33 results on '"Bennewith, Kevin L."'
Search Results
2. Relating Macroscopic PET Radiomics Features to Microscopic Tumor Phenotypes Using a Stochastic Mathematical Model of Cellular Metabolism and Proliferation.
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Ahn, Hailey S. H., Oloumi Yazdi, Yas, Wadsworth, Brennan J., Bennewith, Kevin L., Rahmim, Arman, and Klyuzhin, Ivan S.
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TUMOR diagnosis ,RESEARCH funding ,RADIOMICS ,CELL proliferation ,POSITRON emission tomography ,XENOGRAFTS ,DESCRIPTIVE statistics ,MATHEMATICAL models ,TUMORS ,THEORY ,PHENOTYPES - Abstract
Simple Summary: Radiomics analysis of positron emission tomography (PET) images can provide objective measurements of tumor heterogeneity and spatial patterns. However, the relatively low resolution, high noise, and limited longitudinal data availability make it difficult to systematically investigate the relationship between the microscopic tumor phenotypes and corresponding PET radiomics signatures. To address this challenge, we use a multiscale, stochastic mathematical model of tumor growth to generate cross-sections of tumors in vascularized normal tissue on a microscopic level. By varying the biological parameters of the model, distinct tumor phenotypes are obtained, and their corresponding PET images are generated. The simulated data are then used to find the optimal combination of PET radiomics features that can reliably distinguish visually similar tumor phenotypes. In addition, we study the longitudinal changes in the discriminative power of radiomics features with tumor growth from a single cell to approximately one million cells. Cancers can manifest large variations in tumor phenotypes due to genetic and microenvironmental factors, which has motivated the development of quantitative radiomics-based image analysis with the aim to robustly classify tumor phenotypes in vivo. Positron emission tomography (PET) imaging can be particularly helpful in elucidating the metabolic profiles of tumors. However, the relatively low resolution, high noise, and limited PET data availability make it difficult to study the relationship between the microenvironment properties and metabolic tumor phenotype as seen on the images. Most of previously proposed digital PET phantoms of tumors are static, have an over-simplified morphology, and lack the link to cellular biology that ultimately governs the tumor evolution. In this work, we propose a novel method to investigate the relationship between microscopic tumor parameters and PET image characteristics based on the computational simulation of tumor growth. We use a hybrid, multiscale, stochastic mathematical model of cellular metabolism and proliferation to generate simulated cross-sections of tumors in vascularized normal tissue on a microscopic level. The generated longitudinal tumor growth sequences are converted to PET images with realistic resolution and noise. By changing the biological parameters of the model, such as the blood vessel density and conditions for necrosis, distinct tumor phenotypes can be obtained. The simulated cellular maps were compared to real histology slides of SiHa and WiDr xenografts imaged with Hoechst 33342 and pimonidazole. As an example application of the proposed method, we simulated six tumor phenotypes that contain various amounts of hypoxic and necrotic regions induced by a lack of oxygen and glucose, including phenotypes that are distinct on the microscopic level but visually similar in PET images. We computed 22 standardized Haralick texture features for each phenotype, and identified the features that could best discriminate the phenotypes with varying image noise levels. We demonstrated that "cluster shade" and "difference entropy" are the most effective and noise-resilient features for microscopic phenotype discrimination. Longitudinal analysis of the simulated tumor growth showed that radiomics analysis can be beneficial even in small lesions with a diameter of 3.5–4 resolution units, corresponding to 8.7–10.0 mm in modern PET scanners. Certain radiomics features were shown to change non-monotonically with tumor growth, which has implications for feature selection for tracking disease progression and therapy response. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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3. Loss of Parkinson’s susceptibility gene LRRK2 promotes carcinogen-induced lung tumorigenesis
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Lebovitz, Chandra, Wretham, Nicole, Osooly, Maryam, Milne, Katy, Dash, Tia, Thornton, Shelby, Tessier-Cloutier, Basile, Sathiyaseelan, Paalini, Bortnik, Svetlana, Go, Nancy Erro, Halvorsen, Elizabeth, Cederberg, Rachel A., Chow, Norman, Dos Santos, Nancy, Bennewith, Kevin L., Nelson, Brad H., Bally, Marcel B., Lam, Wan L., and Gorski, Sharon M.
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- 2021
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4. Ionizing Radiation Enhances Breast Tumor Cell Migration In Vitro
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Young, Ada G. H. and Bennewith, Kevin L.
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- 2017
5. Cancer-Associated Fibroblast Heterogeneity in Malignancy with Focus on Oral Squamous Cell Carcinoma.
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Arebro, Julia, Lee, Che-Min, Bennewith, Kevin L., and Garnis, Cathie
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SQUAMOUS cell carcinoma ,PROGNOSIS ,HETEROGENEITY ,TUMOR microenvironment ,CANCER cells - Abstract
Oral squamous cell carcinoma (OSCC) remains an understudied and significant global cancer killer and dismal survival rates have not changed in decades. A better understanding of the molecular basis of OSCC progression and metastasis is needed to develop new approaches for treating this disease. The supportive network surrounding cancer tumor cells known as the tumor microenvironment (TME) has gained increasing interest lately since it performs essential protumorigenic functions. Cancer-associated fibroblasts (CAFs) are one of the main cell types in the TME and are known to play a key role in influencing the biological behavior of tumors. CAFs present a heterogeneity both in phenotype as well as functions, leading to the suggestion of different CAF subtypes in several cancer forms. The task to subtype CAFs in OSCC has, however, just begun, and there is today no united way of subtyping CAFs in this disease. This review aims to define the features of CAFs and to summarize CAF subtype research in malignancy with focus on OSCC including aspects as disease prognosis and therapeutic opportunities. [ABSTRACT FROM AUTHOR]
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- 2024
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6. HPV status is associated with altered PIWI-interacting RNA expression pattern in head and neck cancer
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Firmino, Natalie, Martinez, Victor D., Rowbotham, David A., Enfield, Katey S.S., Bennewith, Kevin L., and Lam, Wan L.
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- 2016
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7. Targeting myeloid-derived suppressor cells in combination with primary mammary tumor resection reduces metastatic growth in the lungs
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Bosiljcic, Momir, Cederberg, Rachel A., Hamilton, Melisa J., LePard, Nancy E., Harbourne, Bryant T., Collier, Jenna L., Halvorsen, Elizabeth C., Shi, Rocky, Franks, S. Elizabeth, Kim, Ada Y., Banáth, Judit P., Hamer, Mark, Rossi, Fabio M., and Bennewith, Kevin L.
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- 2019
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8. Induced Vascular Normalization—Can One Force Tumors to Surrender to a Better Microenvironment?
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Sun, Xu Xin, Nosrati, Zeynab, Ko, Janell, Lee, Che-Min, Bennewith, Kevin L., and Bally, Marcel B.
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DRUG delivery systems ,IMMUNE checkpoint inhibitors ,OVERALL survival ,BLOOD vessels ,TUMOR microenvironment ,PROGRAMMED cell death 1 receptors - Abstract
Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor's blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered. [ABSTRACT FROM AUTHOR]
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- 2023
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9. Emerging roles of regulatory T cells in tumour progression and metastasis
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Halvorsen, Elizabeth C., Mahmoud, Sahar M., and Bennewith, Kevin L.
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- 2014
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10. Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment.
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Decotret, Lisa R., Shi, Rocky, Thomas, Kiersten N., Hsu, Manchi, Pallen, Catherine J., and Bennewith, Kevin L.
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Organotypic cultures of murine brain slices are well-established tools in neuroscience research, including electrophysiology studies, modeling neurodegeneration, and cancer research. Here, we present an optimized ex vivo brain slice invasion assay that models glioblastoma multiforme (GBM) cell invasion into organotypic brain slices. Using this model, human GBM spheroids can be implanted with precision onto murine brain slices and cultured ex vivo to allow tumour cell invasion into the brain tissue. Traditional top-down confocal microscopy allows for imaging of GBM cell migration along the top of the brain slice, but there is limited resolution of tumour cell invasion into the slice. Our novel imaging and quantification technique involves embedding stained brain slices into an agar block, re-sectioning the slice in the Z-direction onto slides, and then using confocal microscopy to image cellular invasion into the brain tissue. This imaging technique allows for the visualization of invasive structures beneath the spheroid that would otherwise go undetected using traditional microscopy approaches. Our ImageJ macro (BraInZ) allows for the quantification of GBM brain slice invasion in the Z-direction. Importantly, we note striking differences in the modes of motility observed when GBM cells invade into Matrigel in vitro versus into brain tissue ex vivo highlighting the importance of incorporating the brain microenvironment when studying GBM invasion. In summary, our version of the ex vivo brain slice invasion assay improves upon previously published models by more clearly differentiating between migration along the top of the brain slice versus invasion into the slice. [ABSTRACT FROM AUTHOR]
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- 2023
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11. Hypoxia-Induced Lysyl Oxidase Is a Critical Mediator of Bone Marrow Cell Recruitment to Form the Premetastatic Niche
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Erler, Janine T., Bennewith, Kevin L., Cox, Thomas R., Lang, Georgina, Bird, Demelza, Koong, Albert, Le, Quynh-Thu, and Giaccia, Amato J.
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- 2009
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12. Serum inhibits the immunosuppressive function of myeloid-derived suppressor cells isolated from 4T1 tumor-bearing mice
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Hamilton, Melisa J., Banáth, Judit P., Lam, Vivian, LePard, Nancy E., Krystal, Gerald, and Bennewith, Kevin L.
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- 2012
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13. A low carbohydrate, high protein diet combined with celecoxib markedly reduces metastasis
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Ho, Victor W., Hamilton, Melisa J., Dang, Ngoc-Ha Thi, Hsu, Brian E., Adomat, Hans H., Guns, Emma S., Weljie, Aalim, Samudio, Ismael, Bennewith, Kevin L., and Krystal, Gerald
- Published
- 2014
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14. Eosinophils Decrease Pulmonary Metastatic Mammary Tumor Growth.
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Cederberg, Rachel A., Franks, Sarah Elizabeth, Wadsworth, Brennan J., So, Alvina, Decotret, Lisa R., Hall, Michael G., Shi, Rocky, Hughes, Michael R., McNagny, Kelly M., and Bennewith, Kevin L.
- Abstract
Metastatic breast cancer is challenging to effectively treat, highlighting the need for an improved understanding of host factors that influence metastatic tumor cell colonization and growth in distant tissues. The lungs are a common site of breast cancer metastasis and are host to a population of tissue-resident eosinophils. Eosinophils are granulocytic innate immune cells known for their prominent roles in allergy and Th2 immunity. Though their presence in solid tumors and metastases have been reported for decades, the influence of eosinophils on metastatic tumor growth in the lungs is unclear. We used transgenic mouse models characterized by elevated pulmonary eosinophils (IL5Tg mice) and eosinophil-deficiency (DdblGATA mice), as well as antibody-mediated depletion of eosinophils, to study the role of eosinophils in EO771 mammary tumor growth in the lungs. We found that IL5Tg mice exhibit reduced pulmonary metastatic colonization and decreased metastatic tumor burden compared to wild-type (WT) mice or eosinophildeficient mice. Eosinophils co-cultured with tumor cells ex vivo produced peroxidase activity and induced tumor cell death, indicating that eosinophils are capable of releasing eosinophil peroxidase (EPX) and killing EO771 tumor cells. We found that lung eosinophils expressed phenotypic markers of activation during EO771 tumor growth in the lungs, and that metastatic growth was accelerated in eosinophil-deficient mice and in WT mice after immunological depletion of eosinophils. Our results highlight an important role for eosinophils in restricting mammary tumor cell growth in the lungs and support further work to determine whether strategies to trigger local eosinophil degranulation may decrease pulmonary metastatic growth. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Oxygen Measurement in Microdevices.
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Grist, Samantha M., Bennewith, Kevin L., and Cheung, Karen C.
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- 2022
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16. Lysyl oxidase is essential for hypoxia-induced metastasis
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Erler, Janine T., Bennewith, Kevin L., Nicolau, Monica, Dornhöfer, Nadja, Kong, Christina, Le, Quynh-Thu, Chi, Jen-Tsan Ashley, Jeffrey, Stefanie S., and Giaccia, Amato J.
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- 2006
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17. Retraction Note: Lysyl oxidase is essential for hypoxia-induced metastasis
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Erler, Janine T., Bennewith, Kevin L., Nicolau, Monica, Dornhöfer, Nadja, Kong, Christina, Le, Quynh-Thu, and Chi, Jen-Tsan Ashley
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Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
A Retraction to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Janine T. Erler [sup.1] , Kevin L. Bennewith [sup.1] , Monica Nicolau [sup.2] , Nadja Dornhöfer [sup.4] , Christina Kong [sup.3] , Quynh-Thu Le [sup.1] , Jen-Tsan Ashley Chi [...]
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- 2020
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18. Evaluation of 18F-EF5 for detection of hypoxia in localized adenocarcinoma of the prostate.
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Wadsworth, Brennan J., Decotret, Lisa R., Villamil, Carlos, Yapp, Donald, Wilson, Don, Benard, Francois, McKenzie, Michael, and Bennewith, Kevin L.
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ADENOCARCINOMA ,BIOPSY ,IMMUNOHISTOCHEMISTRY ,CANCER patients ,RADIOPHARMACEUTICALS ,DESCRIPTIVE statistics ,MEMBRANE proteins ,PROSTATE tumors ,HYPOXEMIA - Abstract
A common feature of solid tumours that are resistant to therapy is the presence of regions with low oxygen content (i.e., hypoxia). Oxygen electrode studies suggest that localized prostate adenocarcinoma is commonly hypoxic, although conflicting data have been reported between immunohistochemical detection of hypoxia-induced proteins in biopsy specimens and positron emission tomography (PET) imaging of
18 F-labeled hypoxia reporters. Although the 2-nitroimidazole18 F-EF5 is well-established to label hypoxic tumour cells in pre-clinical tumour models and clinical trials of multiple primary tumour sites, it has yet to be tested in prostate cancer. The purpose of this study was to evaluate the feasibility of using18 F-EF5 to detect hypoxia in clinical prostate tumours. Patients with localized adenocarcinoma of the prostate were recruited for pre-treatment18 F-EF5 PET scans. Immunohistochemistry was conducted on diagnostic biopsies to assess the expression of glucose transporter 1 (GLUT1), osteopontin (OPN), and carbonic anhydrase IX (CAIX). Immunoreactivity scores of staining intensity and frequency were used to indicate the presence of tumour hypoxia. We found low tumour-to-muscle ratios of18 F-EF5 uptake that were not consistent with tumour hypoxia, causing early termination of the study. However, we observed GLUT1 and OPN expression in all prostate tumour biopsies, indicating the presence of hypoxia in all tumours. Our data do not support the use of18 F-EF5 PET to detect hypoxia in prostate adenocarcinoma, and suggest the use of immunohistochemistry to quantify expression of the hypoxia-inducible proteins GLUT1 and OPN as indications of prostate tumour hypoxia. [ABSTRACT FROM AUTHOR]- Published
- 2021
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19. Targeting hypoxic tumour cells to overcome metastasis
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Bennewith Kevin L and Dedhar Shoukat
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The microenvironment within solid tumours can influence the metastatic dissemination of tumour cells, and recent evidence suggests that poorly oxygenated (hypoxic) cells in primary tumours can also affect the survival and proliferation of metastatic tumour cells in distant organs. Hypoxic tumour cells have been historically targeted during radiation therapy in attempts to improve loco-regional control rates of primary tumours since hypoxic cells are known to be resistant to ionizing radiation-induced DNA damage. There are, therefore, a number of therapeutic strategies to directly target hypoxic cells in primary (and metastatic) tumours, and several compounds are becoming available to functionally inhibit hypoxia-induced proteins that are known to promote metastasis. This mini-review summarizes several established and emerging experimental strategies to target hypoxic cells in primary tumours with potential clinical application to the treatment of patients with tumour metastases or patients at high risk of developing metastatic disease. Targeting hypoxic tumour cells to reduce metastatic disease represents an important advance in the way scientists and clinicians view the influence of tumour hypoxia on therapeutic outcome.
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- 2011
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20. Germinal center hypoxia in tumor-draining lymph nodes negatively regulates tumor-induced humoral immune responses in mouse models of breast cancer.
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Firmino, Natalie S., Cederberg, Rachel A., Che-Min Lee, Shi, Rocky, Wadsworth, Brennan J., Franks, S. Elizabeth, Thomas, Kiersten N., Decotret, Lisa R., and Bennewith, Kevin L.
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GERMINAL centers ,LYMPH nodes ,BREAST cancer ,HYPOXEMIA ,LABORATORY mice ,LYMPH node cancer - Abstract
Hypoxia develops in germinal centers (GCs) induced by model antigens; however, it is unknown whether tumor-reactive GCs are also hypoxic. We identified GC hypoxia in lymph nodes (LNs) draining murine mammary tumors and lethally irradiated tumor cells, and found that hypoxia is associated with the levels of antibody-secreting B cells. Hypoxic culture conditions impaired the proliferation of activated B cells, and inhibited class-switching to IgG1 and IgA immunoglobulin isotypes in vitro. To assess the role of the hypoxic response in tumor-reactive GCs in vivo, we deleted von Hippel-Lindau factor (VHL) in class-switched B cells and found decreased GC B cells in tumor-draining LNs, reduced class-switched and tumor-specific antibodies in the circulation, and modified phenotypes of tumor-infiltrating T cells and macrophages. We also detected the hypoxia marker carbonic anhydrase IX in the GCs of LNs from breast cancer patients, providing evidence that GC hypoxia develops in humans. We conclude that GC hypoxia develops in TDLNs, and that the hypoxic response negatively regulates tumor-induced humoral immune responses in preclinical models. [ABSTRACT FROM AUTHOR]
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- 2021
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21. 2-18F-Fluoroethanol Is a PET Reporter of Solid Tumor Perfusion.
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Wadsworth, Brennan J., Jinhe Pan, Dude, Iulia, Colpo, Nadine, Bosiljcic, Momir, Kuo-Shyan Lin, Benard, Francois, and Bennewith, Kevin L.
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- 2017
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22. Emerging roles of T helper 17 and regulatory T cells in lung cancer progression and metastasis.
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Marshall, Erin A., Ng, Kevin W., Kung, Sonia H. Y., Conway, Emma M., Martinez, Victor D., Halvorsen, Elizabeth C., Rowbotham, David A., Vucic, Emily A., Plumb, Adam W., Becker-Santos, Daiana D., Enfield, Katey S. S., Kennett, Jennifer Y., Bennewith, Kevin L., Lockwood, William W., Lam, Stephen, English, John C., Abraham, Ninan, and Lam, Wan L.
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T helper cells ,LUNG cancer risk factors ,CANCER invasiveness ,METASTASIS ,LUNG cancer prognosis ,CD4 antigen - Abstract
Lung cancer is a leading cause of cancer-related deaths worldwide. Lung cancer risk factors, including smoking and exposure to environmental carcinogens, have been linked to chronic inflammation. An integral feature of inflammation is the activation, expansion and infiltration of diverse immune cell types, including CD4
+ T cells. Within this T cell subset are immunosuppressive regulatory T (Treg) cells and pro-inflammatory T helper 17 (Th17) cells that act in a fine balance to regulate appropriate adaptive immune responses. In the context of lung cancer, evidence suggests that Tregs promote metastasis and metastatic tumor foci development. Additionally, Th17 cells have been shown to be an integral component of the inflammatory milieu in the tumor microenvironment, and potentially involved in promoting distinct lung tumor phenotypes. Studies have shown that the composition of Tregs and Th17 cells are altered in the tumor microenvironment, and that these two CD4+ T cell subsets play active roles in promoting lung cancer progression and metastasis. We review current knowledge on the influence of Treg and Th17 cells on lung cancer tumorigenesis, progression, metastasis and prognosis. Furthermore, we discuss the potential biological and clinical implications of the balance among Treg/Th17 cells in the context of the lung tumor microenvironment and highlight the potential prognostic function and relationship to metastasis in lung cancer. [ABSTRACT FROM AUTHOR]- Published
- 2016
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23. Macrophages, Inflammation, and Lung Cancer.
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Conway, Emma M., Pikor, Larissa A., Kung, Sonia H. Y., Hamilton, Melisa J., Lam, Stephen, Lam, Wan L., and Bennewith, Kevin L.
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TREATMENT of lung tumors ,IMMUNOTHERAPY ,INFLAMMATION ,LUNG tumors ,MACROPHAGES ,PROGNOSIS ,RESEARCH funding ,SURVIVAL ,PHENOTYPES ,DISEASE progression - Abstract
Lung cancer is the leading cause of cancer mortality worldwide, and at only 18%, it has one of the lowest 5-year survival rates of all malignancies. With its highly complex mutational landscape, treatment strategies against lung cancer have proved largely ineffective. However with the recent success of immunotherapy trials in lung cancer, there is renewed enthusiasm in targeting the immune component of tumors. Macrophages make up the majority of the immune infiltrate in tumors and are a key cell type linking inflammation and cancer. Although the mechanisms through which inflammation promotes cancer are not fully understood, two connected hypotheses have emerged: an intrinsic pathway, driven by genetic alterations that lead to neoplasia and inflammation, and an extrinsic pathway, driven by inflammatory conditions that increase cancer risk. Here, we discuss the contribution of macrophages to these pathways and subsequently their roles in established tumors. We highlight studies investigating the association of macrophages with lung cancer prognosis and discuss emerging therapeutic strategies for targeting macrophages in the tumor microenvironment. [ABSTRACT FROM AUTHOR]
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- 2016
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24. Multiple Components of the VHL Tumor Suppressor Complex Are Frequently Affected by DNA Copy Number Loss in Pheochromocytoma.
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Rowbotham, David A., Enfield, Katey S. S., Martinez, Victor D., Thu, Kelsie L., Vucic, Emily A., Stewart, Greg L., Bennewith, Kevin L., and Lam, Wan L.
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DEOXYRIBOSE ,PHEOCHROMOCYTOMA ,TUMOR suppressor proteins ,TUMOR suppressor genes ,OXYGEN - Abstract
Pheochromocytomas (PCC) are rare tumors that arise in chromaffin tissue of the adrenal gland. PCC are frequently inherited through predisposing mutations in genes such as the von Hippel-Lindau (VHL) tumor suppressor. VHL is part of the VHL elongin BC protein complex that also includes CUL2/5, TCEB1, TCEB2, and RBX1; in normoxic conditions this complex targets hypoxia-inducible factor 1 alpha (HIF1A) for degradation, thus preventing a hypoxic response. VHL inactivation by genetic mechanisms, such as mutation and loss of heterozygosity, inhibits HIF1A degradation, even in the presence of oxygen, and induces a pseudohypoxic response. However, the described <10% VHL mutation rate cannot account for the high frequency of hypoxic response observed. Indeed, little is known about genetic mechanisms disrupting other complex component genes. Here, we show that, in a panel of 171 PCC tumors, 59.6% harbored gene copy number loss (CNL) of at least one complex component. CNL significantly reduced gene expression and was associated with enrichment of gene targets controlled by HIF1. Interestingly, we show that VHL-related renal clear cell carcinoma harbored disruption of VHL alone. Our results indicate that VHL elongin BC protein complex components other than VHL could be important for PCC tumorigenesis and merit further investigation. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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25. EYA4 is inactivated biallelically at a high frequency in sporadic lung cancer and is associated with familial lung cancer risk
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Wilson, Ian M., Vucic, Emily A., Enfield, Katey S.S., Thu, Kelsie L., Zhang, Yu-An, Chari, Raj, Lockwood, William W., Radulovich, Niki, Starczynowski, Daniel T., Banáth, Judit P., Zhang, May, Pusic, Andrea, Fuller, Megan, Lonergan, Kim M., Rowbotham, David, Yee, John, English, John C., Buys, Timon P.H., Selamat, Suhaida A., Laird-Offringa, Ite A., Liu, Pengyuan, Anderson, Marshall, You, Ming, Tsao, Ming-Sound, Brown, Carolyn J., Bennewith, Kevin L., MacAulay, Calum E., Karsan, Aly, Gazdar, Adi F., Lam, Stephen, and Lam, Wan L.
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EYA4 ,two-hit ,hypermethylation ,tumor suppressor ,TSG ,non-small cell lung cancer - Abstract
In an effort to identify novel biallelically inactivated tumor suppressor genes (TSG) in sporadic invasive and pre-invasive non-small cell lung cancer (NSCLC) genomes, we applied a comprehensive integrated multi-‘omics approach to investigate patient matched, paired NSCLC tumor and non-malignant parenchymal tissues. By surveying lung tumor genomes for genes concomitantly inactivated within individual tumors by multiple mechanisms, and by the frequency of disruption in tumors across multiple cohorts, we have identified a putative lung cancer TSG, Eyes Absent 4 (EYA4). EYA4 is frequently and concomitantly deleted, hypermethylated and underexpressed in multiple independent lung tumor data sets, in both major NSCLC subtypes, and in the earliest stages of lung cancer. We find not only that decreased EYA4 expression is associated with poor survival in sporadic lung cancers, but EYA4 SNPs are associated with increased familial cancer risk, consistent with EYA4’s proximity to the previously reported lung cancer susceptibility locus on 6q. Functionally, we find that EYA4 displays TSG-like properties with a role in modulating apoptosis and DNA repair. Cross examination of EYA4 expression across multiple tumor types suggests a cell type-specific tumorigenic role for EYA4, consistent with a tumor suppressor function in cancers of epithelial origin. This work shows a clear role for EYA4 as a putative TSG in NSCLC.
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- 2015
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26. Peggy Louise Olive 1948–2018.
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Bennewith, Kevin L., Hill, Richard P., and Minchinton, Andrew I.
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RADIOBIOLOGY ,DNA repair ,MEDICAL physics ,OLIVE - Published
- 2019
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27. Liposomal Formulations to Modulate the Tumour Microenvironment and Antitumour Immune Response.
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Gilabert-Oriol, Roger, Ryan, Gemma M., Leung, Ada W.Y., Firmino, Natalie S., Bennewith, Kevin L., and Bally, Marcel B.
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CANCER immunology ,LIPOSOMES ,ANTINEOPLASTIC agents ,IMMUNE response ,TUMOR microenvironment - Abstract
Tumours are complex systems of genetically diverse malignant cells that proliferate in the presence of a heterogeneous microenvironment consisting of host derived microvasculature, stromal, and immune cells. The components of the tumour microenvironment (TME) communicate with each other and with cancer cells, to regulate cellular processes that can inhibit, as well as enhance, tumour growth. Therapeutic strategies have been developed to modulate the TME and cancer-associated immune response. However, modulating compounds are often insoluble (aqueous solubility of less than 1 mg/mL) and have suboptimal pharmacokinetics that prevent therapeutically relevant drug concentrations from reaching the appropriate sites within the tumour. Nanomedicines and, in particular, liposomal formulations of relevant drug candidates, define clinically meaningful drug delivery systems that have the potential to ensure that the right drug candidate is delivered to the right area within tumours at the right time. Following encapsulation in liposomes, drug candidates often display extended plasma half-lives, higher plasma concentrations and may accumulate directly in the tumour tissue. Liposomes can normalise the tumour blood vessel structure and enhance the immunogenicity of tumour cell death; relatively unrecognised impacts associated with using liposomal formulations. This review describes liposomal formulations that affect components of the TME. A focus is placed on formulations which are approved for use in the clinic. The concept of tumour immunogenicity, and how liposomes may enhance radiation and chemotherapy-induced immunogenic cell death (ICD), is discussed. Liposomes are currently an indispensable tool in the treatment of cancer, and their contribution to cancer therapy may gain even further importance by incorporating modulators of the TME and the cancer-associated immune response. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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28. Hypoxia-Inducible mir-210 Regulates Normoxic Gene Expression Involved in Tumor Initiation
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Huang, Xin, Ding, Lianghao, Bennewith, Kevin L., Tong, Ricky T., Welford, Scott M., Ang, K. Kian, Story, Michael, Le, Quynh-Thu, and Giaccia, Amato J.
- Subjects
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HYPOXEMIA , *GENETIC regulation , *CELL cycle , *TRANSCRIPTION factors , *CANCER genetics , *TUMOR markers , *GENE expression , *TUMOR growth - Abstract
Summary: Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth. [Copyright &y& Elsevier]
- Published
- 2009
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29. Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation.
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Wadsworth, Brennan J., Cederberg, Rachel A., Lee, Che-Min, Firmino, Natalie S., Franks, S. Elizabeth, Pan, Jinhe, Colpo, Nadine, Lin, Kuo-Shyan, Benard, Francois, and Bennewith, Kevin L.
- Subjects
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ANGIOTENSIN-receptor blockers , *LOSARTAN , *ANGIOTENSIN II , *POSITRON emission tomography - Abstract
Hypoxic tumour cells are radiation-resistant and are associated with poor therapeutic outcome. A poorly understood source of tumour hypoxia is unstable perfusion, which exposes tumour cells to varying oxygen tensions over time creating "transiently" hypoxic cells. Evidence suggests that angiotensin II type 1 receptor blockers (ARBs) can improve tumour perfusion by reducing collagen deposition from cancer associated fibroblasts (CAFs). However, the influence of ARBs on transient hypoxia and tumour radiation response is unknown. We tested how the ARBs losartan and telmisartan affected the solid tumour microenvironment, using fluorescent perfusion dyes and positron emission tomography to quantify tumour perfusion, and a combination of hypoxia markers and the hemorheological agent pentoxifylline to assess transient tumour hypoxia. We found CAF-containing tumours have reduced collagen I levels in response to telmisartan, but not losartan. Telmisartan significantly increased tumour blood flow, stabilized microregional tumour perfusion, and decreased tumour hypoxia by reducing the development of transient hypoxia. Telmisartan-treated tumours were more responsive to radiation, indicating that telmisartan reduces a therapeutically important population of transiently hypoxic tumour cells. Our findings indicate telmisartan is capable of modifying the tumour microenvironment to stabilize tumour perfusion, reduce transient hypoxia, and improve tumour radiation response. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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30. Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis.
- Author
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El-Naggar, Amal M., Veinotte, Chansey J., Cheng, Hongwei, Grunewald, Thomas G.P., Negri, Gian Luca, Somasekharan, Syam Prakash, Corkery, Dale P., Tirode, Franck, Mathers, Joan, Khan, Debjit, Kyle, Alastair H., Baker, Jennifer H., LePard, Nancy E., McKinney, Steven, Hajee, Shamil, Bosiljcic, Momir, Leprivier, Gabriel, Tognon, Cristina E., Minchinton, Andrew I., and Bennewith, Kevin L.
- Subjects
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SARCOMA , *METASTASIS , *GENETIC translation , *RHABDOMYOSARCOMA , *EPITHELIAL cells , *MESENCHYMAL stem cells - Abstract
Summary Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
31. Carbonic Anhydrase IX Promotes Myeloid- Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production.
- Author
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Chafe, Shawn C., Yuanmei Lou, Sceneay, Jaclyn, Vallejo, Marylou, Hamilton, Melisa J., McDonald, Paul C., Bennewith, Kevin L., Möller, Andreas, and Dedhar, Shoukat
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BONE marrow cells , *BREAST cancer research , *CANCER cells , *METASTASIS , *CARBONIC anhydrase , *TUMOR growth , *SUPPRESSOR cells - Abstract
The mobilization of bone marrow-derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF-driven mobilization of granulocytic mye-loid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-KB in hypoxic breast cancer cells and constitutive activation of the NF-KB pathway in CAIX-deplet-ed cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX-NF-κB-G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
32. Macrophages Are More Potent Immune Suppressors Ex Vivo Than Immature Myeloid-Derived Suppressor Cells Induced by Metastatic Murine Mammary Carcinomas.
- Author
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Hamilton, Melisa J., Bosiljcic, Momir, LePard, Nancy E., Halvorsen, Elizabeth C., Ho, Victor W., Banáth, Judit P., Krystal, Gerald, and Bennewith, Kevin L.
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MACROPHAGES , *IMMUNOSUPPRESSION , *TUMOR growth , *T cell differentiation , *TRETINOIN - Abstract
Myeloid-derived suppressor cells (MDSCs) are emerging as potential promoters of metastatic tumor growth, and there is interest in targeting immature MDSCs by inducing their differentiation into more mature myeloid cells. We used all-trans retinoic acid (ATRA) to differentiate MDSCs in mice bearing metastatic 4T1 or 4TO7 murine mammary tumors, and assessed the immunesuppressive mechanisms and potencies of different myeloid cell subpopulations. Metastatic mammary tumors induced the accumulation of distinct populations of immature CD11b+Gr1+F4/80-Ly6CmidLy6G+ MDSCs ("Gr1+ cells") and mature CD11b+Gr1- F4/80+ cells ("F4/80+ cells") in metastatic target organs. ATRA triggered the differentiation of Gr1+ cells into F4/80+ cells in the lungs and, unexpectedly, enhanced pulmonary metastatic tumor growth. We found that F4/80+Ly6C-Ly6G- mature macrophages (Mfs) were up to 30-fold more potent immune suppressors than Gr1+ cells on a per-cell basis, which we postulate may contribute to the increased metastatic growth observed with ATRA treatment. F4/80+ cells and Gr1+ cells used different reactive oxygen species (ROS)-mediated mechanisms of immunosuppression ex vivo, with F4/80+ cells producing higher levels of ROS, which is consistent with their superior immunosuppressive abilities. These data highlight the potent immunosuppressive functions of Mθs, reveal that Mθs can suppress T cell responses via ROS production, and suggest that ROS inhibitors may be useful in promoting antitumor immune responses. Our findings also caution against using ATRA to modulate myeloid cell differentiation and function to treat breast cancer metastases in the lung, and support the development of therapeutic strategies to enhance antitumor immunity by targeting myeloid cells as a collective group. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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- View/download PDF
33. Myeloid Suppressor Cells Regulate the Lung Environment--Letter.
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Bosiljcic, Momir, Hamilton, Melisa J., Banath, Judit P., LePard, Nancy E., McDougal, Denise C., Jia, Jessica X., Krystal, Gerald, and Bennewith, Kevin L.
- Subjects
- *
CANCER cells , *CANCER invasiveness , *METASTASIS , *BONE marrow , *IMMUNE response , *LABORATORY mice - Abstract
4T1 murine mammary carcinoma cells implanted in syngeneic Balb/c mice are increasingly being used in metastasis research, with some groups using this model to study tumor-induced accumulation of bone marrow-derived cells in metastatic target organs. Bone marrow-derived cells (including CD11b+Gr-1+ myelomonocytic cells) are thought to modify the local lung microenvironment to facilitate subsequent colonization by metastatic tumor cells. While quantification of metastatic 4T1 tumor cells in various tissues can be done using ex vivo colony-forming assays, detection of metastatic 4T1 cells is often facilitated by expressing fluorescent proteins in the tumor cells prior to implantation. We found that Balb/c mice mount a potent immune response against 4T1 cells expressing green fluorescent protein (GFP) that includes the generation of anti-GFP antibodies in the circulation. Importantly, the number of bone marrow-derived CD11b+ Gr-1+ cells and metastatic tumor cells that accumulate in the lungs is significantly decreased in mice implanted with 4T1 cells expressing GFP compared with mice bearing wild-type 4T1 tumors. Taken together, our data caution against the use of GFP-expressing tumor cells in the Balb/c mouse strain, particularly for studying the influence of immunomodulatory cells on tumor cell metastasis. Cancer Res; 71(14); 5050-1. ©2011 AACR. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
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