitumor Assays, Brain Neoplasms pathology, Drug Resistance, Neoplasm physiology, Glioma pathology, Monocytes pathology, Neoplasm Recurrence, Local pathology
- Abstract
The addition of anti-angiogenic therapy to the few treatments available to patients with malignant gliomas was based on the fact that these tumors are highly vascularized and on encouraging results from preclinical and clinical studies. However, tumors that initially respond to this therapy invariably recur with the acquisition of a highly aggressive and invasive phenotype. Although several myeloid populations have been associated to this pattern of recurrence, a specific targetable population has not been yet identified. Here, we present evidence for the accumulation of Tie2-expressing monocytes/macrophages (TEMs) at the tumor/normal brain interface of mice treated with anti-VEGF therapies in regions with heightened tumoral invasion. Furthermore, we describe the presence of TEMs in malignant glioma surgical specimens that recurred after bevacizumab treatment. Our studies showed that TEMs enhanced the invasive properties of glioma cells and secreted high levels of gelatinase enzymatic proteins. Accordingly, Tie2⁺MMP9⁺ monocytic cells were consistently detected in the invasive tumor edge upon anti-VEGF therapies. Our results suggest the presence of a specific myeloid/monocytic subpopulation that plays a pivotal role in the mechanism of escape of malignant gliomas from anti-VEGF therapies and therefore constitutes a new cellular target for combination therapies in patients selected for anti-angiogenesis treatment.
- Published
- 2014
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33. Human omental-derived adipose stem cells increase ovarian cancer proliferation, migration, and chemoresistance.
- Author
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Nowicka A, Marini FC, Solley TN, Elizondo PB, Zhang Y, Sharp HJ, Broaddus R, Kolonin M, Mok SC, Thompson MS, Woodward WA, Lu K, Salimian B, Nagrath D, and Klopp AH
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Female, Humans, Mice, Neoplasm Metastasis, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms radiotherapy, Transcriptome, Adipose Tissue pathology, Cell Movement, Drug Resistance, Neoplasm, Neoplastic Stem Cells pathology, Omentum pathology, Ovarian Neoplasms pathology
- Abstract
Objectives: Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination., Materials and Methods: We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment., Results: O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries., Conclusions: ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.
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- 2013
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34. Quantitative multispectral analysis following fluorescent tissue transplant for visualization of cell origins, types, and interactions.
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Spaeth EL, Booth CM, and Marini FC
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- Animals, Bone Marrow Cells metabolism, Bone Marrow Cells physiology, Female, Fluorescent Antibody Technique methods, Fluorescent Dyes chemistry, Green Fluorescent Proteins analysis, Indoles chemistry, Luminescent Proteins analysis, Luminescent Proteins metabolism, Mice, Mice, Transgenic, Neoplasm Transplantation, Red Fluorescent Protein, Bone Marrow Cells cytology, Bone Marrow Transplantation methods, Flow Cytometry methods, Green Fluorescent Proteins biosynthesis, Green Fluorescent Proteins genetics, Microscopy, Fluorescence methods, Ovarian Neoplasms pathology
- Abstract
With the desire to understand the contributions of multiple cellular elements to the development of a complex tissue; such as the numerous cell types that participate in regenerating tissue, tumor formation, or vasculogenesis, we devised a multi-colored cellular transplant model of tumor development in which cell populations originate from different fluorescently colored reporter gene mice and are transplanted, engrafted or injected in and around a developing tumor. These colored cells are then recruited and incorporated into the tumor stroma. In order to quantitatively assess bone marrow derived tumor stromal cells, we transplanted GFP expressing transgenic whole bone marrow into lethally irradiated RFP expressing mice as approved by IACUC. 0ovarian tumors that were orthotopically injected into the transplanted mice were excised 6-8 weeks post engraftment and analyzed for bone marrow marker of origin (GFP) as well as antibody markers to detect tumor associated stroma using multispectral imaging techniques. We then adapted a methodology we call MIMicc- Multispectral Interrogation of Multiplexed cellular compositions, using multispectral unmixing of fluoroprobes to quantitatively assess which labeled cell came from which starting populations (based on original reporter gene labels), and as our ability to unmix 4, 5, 6 or more spectra per slide increases, we've added additional immunohistochemistry associated with cell lineages or differentiation to increase precision. Utilizing software to detect co-localized multiplexed-fluorescent signals, tumor stromal populations can be traced, enumerated and characterized based on marker staining.
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- 2013
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35. Mesenchymal CD44 expression contributes to the acquisition of an activated fibroblast phenotype via TWIST activation in the tumor microenvironment.
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Spaeth EL, Labaff AM, Toole BP, Klopp A, Andreeff M, and Marini FC
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- Animals, Apoptosis, Blotting, Western, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Cell Differentiation, Cell Movement, Cell Proliferation, Chromatin Immunoprecipitation, Culture Media, Conditioned pharmacology, Female, Fibroblasts metabolism, Humans, Immunoenzyme Techniques, Mammary Neoplasms, Animal genetics, Mammary Neoplasms, Animal metabolism, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Ovarian Neoplasms genetics, Ovarian Neoplasms metabolism, Phenotype, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Twist-Related Protein 1 genetics, Fibroblasts pathology, Hyaluronan Receptors physiology, Mammary Neoplasms, Animal pathology, Mesenchymal Stem Cells pathology, Ovarian Neoplasms pathology, Tumor Microenvironment, Twist-Related Protein 1 metabolism
- Abstract
Tumor-stroma interactions play a crucial role in cancer progression by eliciting factors that promote proliferative, angiogenic, and invasive supports to the tumor microenvironment. Mesenchymal stromal/stem cells (MSC) contribute to stroma in part as cancer-associated fibroblasts (CAF), but a complete understanding of how MSC contribute to the tumor stroma is lacking. In this study, we show how CAF phenotypes rely upon MSC expression of the multifunctional cell surface glycoprotein CD44, a putative stem cell marker. Through bone marrow transplantation experiments in a transgenic mouse model of cancer, we determined that CD44 deficiency leads to a relative reduction in the contribution of bone marrow-derived cells to tumor stroma. CD44 attenuation in MSC limited their expression of CAF markers induced by tumor conditioning, and these MSC migrated poorly and provided weak angiogenic support compared with wild-type MSC. These defects were linked to deficiencies in the ability of CD44-attenuated MSC to transcriptionally upregulate Twist expression. Together, our results establish that CD44 expression contributes to critical functions in the tumor stroma.
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- 2013
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36. Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies.
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Orlando G, Booth C, Wang Z, Totonelli G, Ross CL, Moran E, Salvatori M, Maghsoudlou P, Turmaine M, Delario G, Al-Shraideh Y, Farooq U, Farney AC, Rogers J, Iskandar SS, Burns A, Marini FC, De Coppi P, Stratta RJ, and Soker S
- Subjects
- Animals, Antigens metabolism, Biomarkers metabolism, Chickens, Extracellular Matrix ultrastructure, Humans, Immunohistochemistry, Kidney blood supply, Kidney cytology, Kidney ultrastructure, Kidney Transplantation, Neovascularization, Physiologic, Pressure, Extracellular Matrix metabolism, Kidney physiology, Regeneration physiology, Regenerative Medicine methods, Tissue Scaffolds chemistry
- Abstract
In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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37. TGF-β mediates homing of bone marrow-derived human mesenchymal stem cells to glioma stem cells.
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Shinojima N, Hossain A, Takezaki T, Fueyo J, Gumin J, Gao F, Nwajei F, Marini FC, Andreeff M, Kuratsu J, and Lang FF
- Subjects
- Adenoviridae genetics, Animals, Apoptosis, Blotting, Western, Bone Marrow metabolism, Brain Neoplasms metabolism, Brain Neoplasms pathology, Cell Proliferation, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Glioma metabolism, Humans, Mesenchymal Stem Cells metabolism, Neoplastic Stem Cells metabolism, Rats, Receptors, Transforming Growth Factor beta genetics, Receptors, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta genetics, Xenograft Model Antitumor Assays, Bone Marrow pathology, Cell Differentiation, Glioma pathology, Mesenchymal Stem Cells cytology, Neoplastic Stem Cells pathology, Transforming Growth Factor beta metabolism
- Abstract
Although studies have suggested that bone marrow human mesenchymal stem cells (BM-hMSC) may be used as delivery vehicles for cancer therapy, it remains unclear whether BM-hMSCs are capable of targeting cancer stem cells, including glioma stem cells (GSC), which are the tumor-initiating cells responsible for treatment failures. Using standard glioma models, we identify TGF-β as a tumor factor that attracts BM-hMSCs via TGF-β receptors (TGFβR) on BM-hMSCs. Using human and rat GSCs, we then show for the first time that intravascularly administered BM-hMSCs home to GSC-xenografts that express TGF-β. In therapeutic studies, we show that BM-hMSCs carrying the oncolytic adenovirus Delta-24-RGD prolonged the survival of TGF-β-secreting GSC xenografts and that the efficacy of this strategy can be abrogated by inhibition of TGFβR on BM-hMSCs. These findings reveal the TGF-β/TGFβR axis as a mediator of the tropism of BM-hMSCs for GSCs and suggest that TGF-β predicts patients in whom BM-hMSC delivery will be effective., (©2012 AACR.)
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- 2013
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38. Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.
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Dembinski JL, Wilson SM, Spaeth EL, Studeny M, Zompetta C, Samudio I, Roby K, Andreeff M, and Marini FC
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Female, Genetic Therapy methods, Humans, Immunohistochemistry, Interferon-beta therapeutic use, Male, Mice, Mice, Inbred C57BL, Xenograft Model Antitumor Assays, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells drug effects, Ovarian Neoplasms therapy
- Abstract
Background Aims: Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment., Methods: Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, preferentially engraft and differentiate into α-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stroma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-β (IFN-β). Mice with ovarian carcinomas then received weekly intraperitoneal injections of IFN-β expressing MSCs., Results: Intraperitoneal injections of IFN-β expressing MSCs resulted in complete eradication of tumors in 70% of treated OVCAR3 mice (P = 0.004) and an increased survival of treated SKOV3 mice compared with controls (P = 0.01). Similar tumor growth control was observed using murine IFN-β delivered by murine MSCs in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSCs produced IFN-β-induced caspase-dependent tumor cell apoptosis., Conclusions: Our results demonstrate that ovarian carcinoma engrafts MSCs to participate in myofibrovascular networks and that IFN-β produced by MSCs intratumorally modulates tumor kinetics, resulting in prolonged survival., (Published by Elsevier Inc.)
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- 2013
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39. Thymidine kinase suicide gene-mediated ganciclovir ablation of autologous gene-modified rhesus hematopoiesis.
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Barese CN, Krouse AE, Metzger ME, King CA, Traversari C, Marini FC, Donahue RE, and Dunbar CE
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- Animals, Antiviral Agents therapeutic use, DNA Replication, Genetic Therapy methods, Hematopoietic Stem Cells cytology, Macaca mulatta, Retroviridae genetics, Transduction, Genetic, Ganciclovir therapeutic use, Genes, Transgenic, Suicide, Genetic Vectors, Hematopoiesis genetics, Thymidine Kinase genetics
- Abstract
Despite the genotoxic complications encountered in clinical gene therapy trials for primary immunodeficiency diseases targeting hematopoietic cells with integrating vectors; this strategy holds promise for the cure of several monogenic blood, metabolic and neurodegenerative diseases. In this study, we asked whether the inclusion of a suicide gene in a standard retrovirus vector would allow elimination of vector-containing stem and progenitor cells and their progeny in vivo following transplantation, using our rhesus macaque transplantation model. Following stable engraftment with autologous CD34(+) cells transduced with a retrovirus vector encoding a highly sensitive modified Herpes simplex virus thymidine kinase SR39, the administration of the antiviral prodrug ganciclovir (GCV) was effective in completely eliminating vector-containing cells in all hematopoietic lineages in vivo. The sustained absence of vector-containing cells over time, without additional GCV administration, suggests that the ablation of TkSR39 GCV-sensitive cells occurred in the most primitive hematopoietic long-term repopulating stem or progenitor cell compartment. These results are a proof-of-concept that the inclusion of a suicide gene in integrating vectors, in addition to a therapeutic gene, can provide a mechanism for later elimination of vector-containing cells, thereby increasing the safety of gene transfer.
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- 2012
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40. Ganglioside GD2 identifies breast cancer stem cells and promotes tumorigenesis.
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Battula VL, Shi Y, Evans KW, Wang RY, Spaeth EL, Jacamo RO, Guerra R, Sahin AA, Marini FC, Hortobagyi G, Mani SA, and Andreeff M
- Subjects
- Animals, Biomarkers, Tumor genetics, Breast Neoplasms genetics, Breast Neoplasms pathology, CD24 Antigen genetics, CD24 Antigen metabolism, Cell Line, Transformed, Cell Line, Tumor, Epithelial-Mesenchymal Transition genetics, Female, Gangliosides genetics, Gene Expression Regulation, Enzymologic genetics, Gene Expression Regulation, Neoplastic genetics, Gene Knockdown Techniques, Humans, Hyaluronan Receptors genetics, Hyaluronan Receptors metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Neoplasm Transplantation, Neoplastic Stem Cells pathology, Neoplastic Stem Cells transplantation, Sialyltransferases biosynthesis, Sialyltransferases genetics, Transplantation, Heterologous, Biomarkers, Tumor biosynthesis, Breast Neoplasms metabolism, Gangliosides biosynthesis, Neoplastic Stem Cells metabolism
- Abstract
Cancer stem cells (CSCs) are a small subpopulation of cancer cells that have increased resistance to conventional therapies and are capable of establishing metastasis. However, only a few biomarkers of CSCs have been identified. Here, we report that ganglioside GD2 (a glycosphingolipid) identifies a small fraction of cells in human breast cancer cell lines and patient samples that are capable of forming mammospheres and initiating tumors with as few as 10 GD2+ cells. In addition, the majority of GD2+ cells are also CD44hiCD24lo, the previously established CSC-associated cell surface phenotype. Gene expression analysis revealed that GD3 synthase (GD3S) is highly expressed in GD2+ as well as in CD44hiCD24lo cells and that interference with GD3S expression, either by shRNA or using a pharmacological inhibitor, reduced the CSC population and CSC-associated properties. GD3S knockdown completely abrogated tumor formation in vivo. Also, induction of epithelial-mesenchymal transition (EMT) in transformed human mammary epithelial cells (HMLER cells) dramatically increased GD2 as well as GD3S expression in these cells, suggesting a role of EMT in the origin of GD2+ breast CSCs. In summary, we identified GD2 as a new CSC-specific cell surface marker and GD3S as a potential therapeutic target for CSCs, with the possibility of improving survival and cure rates in patients with breast cancer.
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- 2012
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41. Human amniotic fluid-derived mesenchymal stem cells as therapeutic vehicles: a novel approach for the treatment of bladder cancer.
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Bitsika V, Roubelakis MG, Zagoura D, Trohatou O, Makridakis M, Pappa KI, Marini FC, Vlahou A, and Anagnou NP
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- Animals, Cell Line, Tumor, Cell Movement, Cell Proliferation drug effects, Coculture Techniques, Culture Media, Conditioned pharmacology, Drug Delivery Systems, Green Fluorescent Proteins biosynthesis, Humans, Interferon-beta biosynthesis, Interferon-beta blood, Interferon-beta pharmacology, Interleukin-8 physiology, Kaplan-Meier Estimate, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Proteome metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins blood, Recombinant Proteins pharmacology, Tumor Burden, Urinary Bladder Neoplasms pathology, Vascular Endothelial Growth Factor A physiology, Amniotic Fluid cytology, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells physiology, Urinary Bladder Neoplasms therapy
- Abstract
Recent studies support cell-based therapies for cancer treatment. An advantageous cell type for such therapeutic schemes are the mesenchymal stem cells (MSCs) that can be easily propagated in culture, genetically modified to express therapeutic proteins, and exhibit an innate tropism to solid tumors in vivo. Recently, we successfully isolated and expanded MSCs from second-trimester amniotic fluid (AF-MSCs). The main characteristic of AF-MSCs is their efficient and rapid expansion in vitro. Herein, we investigated the AF-MSCs tropism and capability to transport interferon beta (IFNβ) to the region of neoplasia in a bladder tumor model. To this end, we used the T24M bladder cancer cell line, previously generated from our studies, and developed a disease progression model in immunosuppressed mice, that can recapitulate the molecular events of bladder carcinogenesis. Our results documented that AF-MSCs exhibited high motility, when migrated either to T24M cells or to T24M-conditioned medium, and we further identified and studied the secreted factors which may trigger these enhanced migratory properties. Further, lentivirus-transduced AF-MSCs, expressing green fluorescent protein (GFP) or IFNβ, were intravenously administered to T24M tumor-bearing animals at multiple doses to examine their therapeutic effect. GFP- and IFNβ-AF-MSCs successfully migrated and colonized at the tumor site. Notably, significant inhibition of tumor growth as well as prolonged survival of mice were observed in the presence of IFNβ-AF-MSCs. Collectively, these results document the great potential of AF-MSCs as anti-cancer vehicles, implemented by the targeting of the tumor site and further facilitated by their high proliferation rate and expansion efficiency in culture.
- Published
- 2012
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42. Tracking inflammation-induced mobilization of mesenchymal stem cells.
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Spaeth EL, Kidd S, and Marini FC
- Subjects
- Adipocytes cytology, Animals, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Cell Differentiation, Cell Line, Cell Separation methods, Chondrocytes cytology, Humans, Mesenchymal Stem Cell Transplantation methods, Mice, Osteocytes cytology, Tumor Microenvironment, Cell Movement physiology, Cell Tracking methods, Inflammation metabolism, Mesenchymal Stem Cells cytology, Mesenchymal Stem Cells metabolism
- Abstract
The act of migration is similar for many cell types. The migratory mechanism of mesenchymal stem cells (MSC) is not completely elucidated, yet many of the initial studies have been based on current understanding of the leukocyte migration. A normal function of MSC is the ability of the cell to migrate to and repair wounded tissue. This wound healing property of MSC originates with migration towards inflammatory signals produced by the wounded environment [1]. A tumor and its microenvironment are capable of eliciting a similar inflammatory response from the MSC, thus resulting in migration of the MSC towards the tumor microenvironment. We have shown MSC migration both in vitro and in vivo. In this chapter, we elucidate several in vivo methods to study MSC migration and mobilization to the tumor microenvironment. The first model is an exogenous model of MSC migration that can be performed in both xenograft and syngenic systems with in vitro expanded MSC. The second model utilizes transgenic-fluorescent--colored mice to follow endogenous bone marrow components including MSC. The third technique enables us to analyze data from the transgenic model through multispectral imaging. Furthermore, the migratory phenotype of MSC can be exploited for use in tumor-targeted gene delivery therapy has been efficacious in animal model studies and is an anticipated therapeutic device in clinical trials.
- Published
- 2012
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43. Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma.
- Author
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Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, Andreeff M, and Marini FC
- Subjects
- Animals, Biomarkers metabolism, Bone Marrow Cells metabolism, Cell Line, Tumor, Female, Green Fluorescent Proteins metabolism, Mice, Mice, Inbred C57BL, Models, Biological, Adipose Tissue pathology, Bone Marrow Cells pathology, Mesenchymal Stem Cells pathology, Tumor Microenvironment
- Abstract
To meet the requirements for rapid tumor growth, a complex array of non-neoplastic cells are recruited to the tumor microenvironment. These cells facilitate tumor development by providing matrices, cytokines, growth factors, as well as vascular networks for nutrient and waste exchange, however their precise origins remain unclear. Through multicolored tissue transplant procedures; we have quantitatively determined the contribution of bone marrow-derived and adipose-derived cells to stromal populations within syngeneic ovarian and breast murine tumors. Our results indicate that subpopulations of tumor-associated fibroblasts (TAFs) are recruited from two distinct sources. The majority of fibroblast specific protein (FSP) positive and fibroblast activation protein (FAP) positive TAFs originate from mesenchymal stem/stromal cells (MSC) located in bone marrow sources, whereas most vascular and fibrovascular stroma (pericytes, α-SMA(+) myofibroblasts, and endothelial cells) originates from neighboring adipose tissue. These results highlight the capacity for tumors to utilize multiple sources of structural cells in a systematic and discriminative manner.
- Published
- 2012
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44. Targeting neuropilin-1 in human leukemia and lymphoma.
- Author
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Karjalainen K, Jaalouk DE, Bueso-Ramos CE, Zurita AJ, Kuniyasu A, Eckhardt BL, Marini FC, Lichtiger B, O'Brien S, Kantarjian HM, Cortes JE, Koivunen E, Arap W, and Pasqualini R
- Subjects
- Acute Disease, Amino Acid Sequence, Apoptosis drug effects, Binding Sites genetics, Bone Marrow Cells metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Humans, Immunohistochemistry, K562 Cells, Leukemia genetics, Leukemia pathology, Leukemia, Myeloid genetics, Leukemia, Myeloid metabolism, Leukemia, Myeloid pathology, Lymphoma genetics, Lymphoma pathology, Molecular Sequence Data, Neuropilin-1 genetics, Oligopeptides genetics, Oligopeptides metabolism, Peptide Library, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology, Protein Binding, RNA Interference, U937 Cells, Leukemia metabolism, Lymphoma metabolism, Neuropilin-1 metabolism, Oligopeptides pharmacology
- Abstract
Targeted drug delivery offers an opportunity for the development of safer and more effective therapies for the treatment of cancer. In this study, we sought to identify short, cell-internalizing peptide ligands that could serve as directive agents for specific drug delivery in hematologic malignancies. By screening of human leukemia cells with a combinatorial phage display peptide library, we isolated a peptide motif, sequence Phe-Phe/Tyr-Any-Leu-Arg-Ser (F(F)/(Y)XLRS), which bound to different leukemia cell lines and to patient-derived bone marrow samples. The motif was internalized through a receptor-mediated pathway, and we next identified the corresponding receptor as the transmembrane glycoprotein neuropilin-1 (NRP-1). Moreover, we observed a potent anti-leukemia cell effect when the targeting motif was synthesized in tandem to the pro-apoptotic sequence (D)(KLAKLAK)₂. Finally, our results confirmed increased expression of NRP-1 in representative human leukemia and lymphoma cell lines and in a panel of bone marrow specimens obtained from patients with acute lymphoblastic leukemia or acute myelogenous leukemia compared with normal bone marrow. These results indicate that NRP-1 could potentially be used as a target for ligand-directed therapy in human leukemias and lymphomas and that the prototype CGFYWLRSC-GG-(D)(KLAKLAK)₂ is a promising drug candidate in this setting.
- Published
- 2011
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45. Imaging long-term fate of intramyocardially implanted mesenchymal stem cells in a porcine myocardial infarction model.
- Author
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Perin EC, Tian M, Marini FC 3rd, Silva GV, Zheng Y, Baimbridge F, Quan X, Fernandes MR, Gahremanpour A, Young D, Paolillo V, Mukhopadhyay U, Borne AT, Uthamanthil R, Brammer D, Jackson J, Decker WK, Najjar AM, Thomas MW, Volgin A, Rabinovich B, Soghomonyan S, Jeong HJ, Rios JM, Steiner D, Robinson S, Mawlawi O, Pan T, Stafford J, Kundra V, Li C, Alauddin MM, Willerson JT, Shpall E, and Gelovani JG
- Subjects
- Animals, Arabinofuranosyluracil analogs & derivatives, Cell Line, Cell Separation, Cell Survival, Disease Models, Animal, Echocardiography, Endothelial Cells diagnostic imaging, Endothelial Cells pathology, Feasibility Studies, Genes, Reporter genetics, Herpesvirus 1, Human enzymology, Lymph Nodes pathology, Lymphatic Vessels pathology, Lymphography, Magnetic Resonance Imaging, Mesenchymal Stem Cells diagnostic imaging, Mesenchymal Stem Cells metabolism, Mice, Myocardial Infarction diagnosis, Myocardial Infarction surgery, Myocardium metabolism, Swine, Thymidine Kinase genetics, Time Factors, Cell Differentiation, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells cytology, Myocardial Infarction pathology, Myocardium pathology, Positron-Emission Tomography, Tomography, X-Ray Computed
- Abstract
The long-term fate of stem cells after intramyocardial delivery is unknown. We used noninvasive, repetitive PET/CT imaging with [(18)F]FEAU to monitor the long-term (up to 5 months) spatial-temporal dynamics of MSCs retrovirally transduced with the sr39HSV1-tk gene (sr39HSV1-tk-MSC) and implanted intramyocardially in pigs with induced acute myocardial infarction. Repetitive [(18)F]FEAU PET/CT revealed a biphasic pattern of sr39HSV1-tk-MSC dynamics; cell proliferation peaked at 33-35 days after injection, in periinfarct regions and the major cardiac lymphatic vessels and lymph nodes. The sr39HSV1-tk-MSC-associated [(18)F]FEAU signals gradually decreased thereafter. Cardiac lymphography studies using PG-Gd-NIRF813 contrast for MRI and near-infrared fluorescence imaging showed rapid clearance of the contrast from the site of intramyocardial injection through the subepicardial lymphatic network into the lymphatic vessels and periaortic lymph nodes. Immunohistochemical analysis of cardiac tissue obtained at 35 and 150 days demonstrated several types of sr39HSV1-tk expressing cells, including fibro-myoblasts, lymphovascular cells, and microvascular and arterial endothelium. In summary, this study demonstrated the feasibility and sensitivity of [(18)F]FEAU PET/CT imaging for long-term, in-vivo monitoring (up to 5 months) of the fate of intramyocardially injected sr39HSV1-tk-MSC cells. Intramyocardially transplanted MSCs appear to integrate into the lymphatic endothelium and may help improve myocardial lymphatic system function after MI.
- Published
- 2011
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46. Dissecting mesenchymal stem cell movement: migration assays for tracing and deducing cell migration.
- Author
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Spaeth EL and Marini FC
- Subjects
- Adipocytes physiology, Animals, Cell Line, Tumor, Cell Separation, Gene Transfer Techniques, Humans, Immunohistochemistry, Luminescent Measurements, Luminescent Proteins analysis, Mesenchymal Stem Cells physiology, Mice, Neoplasms pathology, Osteoblasts physiology, Adipocytes cytology, Cell Differentiation physiology, Cell Migration Assays, Cell Movement, Mesenchymal Stem Cells cytology, Osteoblasts cytology
- Abstract
Targeted migration is a necessary attribute for any gene delivery vehicle. Mesenchymal stem cells (MSC) have been used as effective delivery vehicles for treatments against cancer, graft versus host disease, -arthritis, multiple sclerosis, and many other diseases. MSC migrate toward sites of inflammation, however, the true migratory mechanism has yet to be elucidated. There are several receptors and respective chemokines known to be involved in the migration of the MSC. Further insight to MSC migration will be revealed both in vivo and in vitro through the application of migration assays from the most simple, to the more technologically demanding.
- Published
- 2011
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47. Mesenchymal stromal cells alone or expressing interferon-beta suppress pancreatic tumors in vivo, an effect countered by anti-inflammatory treatment.
- Author
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Kidd S, Caldwell L, Dietrich M, Samudio I, Spaeth EL, Watson K, Shi Y, Abbruzzese J, Konopleva M, Andreeff M, and Marini FC
- Subjects
- Animals, Antineoplastic Agents immunology, Antineoplastic Agents therapeutic use, Cell Growth Processes immunology, Cell Line, Tumor, Genetic Therapy, Growth Inhibitors immunology, Growth Inhibitors therapeutic use, Humans, Immunosuppression Therapy, Inflammation, Interferon-beta genetics, Interferon-beta immunology, Mesenchymal Stem Cells immunology, Mesenchymal Stem Cells pathology, Mice, Mice, SCID, Neoplasm Transplantation, Pancreatic Neoplasms immunology, Pancreatic Neoplasms pathology, Stromal Cells pathology, Stromal Cells transplantation, Transgenes genetics, Interferon-beta metabolism, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells metabolism, Pancreatic Neoplasms therapy, Stromal Cells metabolism
- Abstract
Background Aims: Because of the inflammatory nature and extensive stromal compartment in pancreatic tumors, we investigated the role of mesenchymal stromal cells (MSC) to engraft selectively in pancreatic carcinomas and serve as anti-tumor drug delivery vehicles to control pancreatic cancer progression., Methods: Human pancreatic carcinoma cells, PANC-1, expressing renilla luciferase were orthotopically implanted into SCID mice and allowed to develop for 10 days. Firefly luciferase-transduced MSC or MSC expressing interferon (IFN)-beta were then injected intraperitoneally weekly for 3 weeks. Mice were monitored by bioluminescent imaging for expression of renilla (PANC-1) and firefly (MSC) luciferase., Results: MSC selectively homed to sites of primary and metastatic pancreatic tumors and inhibited tumor growth (P=0.032). The production of IFN-beta within the tumor site by MSC-IFN-beta further suppressed tumor growth (P=0.0000083). Prior studies indicated that MSC home to sites of inflammation; therefore, we sought to alter the tumor microenvironment through treatment with a potent anti-inflammatory agent. After treatment, inflammation-associated mediators were effectively down-regulated, including NFkappaB, vascular endothelial growth factor (VEGF) and interleukin (IL)-6 as well as chemokines involved in MSC migration (CCL3 and CCL25). Treatment with the anti-inflammatory agent CDDO-Me before and after MSC-IFN-beta injections resulted in reduction of MSC in the tumors and reversed the positive effect of tumor inhibition by MSC-IFN-beta alone (P=0.041)., Conclusions: These results suggest that MSC exhibit innate anti-tumor effects against PANC-1 cells and can serve as delivery vehicles for IFN-beta for the treatment of pancreatic cancer. However, these beneficial effects may be lost in therapies combining MSC with anti-inflammatory agents.
- Published
- 2010
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48. Epithelial-mesenchymal transition-derived cells exhibit multilineage differentiation potential similar to mesenchymal stem cells.
- Author
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Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang RY, Brisken C, Guerra R, Andreeff M, and Mani SA
- Subjects
- Adipocytes cytology, Cell Differentiation genetics, Cells, Cultured, Chondrogenesis genetics, Chondrogenesis physiology, Epithelial-Mesenchymal Transition genetics, Flow Cytometry, Humans, Mesenchymal Stem Cells metabolism, Osteoblasts cytology, Receptor, Platelet-Derived Growth Factor beta genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, Reverse Transcriptase Polymerase Chain Reaction, Cell Differentiation physiology, Epithelial-Mesenchymal Transition physiology, Mesenchymal Stem Cells cytology
- Abstract
The epithelial-to-mesenchymal transition (EMT) is an embryonic process that becomes latent in most normal adult tissues. Recently, we have shown that induction of EMT endows breast epithelial cells with stem cell traits. In this report, we have further characterized the EMT-derived cells and shown that these cells are similar to mesenchymal stem cells (MSCs) with the capacity to differentiate into multiple tissue lineages. For this purpose, we induced EMT by ectopic expression of Twist, Snail, or transforming growth factor-beta in immortalized human mammary epithelial cells. We found that the EMT-derived cells and MSCs share many properties including the antigenic profile typical of MSCs, that is, CD44(+), CD24(-), and CD45(-). Conversely, MSCs express EMT-associated genes, such as Twist, Snail, and mesenchyme forkhead 1 (FOXC2). Interestingly, CD140b (platelet-derived growth factor receptor-beta), a marker for naive MSCs, is exclusively expressed in EMT-derived cells and not in their epithelial counterparts. Moreover, functional analyses revealed that EMT-derived cells but not the control cells can differentiate into alizarin red S-positive mature osteoblasts, oil red O-positive adipocytes and alcian blue-positive chondrocytes similar to MSCs. We also observed that EMT-derived cells but not the control cells invade and migrate towards MDA-MB-231 breast cancer cells similar to MSCs. In vivo wound homing assays in nude mice revealed that the EMT-derived cells home to wound sites similar to MSCs. In conclusion, we have demonstrated that the EMT-derived cells are similar to MSCs in gene expression, multilineage differentiation, and ability to migrate towards tumor cells and wound sites.
- Published
- 2010
- Full Text
- View/download PDF
49. Reduction of nontarget infection and systemic toxicity by targeted delivery of conditionally replicating viruses transported in mesenchymal stem cells.
- Author
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Dembinski JL, Spaeth EL, Fueyo J, Gomez-Manzano C, Studeny M, Andreeff M, and Marini FC
- Subjects
- Animals, Breast Neoplasms genetics, Breast Neoplasms therapy, Breast Neoplasms virology, Cell Line, Tumor, Female, Humans, Immunoenzyme Techniques, Melanoma, Experimental genetics, Melanoma, Experimental therapy, Melanoma, Experimental virology, Mice, Ovarian Neoplasms genetics, Ovarian Neoplasms therapy, Ovarian Neoplasms virology, Survival Rate, Xenograft Model Antitumor Assays, Adenoviridae genetics, Genetic Vectors therapeutic use, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells virology, Oncolytic Virotherapy, Virus Replication
- Abstract
The fiber-modified adenoviral vector Delta-24-RGD (D24RGD) offers vast therapeutic potential. Direct injection of D24RGD has been used to successfully target ovarian tumors in mice. However, systemic toxicity, especially in the liver, profoundly limits the efficacy of direct viral vector delivery. Mesenchymal stem cells (MSC) have the ability to function as a vector for targeted gene therapy because of their preferential engraftment into solid tumors and participation in tumor stroma formation. We show that MSC-guided delivery of D24RGD is specific and efficient and reduces the overall systemic toxicity in mice to negligible levels compared with D24RGD alone. In our model, we found efficient targeted delivery of MSC-D24RGD to both breast and ovarian cell lines. Furthermore, immunohistochemical staining for adenoviral hexon protein confirmed negligible levels of systemic toxicity in mice that were administered MSC-D24RGD compared with those that were administered D24RGD. These data suggest that delivery of D24RGD through MSC not only increases the targeted delivery efficiency, but also reduces the systemic exposure of the virus, thereby reducing overall systemic toxicity to the host and ultimately enhancing its value as an anti-tumor therapeutic candidate.
- Published
- 2010
- Full Text
- View/download PDF
50. Human bone marrow-derived mesenchymal stem cells for intravascular delivery of oncolytic adenovirus Delta24-RGD to human gliomas.
- Author
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Yong RL, Shinojima N, Fueyo J, Gumin J, Vecil GG, Marini FC, Bogler O, Andreeff M, and Lang FF
- Subjects
- Adenoviridae genetics, Adenoviridae physiology, Adenovirus E1A Proteins genetics, Animals, Bone Marrow Cells pathology, Bone Marrow Cells virology, Brain Neoplasms virology, Glioblastoma virology, Humans, Injections, Intra-Arterial, Male, Mesenchymal Stem Cells pathology, Mice, Mice, Nude, Oligopeptides, Transduction, Genetic, Virus Replication, Xenograft Model Antitumor Assays, Brain Neoplasms therapy, Glioblastoma therapy, Mesenchymal Stem Cells virology, Oncolytic Virotherapy methods
- Abstract
Delta24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Delta24-RGD to human gliomas. To assess cellular events, green fluorescent protein-labeled hMSCs carrying Delta24-RGD (hMSC-Delta24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (E1A and hexon) at increasing times. hMSC-Delta24 selectively localized to glioma xenografts and released Delta24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase- labeled glioma xenografts, treated with hMSC-Delta24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Delta24-treated animals compared with controls (P < 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta24-treated animals (P < 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Delta24 selectively localize to human gliomas and are capable of delivering and releasing Delta24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice.
- Published
- 2009
- Full Text
- View/download PDF
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