50 results on '"Xinming Su"'
Search Results
2. The stiffness of the extracellular matrix is a key factor in tumor progression
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Yue Zheng, Xinming Su, and Shiwei Duan
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Medicine - Published
- 2024
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3. Tumor‐derived extracellular vesicles and particles (EVPs): pivotal vectors in driving metabolic reprogramming
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Xinming Su, Peijie Zheng, and Shiwei Duan
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cancer ,chemotherapy toxicity ,extracellular vesicles and particles ,liver metabolism ,metabolic reprogramming ,nonalcoholic fatty liver disease ,Medicine - Published
- 2023
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4. Histone deacetylase 8 regulates NF-κB-related inflammation in asthmatic mice through H3K9 acetylation
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Yuan Ren, Menglu Li, Shiyao Bai, Xinming Su, and Peifang Wei
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Medicine - Published
- 2022
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5. Transferrin receptor in primary and metastatic breast cancer: Evaluation of expression and experimental modulation to improve molecular targeting.
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Francesca Fontana, Alison K Esser, Christopher Egbulefu, Partha Karmakar, Xinming Su, John S Allen, Yalin Xu, Jennifer L Davis, Ariel Gabay, Jingyu Xiang, Kristin A Kwakwa, Brad Manion, Suzanne Bakewell, Shunqiang Li, Haeseong Park, Gregory M Lanza, Samuel Achilefu, and Katherine N Weilbaecher
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Medicine ,Science - Abstract
BackgroundConjugation of transferrin (Tf) to imaging or nanotherapeutic agents is a promising strategy to target breast cancer. Since the efficacy of these biomaterials often depends on the overexpression of the targeted receptor, we set out to survey expression of transferrin receptor (TfR) in primary and metastatic breast cancer samples, including metastases and relapse, and investigate its modulation in experimental models.MethodsGene expression was investigated by datamining in twelve publicly-available datasets. Dedicated Tissue microarrays (TMAs) were generated to evaluate matched primary and bone metastases as well as and pre and post chemotherapy tumors from the same patient. TMA were stained with the FDA-approved MRQ-48 antibody against TfR and graded by staining intensity (H-score). Patient-derived xenografts (PDX) and isogenic metastatic mouse models were used to study in vivo TfR expression and uptake of transferrin.ResultsTFRC gene and protein expression were high in breast cancer of all subtypes and stages, and in 60-85% of bone metastases. TfR was detectable after neoadjuvant chemotherapy, albeit with some variability. Fluorophore-conjugated transferrin iron chelator deferoxamine (DFO) enhanced TfR uptake in human breast cancer cells in vitro and proved transferrin localization at metastatic sites and correlation of tumor burden relative to untreated tumor mice.ConclusionsTfR is expressed in breast cancer, primary, metastatic, and after neoadjuvant chemotherapy. Variability in expression of TfR suggests that evaluation of the expression of TfR in individual patients could identify the best candidates for targeting. Further, systemic iron chelation with DFO may upregulate receptor expression and improve uptake of therapeutics or tracers that use transferrin as a homing ligand.
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- 2023
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6. Hepatic lipids promote liver metastasis
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Yongjia Li, Xinming Su, Nidhi Rohatgi, Yan Zhang, Jonathan R. Brestoff, Kooresh I. Shoghi, Yalin Xu, Clay F. Semenkovich, Charles A. Harris, Lindsay L. Peterson, Katherine N. Weilbaecher, Steven L. Teitelbaum, and Wei Zou
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Hepatology ,Oncology ,Medicine - Abstract
Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible.
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- 2020
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7. Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types.
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Sarah R Amend, William C Wilson, Liang Chu, Lan Lu, Pengyuan Liu, Daniel Serie, Xinming Su, Yalin Xu, Dingyan Wang, Anthony Gramolini, Xiao-Yan Wen, Julie O'Neal, Michelle Hurchla, Celine M Vachon, Graham Colditz, Ravi Vij, Katherine N Weilbaecher, and Michael H Tomasson
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Medicine ,Science - Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy.
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- 2015
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8. Targeted Therapy to β3 Integrin Reduces Chemoresistance in Breast Cancer Bone Metastases
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Samuel Achilefu, Michael H. Ross, Jingyu Xiang, Kristin A. Kwakwa, Elizabeth Cordell, Alison K. Esser, Vivek Sharma, Kristen Pagliai, Francesca Fontana, Jennifer L. Davis, Deborah J. Veis, Suzanne J. Bakewell, Xinming Su, Gregory M. Lanza, Katherine N. Weilbaecher, Gregory C. Fox, Christopher G. Maher, Jothilingam Sivapackiam, James A. J. Fitzpatrick, Yalin Xu, Ha X. Dang, and Sheila A. Stewart
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0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Integrin ,Antineoplastic Agents ,Bone Neoplasms ,Breast Neoplasms ,Docetaxel ,mTORC1 ,Article ,Targeted therapy ,Transcriptome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Chemotherapy ,biology ,business.industry ,Integrin beta3 ,medicine.disease ,Survival Analysis ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Female ,business ,medicine.drug - Abstract
Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3+ tumor cells in murine bone metastases after docetaxel chemotherapy. β3+ tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples (n = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect in vitro, but significantly enhanced in vivo docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.
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- 2021
9. Breast cancer–derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment
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Jingyu Xiang, Wen-Chih Lee, Junyi Su, Leonel Hernandez-Aya, Jad I. Belle, Gregory M. Lanza, Christopher Egbulefu, Gregory C. Fox, Deborah J. Veis, Katherine N. Weilbaecher, Samuel Achilefu, Yalin Xu, Kristin A. Kwakwa, Xinming Su, Jennifer L. Davis, Wing Hing Wong, Helen M Tomasson, Partha Karmakar, David G. DeNardo, Melisa A Meyer, Sheila A. Stewart, Takayuki Kobayashi, Francesca Fontana, and Suzanne J. Bakewell
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Myeloid ,medicine.medical_treatment ,T cell ,Breast Neoplasms ,complex mixtures ,Mice ,Breast cancer ,Cancer immunotherapy ,Cell Line, Tumor ,Cyclic AMP ,Immune Tolerance ,Tumor Microenvironment ,Medicine ,Animals ,Humans ,Myeloid Cells ,Tumor microenvironment ,Arginase ,business.industry ,Granulocyte-Macrophage Colony-Stimulating Factor ,General Medicine ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Tumor progression ,Cancer research ,Female ,business ,Research Article - Abstract
Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.
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- 2021
10. Identification of histone acetylation in a murine model of allergic asthma by proteomic analysis
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Menglu Li, Shi-Yao Bai, Lingfei Kong, Yuan Ren, and Xinming Su
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0301 basic medicine ,Proteomics ,Myocytes, Smooth Muscle ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Pathogenesis ,Histones ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Lung ,Original Research ,Mice, Inbred BALB C ,biology ,Acetylation ,Epithelial Cells ,Eosinophil ,Molecular biology ,Immunohistochemistry ,Asthma ,respiratory tract diseases ,Blot ,Disease Models, Animal ,030104 developmental biology ,Histone ,medicine.anatomical_structure ,030228 respiratory system ,biology.protein ,Female ,medicine.symptom ,Protein Processing, Post-Translational - Abstract
The pathogenesis of asthma is closely related to histone acetylation modification, but the specific acetylation sites related to this process remain indistinct. Herein, our study sought to identify differentially modified acetylation sites and their expression distribution in cells involved in asthma in lung tissues. The airway hyper-responsiveness, inflammation, and remodeling were assessed by non-invasive whole-body plethysmography, ELISA, and hematoxylin-eosin staining to confirm the successful establishment of the allergic asthma model. Afterward, the differentially modified acetylation sites in asthmatic lung tissues were identified and validated by using proteomics and western blotting, respectively. The immunohistochemistry analysis was applied to reveal the distribution of identified acetylation sites in asthmatic lung tissues. A total of 15 differentially modified acetylation sites, including 13 upregulated (H3K9ac, H3K14ac, H3K18ac, H3K23ac,H3K27ac, H3K36ac, H2B1KK120ac, H2B2BK20ac, H2BK16ac, H2BK20ac, H2BK108ac, H2BK116ac, and H2BK120ac) and 2 downregulated (H2BK5ac and H2BK11ac) sites were identified and validated. Furthermore, immunohistochemical staining of lung tissues showed that nine of the identified histone acetylation sites (H2BK5, H2BK11, H3K18, H2BK116, H2BK20, H2BK120, H3K9, H3K36, and H3K27) were differentially expressed in airway epithelial cells, and the acetylation of identified H3 histones were observed in both eosinophil and perivascular inflammatory cells. Additionally, differential expression of histone acetylation sites was also observed in nucleus of airway epithelial cells, vascular smooth muscle cells, perivascular inflammatory cells, and airway smooth muscle cells. In conclusion, we identified potential acetylation sites associated with asthma pathogenesis. These findings may contribute greatly in the search for therapeutic approaches for allergic asthma.
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- 2020
11. Hepatic lipids promote liver metastasis
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Clay F. Semenkovich, Nidhi Rohatgi, Katherine N. Weilbaecher, Xinming Su, Steven L. Teitelbaum, Wei Zou, Kooresh I. Shoghi, Lindsay L. Peterson, Jonathan R. Brestoff, Yongjia Li, Yalin Xu, Yan Zhang, and Charles A. Harris
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0301 basic medicine ,Lipolysis ,Mitochondria, Liver ,Metastasis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Humans ,Obesity ,Neoplasm Metastasis ,Cancer ,Hepatology ,business.industry ,Fatty liver ,Liver Neoplasms ,General Medicine ,Hep G2 Cells ,medicine.disease ,Metformin ,Transplantation ,Mice, Inbred C57BL ,030104 developmental biology ,Glucose ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Hepatocytes ,Medicine ,Female ,Steatosis ,Metabolic syndrome ,business ,Research Article ,medicine.drug - Abstract
Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible., Nonalcoholic fatty liver disease promotes liver metastasis in mice, likely due to lipid transfer to tumor cells.
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- 2020
12. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance
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Brett L. Knolhoff, Rebecca Aft, Cynthia X. Ma, Roberta Faccio, William G. Hawkins, Xinming Su, David G. DeNardo, David C. Linehan, Ryan C. Fields, Grant A. Challen, Timothy M. Nywening, Melissa A. Meyer, John M. Baer, Roheena Z. Panni, and Katherine N. Weilbaecher
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0301 basic medicine ,T-Lymphocytes ,Thrombomodulin ,medicine.medical_treatment ,Cellular differentiation ,General Physics and Astronomy ,CD8-Positive T-Lymphocytes ,Mice ,0302 clinical medicine ,lcsh:Science ,Immunologic Surveillance ,Oligonucleotide Array Sequence Analysis ,Mice, Inbred BALB C ,Multidisciplinary ,Stem Cells ,Cell Differentiation ,3. Good health ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Antigens, Surface ,Interferon Regulatory Factors ,Cytokines ,Female ,Immunotherapy ,Myelopoiesis ,Integrin alpha Chains ,Science ,Antineoplastic Agents ,Bone Marrow Cells ,Breast Neoplasms ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Antigens, CD ,Immunity ,medicine ,Animals ,Humans ,business.industry ,Dendritic Cells ,General Chemistry ,Dendritic cell ,Mice, Inbred C57BL ,Pancreatic Neoplasms ,Disease Models, Animal ,030104 developmental biology ,Tumor progression ,Cancer research ,lcsh:Q ,Bone marrow ,IRF8 ,business - Abstract
Tumors employ multiple mechanisms to evade immune surveillance. One mechanism is tumor-induced myelopoiesis, whereby the expansion of immunosuppressive myeloid cells can impair tumor immunity. As myeloid cells and conventional dendritic cells (cDCs) are derived from the same progenitors, we postulated that myelopoiesis might impact cDC development. The cDC subset, cDC1, which includes human CD141+ DCs and mouse CD103+ DCs, supports anti-tumor immunity by stimulating CD8+ T-cell responses. Here, to understand how cDC1 development changes during tumor progression, we investigated cDC bone marrow progenitors. We found localized breast and pancreatic cancers induce systemic decreases in cDC1s and their progenitors. Mechanistically, tumor-produced granulocyte-stimulating factor downregulates interferon regulatory factor-8 in cDC progenitors, and thus results in reduced cDC1 development. Tumor-induced reductions in cDC1 development impair anti-tumor CD8+ T-cell responses and correlate with poor patient outcomes. These data suggest immune surveillance can be impaired by tumor-induced alterations in cDC development., Tumors escape the immune system through many mechanisms. Here the authors show that certain tumors inhibit anti-tumor immunity by stopping the production of conventional dendritic cells (cDCs) in the bone marrow, therefore depleting the pool of cDCs available to present antigen to CD8+ T cells.
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- 2018
13. N-cadherin in osteolineage cells modulates stromal support of tumor growth
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Xinming Su, Katherine N. Weilbaecher, Roberto Civitelli, Francesca Fontana, Gregory C. Fox, Jingyu Xiang, Rachel Nassau, Eric Tycksen, and Giulia Leanza
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0301 basic medicine ,Osteolysis ,Stromal cell ,Population ,Diseases of the musculoskeletal system ,Bone-tumor cell interactions ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Transcriptomics ,education ,RC254-282 ,N-cadherin ,education.field_of_study ,Tumor microenvironment ,Cadherin ,business.industry ,musculoskeletal, neural, and ocular physiology ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,RC925-935 ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Bone marrow ,business ,Research Article - Abstract
Highlights • N-cadherin in osteolineage, Osterix+ cells restrains extraskeletal tumor growth. • Osterix+ cells are present in the stromal microenvironment of extraskeletal tumors. • Osterix+ cells are present in normal tissues frequent sites of metastasis. • N-cadherin modulates pro-tumorigenic signaling in tumor associated Osterix+ cells., Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.
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- 2021
14. HTLV-1 viral oncogene HBZ induces osteolytic bone disease in transgenic mice
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Nicole A. Kohart, Daniel Rauch, Alison K. Esser, Jingyu Xiang, Devra Huey, Patrick L. Green, Kiran Vij, Kevin Wu, Xinming Su, Thomas J. Rosol, Lee Ratner, John C. S. Harding, Stefan Niewiesk, Yalin Xu, Michael H. Ross, and Katherine N. Weilbaecher
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0301 basic medicine ,Osteolysis ,Bone disease ,T cell ,bone ,03 medical and health sciences ,0302 clinical medicine ,HBZ ,hemic and lymphatic diseases ,Medicine ,biology ,business.industry ,leukemia ,Wnt signaling pathway ,medicine.disease ,3. Good health ,Lymphoma ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,HTLV-1 ,ATL ,RANKL ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Bone marrow ,business ,Priority Research Paper - Abstract
// Alison K. Esser 1,* , Daniel A. Rauch 1,* , Jingyu Xiang 1 , John C. Harding 1 , Nicole A. Kohart 2 , Michael H. Ross 1 , Xinming Su 1 , Kevin Wu 1 , Devra Huey 2 , Yalin Xu 1 , Kiran Vij 1 , Patrick L. Green 2 , Thomas J. Rosol 2 , Stefan Niewiesk 2 , Lee Ratner 1 and Katherine N. Weilbaecher 1 1 Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Veterinary Biosciences, School of Veterinary Medicine, The Ohio State University, Columbus, OH, USA * Co-authors Correspondence to: Katherine N. Weilbaecher, email: // Keywords : HTLV-1, ATL, leukemia, HBZ, bone Received : June 10, 2017 Accepted : August 03, 2017 Published : August 27, 2017 Abstract Adult T-cell leukemia/lymphoma (ATL) is an aggressive T cell malignancy that occurs in HTLV-1 infected patients. Most ATL patients develop osteolytic lesions and hypercalcemia of malignancy, causing severe skeletal related complications and reduced overall survival. The HTLV-1 virus encodes 2 viral oncogenes, Tax and HBZ. Tax, a transcriptional activator, is critical to ATL development, and has been implicated in pathologic osteolysis. HBZ, HTLV-1 basic leucine zipper transcription factor, promotes tumor cell proliferation and disrupts Wnt pathway modulators; however, its role in ATL induced osteolytic bone loss is unknown. To determine if HBZ is sufficient for the development of bone loss, we established a transgenic Granzyme B HBZ (Gzmb-HBZ) mouse model. Lymphoproliferative disease including tumors, enlarged spleens and/or abnormal white cell counts developed in two-thirds of Gzmb-HBZ mice at 18 months. HBZ positive cells were detected in tumors, spleen and bone marrow. Importantly, pathologic bone loss and hypercalcemia were present at 18 months. Bone-acting factors were present in serum and RANKL, PTHrP and DKK1, key mediators of hypercalcemia and bone loss, were upregulated in Gzmb-HBZ T cells. These data demonstrate that Gzmb-HBZ mice model ATL bone disease and express factors that are current therapeutic targets for metastatic and bone resident tumors.
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- 2017
15. HDAC8 inhibitor attenuates airway responses to antigen stimulus through synchronously suppressing galectin-3 expression and reducing macrophage-2 polarization
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Lingfei Kong, Xuan Zhao, Jian Kang, Menglu Li, Xinming Su, and Yuan Ren
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Indoles ,Ovalbumin ,Galectin 3 ,Hydroxamic Acids ,Histone Deacetylases ,Mice ,Random Allocation ,medicine ,PCI-34051 ,Animals ,Galectin-3 ,Lung ,CD86 ,lcsh:RC705-779 ,Gene knockdown ,Mice, Inbred BALB C ,medicine.diagnostic_test ,biology ,Chemistry ,CD68 ,Macrophages ,Research ,Interleukin ,Cell Polarity ,lcsh:Diseases of the respiratory system ,respiratory system ,M2 Macrophage ,Molecular biology ,respiratory tract diseases ,Bronchoalveolar lavage ,RAW 264.7 Cells ,biology.protein ,Female ,Histone deacetylases8 ,Bronchial Hyperreactivity ,CD163 ,M2 macrophage polarization - Abstract
BackgroundThis study was to investigate of the mechanism by which histone deacetylase (HDAC) 8 inhibitor ameliorated airway hyperresponsiveness (AHR) and allergic airway inflammation.MethodsMice were sensitized and then treated with budesonide (BUD) or PCI-34051 (PCI) prior to exposing to normal saline (NS) or ovalbumin (OVA). The raw264.7 cells were treated with interleukin (IL)-4 and PCI or shRNA alone. Repetitive measurements of enhanced pause (Penh) were executed by increasing concentrations of acetyl-β-methacholine chloride (0 - 50 mg/ml). Cells in bronchoalveolar lavage fluid (BALF) and pathological changes of lungs were examined, respectively. The expression levels of HDAC8, Galecitn (Gal)-3, CD68, CD86, CD163, Arg1 and NOS2 in lungs were measured. Co-regulation of HDAC8 and Gal-3 proteins was observed by immunofluorescence staining and co-immunoprecipitation assay (Co-IP).ResultsSignificant increases in Penh and IL-4 level were detected with a large inflammatory infiltrate, comprised predominantly of macrophages and eosinophils, into the BALF in OVA-exposed lungs. HDAC8, Gal-3, CD68, CD86, CD163, Arg1 and NOS2 proteins were over-expressed with the significant changes in the Arg1 and NOS2 mRNA levels in the lungs and the IL-4-treated cells. PCI intervention obviously reduced the counts of CD163+cells. Furthermore, Gal-3 knockdown suppressed Arg1 expression in the cells. Immunofluorescence staining displayed simultaneous changes in HDAC8 and Gal-3 expression in the investigated samples. Treatment with PCI resulted in synchronous reduction of HDAC8 and Gal-3 expression in the Co-IP complexes.ConclusionsThe HDAC8 inhibitor ameliorates AHR and airway inflammation in animal model of allergic asthma through reducing HDAC8-Gal-3 interaction and M2 macrophage polarization.
- Published
- 2019
16. HTLV-1 viral oncogene HBZ drives bone destruction in adult T cell leukemia
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Xiaogang Cheng, Xinming Su, Gregory C. Fox, Deborah J. Veis, Francesca Fontana, Junyi Su, John C. S. Harding, Hemalatha Sundaramoorthi, Alison K. Esser, Takayuki Kobayashi, Stefan Niewiesk, Yizhen Jia, Patrick L. Green, Yalin Xu, Jingyu Xiang, Amanda R. Panfil, Thomas J. Rosol, Wing Hing Wong, Devra Huey, Katherine N. Weilbaecher, Lee Ratner, and Daniel Rauch
- Subjects
0301 basic medicine ,Male ,Bone disease ,viruses ,T-cell leukemia ,Viral Oncogene ,Retroviridae Proteins ,Osteoclasts ,Kaplan-Meier Estimate ,medicine.disease_cause ,Mice ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Medicine ,Leukemia-Lymphoma, Adult T-Cell ,610 Medicine & health ,Mice, Knockout ,Human T-lymphotropic virus 1 ,biology ,General Medicine ,Gene Expression Regulation, Neoplastic ,Denosumab ,medicine.anatomical_structure ,Basic-Leucine Zipper Transcription Factors ,RANKL ,030220 oncology & carcinogenesis ,Disease Progression ,Heterografts ,Female ,medicine.drug ,Research Article ,Adult ,T cell ,Bone and Bones ,03 medical and health sciences ,Animals ,Humans ,Bone Resorption ,business.industry ,RANK Ligand ,medicine.disease ,Lymphoma ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Cancer research ,biology.protein ,business ,Carcinogenesis ,Transcriptome - Abstract
Osteolytic bone lesions and hypercalcemia are common, serious complications in adult T cell leukemia/lymphoma (ATL), an aggressive T cell malignancy associated with human T cell leukemia virus type 1 (HTLV-1) infection. The HTLV-1 viral oncogene HBZ has been implicated in ATL tumorigenesis and bone loss. In this study, we evaluated the role of HBZ on ATL-associated bone destruction using HTLV-1 infection and disease progression mouse models. Humanized mice infected with HTLV-1 developed lymphoproliferative disease and continuous, progressive osteolytic bone lesions. HTLV-1 lacking HBZ displayed only modest delays to lymphoproliferative disease but significantly decreased disease-associated bone loss compared with HTLV-1-infected mice. Gene expression array of acute ATL patient samples demonstrated increased expression of RANKL, a critical regulator of osteoclasts. We found that HBZ regulated RANKL in a c-Fos-dependent manner. Treatment of HTLV-1-infected humanized mice with denosumab, a monoclonal antibody against human RANKL, alleviated bone loss. Using patient-derived xenografts from primary human ATL cells to induce lymphoproliferative disease, we also observed profound tumor-induced bone destruction and increased c-Fos and RANKL gene expression. Together, these data show the critical role of HBZ in driving ATL-associated bone loss through RANKL and identify denosumab as a potential treatment to prevent bone complications in ATL patients.
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- 2019
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17. CD4+ T cells induce rejection of urothelial tumors after immune checkpoint blockade
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Vivek K. Arora, Xinming Su, Jennifer K. Sehn, Yuji Sato, Christopher G. Maher, Jennifer Bolzenius, and Abdallah M. Eteleeb
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CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,medicine.medical_treatment ,CD8-Positive T-Lymphocytes ,Interferon-gamma ,Mice ,03 medical and health sciences ,Antigen ,Cancer immunotherapy ,Antigens, Neoplasm ,Interferon ,Neoplasms ,MHC class I ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Antibodies, Blocking ,Receptors, Interferon ,Mice, Knockout ,MHC class II ,Tumor microenvironment ,biology ,Chemistry ,Histocompatibility Antigens Class I ,Histocompatibility Antigens Class II ,Neoplasms, Experimental ,General Medicine ,Immune checkpoint ,Mice, Inbred C57BL ,030104 developmental biology ,Urinary Bladder Neoplasms ,biology.protein ,Cancer research ,Immunotherapy ,Lymph Nodes ,Urothelium ,Neoplasm Transplantation ,CD8 ,Research Article ,medicine.drug - Abstract
Immune checkpoint blockade (ICB) provides clinical benefit to a minority of patients with urothelial carcinoma (UC). The role of CD4+ T cells in ICB-induced antitumor activity is not well defined; however, CD4+ T cells are speculated to play a supportive role in the development of CD8+ T cells that kill tumor cells after recognition of tumor antigens presented by MHC class I. To investigate the mechanisms of ICB-induced activity against UC, we developed mouse organoid-based transplantable models that have histologic and genetic similarity to human bladder cancer. We found that ICB can induce tumor rejection and protective immunity with these systems in a manner dependent on CD4+ T cells but not reliant on CD8+ T cells. Evaluation of tumor infiltrates and draining lymph nodes after ICB revealed expansion of IFN-γ-producing CD4+ T cells. Tumor cells in this system express MHC class I, MHC class II, and the IFN-γ receptor (Ifngr1), but none were necessary for ICB-induced tumor rejection. IFN-γ neutralization blocked ICB activity, and, in mice depleted of CD4+ T cells, IFN-γ ectopically expressed in the tumor microenvironment was sufficient to inhibit growth of tumors in which the epithelial compartment lacked Ifngr1. Our findings suggest unappreciated CD4+ T cell-dependent mechanisms of ICB activity, principally mediated through IFN-γ effects on the microenvironment.
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- 2018
18. Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice
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Jian Kang, Lingfei Kong, Yuan Ren, Na Yu, and Xinming Su
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Vascular Endothelial Growth Factor A ,0301 basic medicine ,CD31 ,Immunology ,Nerve Tissue Proteins ,Inflammation ,Pharmacology ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Benzoquinones ,Human Umbilical Vein Endothelial Cells ,medicine ,Animals ,Humans ,Immunology and Allergy ,Nigella sativa ,Thymoquinone ,PI3K/AKT/mTOR pathway ,Mice, Inbred BALB C ,Neovascularization, Pathologic ,business.industry ,Akt/PKB signaling pathway ,Endothelial Cells ,Vascular Endothelial Growth Factor Receptor-2 ,Asthma ,Oncogene Protein v-akt ,Endothelial stem cell ,Vascular endothelial growth factor ,Disease Models, Animal ,Vascular endothelial growth factor A ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Airway Remodeling ,Intercellular Signaling Peptides and Proteins ,Interleukin-4 ,Interleukin-5 ,medicine.symptom ,business ,Signal Transduction - Abstract
Asthma is a chronic obstructive disease which is characterized by recurring airway inflammation, reversible airway obstruction, airway hyper responsiveness and vascular remodeling. Thymoquinone (TQ), an active ingredient isolated from Nigella sativa, was reported to exhibit anti-inflammation and anti-proliferation of in various cancer cells as well as epithelial cells. The aim of this study was to evaluate the effect of TQ on the inflammation, neoangiogenesis and vascular remodeling induced by Ovalbumin (OVA) in asthma mice in vivo and the anti-angiogenesis effects of TQ in VEGF-induced human umbilical vein endothelial cells (HUVECs) in vitro. Our results revealed that TQ inhibited the production of inflammatory factors interleukin-4/-5 (IL-4/-5) by enzyme-linked immunesorbent assay (ELISA). Immunohistochemistry analysis showed that the increase of platelet endothelial cell adhesion molecule-1, which is also known as CD31 and α-smooth muscle actinalpha (α-SMA) expression in asthma mice challenged by OVA was suppressed by TQ. Moreover, TQ suppressed the activation of VEGFR2-PI3K-Akt pathway and up-regulated the expression of Slit glycoprotein-2 (Slit-2) both in vivo and in vitro with the inhibition of tube information in HUVEC cells. Meanwhile immunofluorescence analysis showed that Slit-2 and Roundabout-4 (Robo-4) were co-expressing after TQ treatment in OVA-challenged asthma mice. Our study demonstrates that TQ attenuated the inflammatory reaction by antagonizing IL-4/-5 while the anti-neoangiogenesis effect of TQ is mediated by inhibition of vascular endothelial growth factor (VEGF) expression through VEGFR2/PI3K/Akt signaling pathway, which supports a potential role for TQ in ameliorating asthma.
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- 2016
19. Therapeutic effects of histone deacetylase inhibitors in a murine asthma model
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Xuan Zhao, Jian Kang, Yuan Ren, Menglu Li, Xinming Su, Na Yu, and Lingfei Kong
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0301 basic medicine ,medicine.medical_specialty ,Allergy ,Neurology ,Indoles ,Airway hyperresponsiveness ,Immunology ,Hydroxamic Acids ,Transforming Growth Factor beta1 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Histone deacetylase ,Anti-Asthmatic Agents ,Bronchial asthma ,Lung ,Pharmacology ,Mice, Inbred BALB C ,business.industry ,Therapeutic effect ,Airway inflammation ,respiratory system ,medicine.disease ,Rheumatology ,Actins ,Asthma ,respiratory tract diseases ,Original Research Paper ,Histone Deacetylase Inhibitors ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Airway Remodeling ,Cytokines ,Female ,Collagen ,Bronchial Hyperreactivity ,Airway ,business ,Bronchoalveolar Lavage Fluid - Abstract
Objective and design To investigate the therapeutic effects of various HDAC inhibitors on the development of chronic allergic airway disease in mice with airway inflammation, airway remodeling, and airway hyperresponsiveness. Subjects Wild-type BALB/C mice (N = 72). Treatment Tubastatin A HCl [TSA, a selective histone deacetylase 6 (HDAC6) inhibitor], PCI-34051 (a selective HDAC8 inhibitor), and givinostat (a broad-spectrum HDAC inhibitor that inhibits class I and class II HDACs and several pro-inflammatory cytokines). Methods Mice were divided into six groups: control, asthma, dexamethasone (positive control), TSA, PCI-34051, and givinostat (n = 12 per group). Twenty-four hours after OVA nebulization, airway hyperresponsiveness, inflammation, and remodeling were assessed. Results The chronic asthma mouse model produced typical airway inflammation, airway remodeling, and airway hyperresponsiveness. Administration of PCI-34051 and dexamethasone reduced the eosinophilic inflammation and airway hyperresponsiveness in asthma to reduce the airway remodeling. Treatment with Tubastatin A HCl reduced airway inflammation and was associated with decreased IL-4, IL-5 and total inflammatory cell count, as well as goblet cell metaplasia and subepithelial fibrosis; however, this outcome was not as effective as that with dexamethasone. TGF-β1 expression in the cytoplasm of airway epithelium of mice in the Tubastatin A HCl group was reduced and expression of α-SMA in the airway smooth muscle was also decreased. Conclusions The results suggested that treatment with HDAC inhibitors can reduce airway inflammation, airway remodeling, and airway hyperresponsiveness in chronic allergic airway disease in mice.
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- 2016
20. Novel ERα positive breast cancer model with estrogen independent growth in the bone microenvironment
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Xinming Su, Aude Hélène Capietto, Roberta Faccio, Julie A. Allen, Deborah V. Novack, Robert D. Schreiber, Biancamaria Ricci, and Szeman Ruby Chan
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0301 basic medicine ,Male ,medicine.medical_specialty ,Antineoplastic Agents, Hormonal ,medicine.drug_class ,skeletal metastasis ,Estrogen receptor ,Bone Neoplasms ,Breast Neoplasms ,bone ,endocrine resistance ,03 medical and health sciences ,Mice ,Breast cancer ,breast cancer ,Internal medicine ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Aromatase ,Neoplasm Metastasis ,Mice, Knockout ,biology ,business.industry ,Ovary ,Estrogen Receptor alpha ,Estrogens ,medicine.disease ,3. Good health ,030104 developmental biology ,Endocrinology ,Phenotype ,Oncology ,Cell culture ,Estrogen ,Drug Resistance, Neoplasm ,Cancer cell ,biology.protein ,Ovariectomized rat ,Cancer research ,Female ,Neoplasm Recurrence, Local ,business ,hormone resistance ,Receptors, Progesterone ,Neoplasm Transplantation ,Hormone ,Research Paper - Abstract
// Aude-Helene Capietto 1, 4, * , Szeman Ruby Chan 2, 5, * , Biancamaria Ricci 1 , Julie A. Allen 2 , Xinming Su 3 , Deborah V Novack 2, 3 , Robert D. Schreiber 2 , Roberta Faccio 1 1 Department of Orthopedics, Washington University School of Medicine, St. Louis, MO, USA 2 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA 3 Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA 4 Present address: Genentech, South San Francisco, CA, USA 5 Present address: Janssen Research and Development, Johnson and Johnson, Spring House, PA, USA * These authors contributed equally to this work Correspondence to: Roberta Faccio, email: faccior@wustl.edu Keywords: skeletal metastasis, breast cancer, endocrine resistance, bone, hormone resistance Received: July 17, 2015 Accepted: May 09, 2016 Published: July 06, 2016 ABSTRACT Despite successful therapeutic options for estrogen receptor-α (ERα)+ breast cancer, resistance to endocrine therapy frequently occurs leading to tumor recurrence. In addition to intrinsic changes in the cancer cells, herein we demonstrate that tumor cell-microenvironment interactions can drive recurrence at specific sites. By using two ERα+ cell lines derived from spontaneous mammary carcinomas in STAT1−/− mice (SSM2, SSM3), we establish that the bone microenvironment offers growth advantage over primary site or lung in the absence of ovarian hormones. While SSM3 did not engraft at primary and skeletal locations in the absence of estrogen, SSM2 selectively grew in bone of ovariectomized mice and following administration of aromatase inhibitors. However, SSM2 growth remained hormone-dependent at extraskeletal sites. Unexpectedly, bone-residing SSM2 cells retained ERα expression and JAK2/STAT3 activation regardless of the hormonal status. These data position the bone microenvironment as a unique site for acquisition of tumor/estrogen independency and identify the first ERα+ hormone-independent tumor model in immunocompetent mice.
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- 2016
21. Antagonizing Integrin β3 Increases Immunosuppression in Cancer
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David G. DeNardo, Melissa A. Meyer, Joshua S. Novack, Alison K. Esser, Roberta Faccio, Steven L. Teitelbaum, Michelle A. Hurchla, Jingyu Xiang, Jochen G. Schneider, Francesca Fontana, Michael H. Ross, Kirsten Roomp, Stephen D. Robinson, Deborah V. Novack, Veronica Steri, Julia C. Tomasson, Wei Zou, Gregory C. Fox, Brett L. Knolhoff, Xinming Su, Yalin Xu, Elizabeth A. Morgan, Katherine N. Weilbaecher, Takayuki Kobayashi, and Sarah R. Amend
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0301 basic medicine ,Cancer Research ,Inflammation ,Cilengitide ,Article ,Immune tolerance ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,stomatognathic system ,Neoplasms ,Immune Tolerance ,Tumor Microenvironment ,medicine ,Animals ,Syk Kinase ,Macrophage ,Tumor microenvironment ,biology ,Macrophages ,Integrin beta3 ,Cancer ,medicine.disease ,Mice, Inbred C57BL ,stomatognathic diseases ,STAT1 Transcription Factor ,030104 developmental biology ,Oncology ,Integrin alpha M ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,medicine.symptom ,STAT6 Transcription Factor - Abstract
Integrin β3 is critical for tumor invasion, neoangiogenesis, and inflammation, making it a promising cancer target. However, preclinical and clinical data of integrin β3 antagonists have demonstrated no benefit or worse outcomes. We hypothesized that integrin β3 could affect tumor immunity and evaluated tumors in mice with deletion of integrin β3 in macrophage lineage cells (β3KOM). β3KOM mice had increased melanoma and breast cancer growth with increased tumor-promoting M2 macrophages and decreased CD8+ T cells. Integrin β3 antagonist, cilengitide, also enhanced tumor growth and increased M2 function. We uncovered a negative feedback loop in M2 myeloid cells, wherein integrin β3 signaling favored STAT1 activation, an M1-polarizing signal, and suppressed M2-polarizing STAT6 activation. Finally, disruption of CD8+ T cells, macrophages, or macrophage integrin β3 signaling blocked the tumor-promoting effects of integrin β3 antagonism. These results suggest that effects of integrin β3 therapies on immune cells should be considered to improve outcomes. Cancer Res; 76(12); 3484–95. ©2016 AACR.
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- 2016
22. Dual-therapy with αvβ3-targeted Sn2 lipase-labile fumagillin-prodrug nanoparticles and zoledronic acid in the Vx2 rabbit tumor model
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Xiaoxia Yang, Samuel A. Wickline, Huiying Zhang, Todd A. Williams, John S. Allen, Anne H. Schmieder, Dipanjan Pan, Katherine N. Weilbaecher, Grace Cui, Gregory M. Lanza, Xinming Su, Michael H. Ross, Alison K. Esser, and Jingyu Xiang
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Male ,0301 basic medicine ,Materials science ,Angiogenesis ,Biomedical Engineering ,Pharmaceutical Science ,Medicine (miscellaneous) ,Angiogenesis Inhibitors ,Bioengineering ,Zoledronic Acid ,Article ,Diffusion ,03 medical and health sciences ,0302 clinical medicine ,Nanocapsules ,Osteoclast ,In vivo ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Prodrugs ,General Materials Science ,Molecular Targeted Therapy ,Fumagillin ,Diphosphonates ,Imidazoles ,Cancer ,Neoplasms, Experimental ,Prodrug ,Integrin alphaVbeta3 ,medicine.disease ,Endothelial stem cell ,Amino Acid Transport Systems, Neutral ,Treatment Outcome ,030104 developmental biology ,Zoledronic acid ,medicine.anatomical_structure ,Biochemistry ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Rabbits ,medicine.drug - Abstract
Fumagillin, an unstable anti-angiogenesis mycotoxin, was synthesized into a stable lipase-labile prodrug and incorporated into integrin-targeted lipid-encapsulated nanoparticles (αvβ3-Fum-PD NP). Dual anti-angiogenic therapy combining αvβ3-Fum-PD NP with zoledronic acid (ZA), a long-acting osteoclast inhibitor with proposed anti-angiogenic effects, was evaluated. In vitro, αvβ3-Fum-PD NP reduced (P
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- 2016
23. Stromal-Initiated Changes in the Bone Promote Metastatic Niche Development
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David M. Ornitz, Yu Shi, Bhavna Murali, Xinming Su, Kathleen M. Leahy, Roberta Faccio, Margery Gang, Fanxin Long, Yujie Fu, Kory J. Lavine, Sheila A. Stewart, Xianmin Luo, Ali Zamani, Deborah V. Novack, Gregory D. Longmore, Katherine N. Weilbaecher, Andrew J. Loza, and Megan K. Ruhland
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0301 basic medicine ,Stromal cell ,Bone Neoplasms ,Mice, Transgenic ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Metastasis ,Mice ,03 medical and health sciences ,Breast cancer ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Neoplasm Metastasis ,Interleukin 6 ,lcsh:QH301-705.5 ,Cellular Senescence ,Tumor microenvironment ,Osteoblasts ,Interleukin-6 ,Mammary Neoplasms, Experimental ,Cancer ,food and beverages ,medicine.disease ,Neoplasm Proteins ,030104 developmental biology ,lcsh:Biology (General) ,Immunology ,Cancer research ,biology.protein ,Experimental pathology ,Female ,Cell aging - Abstract
SummaryMore than 85% of advanced breast cancer patients suffer from metastatic bone lesions, yet the mechanisms that facilitate these metastases remain poorly understood. Recent studies suggest that tumor-derived factors initiate changes within the tumor microenvironment to facilitate metastasis. However, whether stromal-initiated changes are sufficient to drive increased metastasis in the bone remains an open question. Thus, we developed a model to induce reactive senescent osteoblasts and found that they increased breast cancer colonization of the bone. Analysis of senescent osteoblasts revealed that they failed to mineralize bone matrix and increased local osteoclastogenesis, the latter process being driven by the senescence-associated secretory phenotype factor, IL-6. Neutralization of IL-6 was sufficient to limit senescence-induced osteoclastogenesis and tumor cell localization to bone, thereby reducing tumor burden. Together, these data suggest that a reactive stromal compartment can condition the niche, in the absence of tumor-derived signals, to facilitate metastatic tumor growth in the bone.
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- 2016
24. CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer
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Alison K. Esser, Foluso O. Ademuyiwa, Eric Chevalier, Michelle A. Hurchla, Barbara Romagnoli, Gérald Tuffin, Sarah R. Amend, Bauer Michael, Rebecca Aft, Kathryn E. Luker, Katherine N. Weilbaecher, Gary D. Luker, Xinming Su, Timothy J. Pluard, Francesca Fontana, Chidananda Mudalagiriyappa, Klaus Dembowsky, Jingyu Xiang, Garry Douglas, and Johann Zimmermann
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Receptors, CXCR4 ,Cancer Research ,Cell Survival ,Mice, Transgenic ,Triple Negative Breast Neoplasms ,Mice, SCID ,Article ,Metastasis ,Epitopes ,chemistry.chemical_compound ,Breast cancer ,Biomimetic Materials ,Cell Movement ,Mice, Inbred NOD ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Animals ,Humans ,Medicine ,Neoplasm Metastasis ,Furans ,Triple-negative breast cancer ,Mice, Inbred BALB C ,CXCR4 antagonist ,business.industry ,Proteins ,Ketones ,medicine.disease ,Survival Analysis ,Xenograft Model Antitumor Assays ,Primary tumor ,Chemokine CXCL12 ,Tumor Burden ,Oncology ,chemistry ,Tumor progression ,Cancer research ,business ,Protein Binding ,Signal Transduction ,Eribulin - Abstract
The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow–disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a “chemotherapy framing” dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. Mol Cancer Ther; 14(11); 2473–85. ©2015 AACR.
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- 2015
25. Association of glutathione S-transferase M1 and T1 genotypes with asthma
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Jian Kang, Yuan Ren, Xinming Su, Lingfei Kong, and Menglu Li
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education.field_of_study ,medicine.medical_specialty ,integumentary system ,biology ,Web of science ,business.industry ,Population ,General Medicine ,Odds ratio ,medicine.disease ,Confidence interval ,03 medical and health sciences ,0302 clinical medicine ,Glutathione S-transferase ,030220 oncology & carcinogenesis ,Meta-analysis ,Internal medicine ,Genotype ,biology.protein ,Medicine ,030212 general & internal medicine ,business ,education ,neoplasms ,Asthma - Abstract
BACKGROUND We performed an updated meta-analysis to clarify the relationship between glutathione S-transferase Mu and theta (GSTM1 and GSTT1, respectively) null/positive genotypes and asthma. METHODS We performed a literature search using PubMed and Web of Science databases in August 2019. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the role of GSTM1 and GSTT1 genotypes in the risk of asthma. RESULTS Overall, we found a significant association with asthma risk in the general population for both the GSTM1 genotype (OR = 1.21; 95% CI: 1.07-1.35; P 2000. CONCLUSION Our meta-analysis provides evidence that GSTM1 and GSTT1 genotypes could be used as asthma-associated biomarkers.
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- 2020
26. Abstract 2613: Integrin beta-3 signaling links chemoresistance and mitochondrial metabolism in breast cancer bone metastases
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Gregory C. Fox, Barbara Muz, Yalin Xu, Samuel Achilefu, Alison K. Esser, Michael H. Ross, Deborah J. Veis, Gregory M. Lanza, Katherine N. Weilbaecher, Ha X. Dang, Abdel Kareem Azab, Christopher G. Maher, Elizabeth Cordell, Xinming Su, and Elizabeth Wilson
- Subjects
Cancer Research ,Chemotherapy ,business.industry ,medicine.medical_treatment ,Cancer ,mTORC1 ,medicine.disease ,Metastasis ,Breast cancer ,Oncology ,Mitochondrial biogenesis ,Docetaxel ,medicine ,Cancer research ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Abstract
We have previously demonstrated that expression of the integrin β3 (β3) subunit is consistently increased in breast cancer (BC) bone metastases across clinical samples and preclinical models. Bone metastases frequently exhibit resistance to chemotherapy. Based on evidence that integrin β3 can function as a promoter of tumor survival and metastasis, we asked whether increased β3 signaling in bone metastases promotes chemoresistance. In established murine bone metastases, the proportion of integrin β3+ tumor cells was increased after docetaxel administration. Genetic deletion of β3 in either MMTV-PyMT-derived BC cells (BO1-FL-GFP, modeling luminal B disease) or 4T1 BC cells (4T1-FL-GFP, modeling triple-negative disease) yielded bone metastases with increased sensitivity to docetaxel treatment in vivo. Retroviral rescue of β3 expression in β3-/- BO1-FL-GFP cells by a signaling-competent human integrin β3 construct (hβ3) restored relative docetaxel chemoresistance in bone metastases. By contrast, expression of a signaling-deficient mutant β3 (Δβ3) failed to restore chemoresistance, suggesting that signaling through β3 is critical to its capacity to promote docetaxel chemoresistance in bone-residing BC cells. Mechanistically, RNAseq analysis of docetaxel response in β3-/- and hβ3-rescued cells revealed β3-mediated enrichment in transcriptional pathways associated with oxidative phosphorylation and metabolism. Direct imaging of mitochondria by super-resolution microscopy and extracellular flux analysis of oxygen consumption rate further confirmed an alternative metabolic response to docetaxel in resistant, β3-expressing tumor cells. mTORC1 plays an important role in mitochondrial biogenesis and cellular metabolism, and can be activated downstream of integrin signaling in certain contexts. Based on transcriptomic data identifying enhanced mTORC1 activity as a possible mediator of β3-dependent metabolic changes, we asked whether mTOR inhibition could restore chemosensitivity in BC bone metastases. In mice bearing chemoresistant, β3-WT metastases, combination of the mTORC1 inhibitor rapamycin with docetaxel yielded synergistic, site-specific attenuation of bone tumor burden. Taken together, our data 1) establish integrin β3 as a mediator of chemoresistance in breast cancer bone metastases, 2) demonstrate a mechanistic link between integrin β3 expression and an alternative metabolic response to docetaxel in resistant cells, and 3) suggest mTORC1 inhibition as a candidate for rational combination with chemotherapy to interrupt treatment resistance in breast cancer bone metastases. Citation Format: Gregory C. Fox, Michael H. Ross, Xinming Su, Yalin Xu, Alison Esser, Elizabeth Cordell, Elizabeth Wilson, Barbara Muz, Ha Dang, Christopher A. Maher, Abdel Kareem Azab, Deborah Veis, Samuel Achilefu, Gregory M. Lanza, Katherine N. Weilbaecher. Integrin beta-3 signaling links chemoresistance and mitochondrial metabolism in breast cancer bone metastases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2613.
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- 2020
27. Treatment with eucalyptol mitigates cigarette smoke-induced lung injury through suppressing ICAM-1 gene expression
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Bing Dai, Yi Tian Sun, Jian Kang, Miao He, Xinming Su, and Na Yu
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Male ,inflammatory cells ,medicine.medical_treatment ,Biophysics ,Down-Regulation ,Lung injury ,Biochemistry ,Cigarette Smoking ,Pulmonary function testing ,Rats, Sprague-Dawley ,Andrology ,Pulmonary Disease, Chronic Obstructive ,03 medical and health sciences ,0302 clinical medicine ,Anti-Infective Agents ,medicine ,Animals ,030212 general & internal medicine ,Molecular Biology ,Research Articles ,ICAM-1 ,COPD ,Eucalyptol ,Lung ,medicine.diagnostic_test ,business.industry ,cigarette smoke ,cytokines ICAM-1 ,lung function ,Lung Injury ,Cell Biology ,respiratory system ,Intercellular Adhesion Molecule-1 ,Intercellular adhesion molecule ,medicine.disease ,respiratory tract diseases ,Bronchoalveolar lavage ,Cytokine ,medicine.anatomical_structure ,030228 respiratory system ,Tobacco Smoke Pollution ,business ,Research Article - Abstract
The present study was conducted to investigate the clinical significance of Eucalyptol in treating cigarette smoke-induced lung injury with the potential mechanism involved in the event. Rats were exposed to air (control) and cigarette smoke (smoking) after they were treated with Eucalyptol (260 mg/kg) orally once a day for 12 weeks. Cell counts of bronchoalveolar lavage fluid (BALF), measurements of mean liner intercept (MLI) and mean alveolar number (MAN), and lung function test were executed in experimental animals. Contents of cytokines and intercellular adhesion molecule (ICAM)-1 in BALF and ICAM-1 protein and mRNA expression in lung tissues were determined by ELISA, immunohistochemistry (IHC), and RT-PCR, respectively. A rat model of chronic obstructive pulmonary disease (COPD) displayed declining lung function, increased cell counts and cytokine production in BALF, and emphysema-like lesions in cigarette smoke-exposed lungs compared with the controls (all P
- Published
- 2018
28. Inhibition of the Stromal p38MAPK/MK2 Pathway Limits Breast Cancer Metastases and Chemotherapy-Induced Bone Loss
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Douglas V. Faget, Bhavna Murali, Elise Alspach, Gabriel Mbalaviele, Qihao Ren, Chun Wang, Radia M. Johnson, Michael H. Ross, Sheila A. Stewart, Kevin C. Flanagan, Barry L. Burnette, Morag Park, Xianmin Luo, Tina Gruosso, Katherine N. Weilbaecher, Xinming Su, Kathleen M. Leahy, Yujie Fu, and Joseph B. Monahan
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0301 basic medicine ,Cancer Research ,Stromal cell ,Paclitaxel ,MAP Kinase Signaling System ,Administration, Oral ,Osteoclasts ,Antineoplastic Agents ,Bone Neoplasms ,Breast Neoplasms ,Protein Serine-Threonine Kinases ,p38 Mitogen-Activated Protein Kinases ,Bone and Bones ,Article ,03 medical and health sciences ,Mice ,Breast cancer ,Drug Therapy ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Neoplasm Metastasis ,Tumor microenvironment ,Kinase ,business.industry ,Macrophages ,Intracellular Signaling Peptides and Proteins ,Induction chemotherapy ,Cancer ,Induction Chemotherapy ,medicine.disease ,Prognosis ,Metastatic breast cancer ,030104 developmental biology ,HEK293 Cells ,Oncology ,Tumor progression ,Cancer research ,Disease Progression ,Quality of Life ,Female ,Stromal Cells ,business - Abstract
The role of the stromal compartment in tumor progression is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells, and its expression levels correlate with poor prognosis. This observation led us to investigate whether inhibition of p38MAPKα could reduce breast cancer metastases in a clinically relevant model. Orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase MK2 each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. This effect was primarily mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity that drastically affects quality of life for patients with cancer. These data underscore the vital role played by stromal-derived factors in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Significance: Pharmacologically targeting the stromal p38MAPK-MK2 pathway limits metastatic breast cancer growth, preserves bone quality, and extends survival. Cancer Res; 78(19); 5618–30. ©2018 AACR.
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- 2018
29. Association between lipid profile and the prevalence of asthma: a meta-analysis and systemic review
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Lingfei Kong, Yuan Ren, Menglu Li, Jian Kang, Xinming Su, and Xuan Zhao
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medicine.medical_specialty ,03 medical and health sciences ,0302 clinical medicine ,Total cholesterol ,Internal medicine ,Prevalence ,Medicine ,Humans ,030212 general & internal medicine ,Triglycerides ,Asthma ,Dyslipidemias ,medicine.diagnostic_test ,business.industry ,Cholesterol, HDL ,General Medicine ,Cholesterol, LDL ,medicine.disease ,Lipids ,Endocrinology ,Cholesterol ,030228 respiratory system ,Meta-analysis ,lipids (amino acids, peptides, and proteins) ,business ,Lipid profile ,Lipoprotein - Abstract
Objective: To explore the association of asthma with serum levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and triglyceride. Methods: PubMed, Cochrane, and Embase databases were systematically searched through November 2015 using the following search terms: dyslipidemia, HDL, LDL, triglyceride, cholesterol, and asthma. Eligible studies included randomized controlled trials (RCTs), retrospective, cohort, and cross-sectional studies. Sensitivity analysis and publication bias were performed. Results: Twenty studies were included in the analysis, with a total 32,604 patients (3,458 in the asthma group and 29,146 in the control group). The pooled analysis found that the mean difference between groups was significantly higher in the asthma group for levels of LDL (6.026 mg/dL, 95% CI = 2.696–9.356, p p = .002) compared with the control group. No association was observed between asthma and control groups for levels of HDL (mean difference = –0.728, 95% CI = –3.146–1.691, p = .555) or triglycerides (mean difference = 1.436, 95% CI = –2.768–5.640, p = .503). Conclusions: Levels of LDL and total cholesterol were higher in patients with asthma than non-asthmatic patients.
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- 2018
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30. Eucalyptol protects lungs against bacterial invasion through attenuating ciliated cell damage and suppressing MUC5AC expression
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Jian Kang, Xinming Su, Bing Dai, Miao He, Na Yu, and Yi‐Tian Sun
- Subjects
0301 basic medicine ,Male ,Physiology ,Clinical Biochemistry ,Down-Regulation ,Bacterial growth ,Mucin 5AC ,Microbiology ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Smoke ,medicine ,Animals ,Cilia ,Lung ,Messenger RNA ,Eucalyptol ,medicine.diagnostic_test ,Bacteria ,Chemistry ,Ciliated columnar epithelium ,Epithelial Cells ,Cell Biology ,Tobacco Products ,respiratory system ,Mucus ,Bacterial Load ,respiratory tract diseases ,Anti-Bacterial Agents ,Disease Models, Animal ,030104 developmental biology ,Bronchoalveolar lavage ,medicine.anatomical_structure ,030228 respiratory system ,Host-Pathogen Interactions ,Airway - Abstract
This study was conducted to investigate whether eucalyptol plays a role in influencing bacterial growth in cigarette smoke-exposed lungs. Rats were exposed to air (control) and cigarette smoke (smoking) in the presence and absence of eucalyptol (260 mg/day). Morphological analysis of lung structures and status of airway mucous production were observed under microscope. Pathological changes of ciliated columnar epithelium in airways were examined using transmission electron microscopy. MUC5AC protein and messenger RNA (mRNA) expression in bronchoalveolar lavage fluid (BALF) and lungs were determined. Application of eucalyptol reduced pulmonary bullae formation and airway mucus overproduction in the smoke-exposed lungs. Treatment with eucalyptol attenuated ciliated cell damage in cigarette smoke-exposed lungs. Bacterial colonies of lungs were obviously lower in the eucalyptol-treated rats than that in the smoking rats (p < 0.01). Treatment with eucalyptol reduced the counts of bacterial colonization residing in the challenged lungs (p < 0.01). Application of eucalyptol not only decreased MUC5AC protein expression in BALF and tobacco-exposed lungs but also suppressed its mRNA expression in the lungs (all p < 0.05). Intervention of eucalyptol benefits elimination of bacterial organisms from tobacco-exposed lungs through attenuating ciliated cell damage and suppressing MUC5AC expression in the lungs.
- Published
- 2017
31. Bone-induced expression of integrin β3 enables targeted nanotherapy of breast cancer metastases
- Author
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Yalin Xu, Dipanjan Pan, Grace Hu, Gregory C. Fox, Khalid S. Mohammad, Xiaoxia Yang, Joshua S. Novack, Deborah V. Novack, Alison K. Esser, Thomas J. Walsh, James A. J. Fitzpatrick, Anne H. Schmieder, Graham A. Colditz, Gabriel H. Lukaszewicz, David L. Waning, Katherine N. Weilbaecher, Gregory M. Lanza, Elizabeth Cordell, Xinming Su, Theresa A. Guise, and Michael H. Ross
- Subjects
0301 basic medicine ,CA15-3 ,Oncology ,Cancer Research ,medicine.medical_specialty ,Mice, Nude ,Bone Neoplasms ,Breast Neoplasms ,Docetaxel ,Article ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,Transforming Growth Factor beta ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Mice, Inbred BALB C ,biology ,business.industry ,Integrin beta3 ,Cancer ,Transforming growth factor beta ,medicine.disease ,Integrin alphaVbeta3 ,Metastatic breast cancer ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,biology.protein ,Nanoparticles ,Female ,Taxoids ,business ,medicine.drug ,Signal Transduction - Abstract
Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site. Cancer Res; 77(22); 6299–312. ©2017 AACR.
- Published
- 2017
32. Effectiveness of inhaled corticosteroids in the treatment of acute asthma in children in the emergency department: A meta-analysis
- Author
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Na Yu, Jian Kang, Lingfei Kong, and Xinming Su
- Subjects
Budesonide ,medicine.medical_specialty ,Administration, Oral ,Placebo ,law.invention ,Randomized controlled trial ,Adrenal Cortex Hormones ,law ,Internal medicine ,Intensive care ,Administration, Inhalation ,medicine ,Flunisolide ,Humans ,Child ,Intensive care medicine ,Randomized Controlled Trials as Topic ,Asthma ,Fluticasone ,Diagnostic Tests, Routine ,business.industry ,General Medicine ,Emergency department ,medicine.disease ,Acute Disease ,Emergency Service, Hospital ,business ,medicine.drug - Abstract
This meta-analysis aimed to compare the treatment of an acute asthma attack in children in the emergency department (ED) with inhaled corticosteroids (ICS) versus placebo or oral systemic corticosteroids (SC) as assessed by the hospital admission rates.After searching Medline, Cochrane, EMBASE, and Google Scholar, we identified ten articles that described randomized controlled trials of ICS versus placebo or oral SC for treating children with asthma attacks in the ED. Primary outcome was the hospital admission rate as defined as inpatient admission or admission into intensive care unit.Across the studies, a range of drugs and doses were used. For ICS, six studies administered budesonide (dose range: 0.4-2 mg), and three studies gave fluticasone/flunisolide (dose range: 0.5-2 mg). Six studies administered oral prednisone (dose range: 1-2 mg/kg/day), and four studies gave placebo. The rate of hospital admissions in patients treated with ICS was not significantly higher than those treated with oral SC. The rate of hospital admissions in patients treated with ICS was significantly lower than those treated with placebo.ICS treatment of children with acute asthma exacerbations showed a similar rate of hospitalization as those treated by SC.
- Published
- 2013
33. Antagonism of Inhibitor of Apoptosis Proteins Increases Bone Metastasis via Unexpected Osteoclast Activation
- Author
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Suwanna Vangveravong, Rong Zeng, Katherine N. Weilbaecher, Deborah V. Novack, Paras Vora, Robert H. Mach, Chang Yang, Xinming Su, Jennifer L. Davis, Lynne Collins, Roberta Faccio, and David Piwnica-Worms
- Subjects
musculoskeletal diseases ,medicine.medical_specialty ,Osteolysis ,business.industry ,Bone metastasis ,medicine.disease ,Inhibitor of apoptosis ,Metastasis ,body regions ,Bone Density Conservation Agents ,Endocrinology ,Zoledronic acid ,medicine.anatomical_structure ,Oncology ,Apoptosis ,Osteoclast ,Internal medicine ,medicine ,Cancer research ,business ,medicine.drug - Abstract
Inhibitor of apoptosis (IAP) proteins play a central role in many types of cancer, and IAP antagonists are in development as anticancer agents. IAP antagonists cause apoptosis in many cells, but they also activate alternative NF-κB signaling through NF-κB–inducing kinase (NIK), which regulates osteoclasts. In bone metastasis, a positive feedback loop between tumors and osteoclasts promotes tumor growth and osteolysis. We therefore tested the effect of IAP antagonists on the bone microenvironment for metastasis. In both drug-sensitive and drug-resistant tumors, growth in bone was favored, as compared with other sites during IAP antagonist treatment. These drugs also caused osteoporosis and increased osteoclastogenesis, mediated by NIK, and enhanced tumor-associated osteolysis. Cotreatment with zoledronic acid, a potent osteoclast inhibitor, reduced IAP antagonist–enhanced tumor growth in bone and osteolysis. Thus, IAP antagonist–based cancer treatment may be compromised by osteoporosis and enhanced skeletal metastasis, which may be prevented by antiresorptive agents. Significance: Although IAP antagonists are a class of anticancer agents with proven efficacy in multiple cancers, we show that these agents can paradoxically increase tumor growth and metastasis in the bone by stabilizing NIK and activating the alternative NF-κB pathway in osteoclasts. Future clinical trials of IAP antagonist–based therapy may require detailed examination of this potential for enhanced bone metastasis and osteoporosis, as well as possible combination with antiresorptive agents. Cancer Discov; 3(2); 212–23. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 125
- Published
- 2013
34. Acetate metabolism in Multiple Myeloma identifies11C-Acetate PET as a novel strategy to image bone disease and response to treatment in preclinical models
- Author
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Francesca Fontana, Xia Ge, Xinming Su, Jingyu Xiang, Simone Cenci, Roberto Civitelli, Kooresh Shoghi, Walter Akers, Andre D'Avignon, Monica Shokeen, and Katherine Weilbaecher
- Subjects
Bone disease ,business.industry ,medicine ,General Medicine ,Pharmacology ,medicine.disease ,business ,Response to treatment ,Acetate metabolism ,Multiple myeloma - Published
- 2016
35. The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
- Author
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Michael J. Rogers, Özge Uluçkan, Desiree H. Floyd, Alun Hughes, Pamela B. Conley, Mark C. Eagleton, Lynne Collins, Emanuela Heller, Deborah V. Novack, Kaiming Wu, Dorota Grabowska, Hongju Deng, Xinming Su, Katherine N. Weilbaecher, Michelle A. Hurchla, Jochen G. Schneider, Jingyu Xiang, David Piwnica-Worms, Sarah Townsley, Wei Zou, Angela C. Hirbe, Clarissa S. Craft, and Thomas H. Steinberg
- Subjects
medicine.medical_specialty ,P2Y receptor ,Osteolysis ,General Medicine ,Biology ,medicine.disease ,Bone resorption ,Bone remodeling ,Adenosine diphosphate ,chemistry.chemical_compound ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Osteoclast ,Internal medicine ,medicine ,Extracellular ,Platelet - Abstract
The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12–/– OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12–/–, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3–/–) OCs, but its effects were substantially blunted in P2ry12–/– OCs. In vivo, P2ry12–/– mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.
- Published
- 2012
36. Triethanolamine as an Additive in the Electrophoretic Deposition of TiTe3O8 Thick Films
- Author
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Paula M. Vilarinho, Xinming Su, and Ai Ying Wu
- Subjects
Chromatography ,Materials science ,Mechanical Engineering ,Suspension (chemistry) ,chemistry.chemical_compound ,Electrophoretic deposition ,chemistry ,Chemical engineering ,Mechanics of Materials ,Homogeneous ,Triethanolamine ,Zeta potential ,Acetone ,medicine ,General Materials Science ,Fourier transform infrared spectroscopy ,Stabilizer (chemistry) ,medicine.drug - Abstract
A successful electrophoretic deposition (EPD) markedly depends on the stability of the suspension. In this study the role of Triethanolamine (TEA) as a stabilizer in EPD of thick films of TiTe3O8 is presented. TiTe3O8 powders were synthesized via a conventional solid-state-reaction method and dispersed in acetone with and without TEA. The stability of the suspensions was addressed by zeta-potential, UV light and FTIR measurements. The specific adsorption of TEA to TiTe3O8 particles results in a high zeta potential and improved stability of the suspensions, allowing the preparation of high quality TiTe3O8 thick films on Pt coated Si substrates. TiTe3O8 films sintered at 700 °C are dense and homogeneous.
- Published
- 2012
37. Human tumor-infiltrating Th17 cells have the capacity to differentiate into IFN-γ+ and FOXP3+ T cells with potent suppressive function
- Author
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Joyce M. Koenig, Daniel F. Hoft, Yanping Zhang, Jian Ye, Eddy C. Hsueh, Guangyong Peng, and Xinming Su
- Subjects
Cellular differentiation ,medicine.medical_treatment ,Immunology ,Receptors, Antigen, T-Cell ,chemical and pharmacologic phenomena ,Biology ,T-Lymphocytes, Regulatory ,Interferon-gamma ,Lymphocytes, Tumor-Infiltrating ,Antigen ,medicine ,Humans ,Immunology and Allergy ,Cell Lineage ,IL-2 receptor ,Cells, Cultured ,T-cell receptor ,FOXP3 ,Cell Differentiation ,Forkhead Transcription Factors ,hemic and immune systems ,Cell biology ,Cytokine ,Gene Expression Regulation ,Th17 Cells ,Interleukin 17 ,Reprogramming - Abstract
Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD4(+) Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-γ-producing and FOXP3(+) cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-γ and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4(+) CD25(+) Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.
- Published
- 2011
38. EGF-recruited JunD/c-fos complexes activate CD2AP gene promoter and suppress apoptosis in renal tubular epithelial cells
- Author
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Jie-Qing Chen, Chao Lu, Xinming Su, Wei Ren, Sheng-Hua Wu, and Guo-Ping Zhou
- Subjects
Chromatin Immunoprecipitation ,Blotting, Western ,Molecular Sequence Data ,Apoptosis ,Cell Separation ,c-Fos ,Cell Line ,Kidney Tubules, Proximal ,Epidermal growth factor ,Genetics ,medicine ,Humans ,RNA, Small Interfering ,Promoter Regions, Genetic ,Adaptor Proteins, Signal Transducing ,DNA Primers ,Kidney ,Base Sequence ,Epidermal Growth Factor ,biology ,Angiotensin II ,Genes, fos ,Signal transducing adaptor protein ,General Medicine ,Transfection ,Blotting, Northern ,Molecular biology ,Cytoskeletal Proteins ,medicine.anatomical_structure ,Cell culture ,Mutagenesis, Site-Directed ,biology.protein ,Signal transduction - Abstract
CD2-associated protein (CD2AP) plays a critical role in the maintenance of the kidney filtration barrier. In this study, we showed that epidermal growth factor (EGF) led to an increase of the CD2AP protein and mRNA in the human renal proximal tubular epithelial cell line HK-2 cells, which was due to the elevation of CD2AP promoter activity. Upon deletion and mutation analysis, electrophoretic mobility shift assays and chromatin immunoprecipitation, an AP-1-like element within CD2AP promoter was characterized, by which EGF recruited c-fos and JunD, two components of AP-1, to the human CD2AP gene promoter and suppressed angiotensin II-induced apoptosis in HK-2 cells. Specific siRNA was synthesized to knock down the human CD2AP gene in HK-2 cells. We found that CD2AP deficiency attenuated the inhibitory effects of EGF and predisposed the renal tubular epithelial cells to undergo angiotensin II-induced apoptosis. Furthermore, EGF-induced increases of CD2AP protein and mRNA expressions in HK-2 cells were significantly inhibited by the transfection of dominant negative JunD or c-fos vector, which was in parallel with a marked reduction of antiapoptotic effect of EGF. These results indicated that the antiapoptotic effect of EGF/CD2AP signal transduction was mediated by JunD and c-fos, at least partially. This study defined a new EGF/AP-1/CD2AP mediated cell-survival signaling, which might be useful to clarify the molecular mechanisms responsible for CD2AP associated kidney diseases.
- Published
- 2009
39. Spatial and Phenotypic Characterization of Vascular Remodeling in a Mouse Model of Asthma
- Author
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Lei Zhang, Ken Ohta, Namiko Taniuchi, Hiroyuki Tashimo, Enjing Jin, Naomi Yamashita, Mohammad Ghazizadeh, Masakazu Fujiwara, Xinming Su, and Oichi Kawanami
- Subjects
Vascular Endothelial Growth Factor A ,Pathology ,medicine.medical_specialty ,Endothelium ,Gene Expression ,Chronic inflammatory disease ,Pathology and Forensic Medicine ,Microcirculation ,Neovascularization ,Mice ,chemistry.chemical_compound ,von Willebrand Factor ,medicine ,Animals ,Lung ,Molecular Biology ,Asthma ,Vascular Endothelial Growth Factor Receptor-1 ,Neovascularization, Pathologic ,business.industry ,Cell Biology ,General Medicine ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Phenotype ,respiratory tract diseases ,Platelet Endothelial Cell Adhesion Molecule-1 ,Trachea ,Vascular endothelial growth factor ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Immunology ,Endothelium, Vascular ,medicine.symptom ,business ,Biomarkers - Abstract
Asthma is a chronic inflammatory disease characterized by airway wall remodeling in which vascular remodeling is thought to be a main contributor. Vascular endothelial growth factor (VEGF) is known as a major regulator of angiogenesis and enhancer of vascular permeability. Here, we define the spatial nature of vascular remodeling and the role of VEGF and its receptors (Flt-1 and Flk-1) in the allergic response in mice (A/J) susceptible to the development of allergen-induced airway hyperresponsiveness using morphometric and quantitative approaches. Increased vascularity, vasodilatation, and endothelial cell proliferation were found in the tracheal and bronchial walls in the early and late phases of asthma. Vascular changes were observed not only in small vessels but also in larger vessels. In contrast to normal control, lung tissue from the asthma model showed dual expression for CD31 and von Willebrand factor in the endothelial cells and α-smooth muscle actin and desmin in the mural cells of the vessels, suggesting a phenotypic and functional transformation. The mRNA levels of VEGF isoforms, VEGF164 and VEGF188, were significantly increased in the tracheal and lung tissue, respectively. In addition, the mRNA level of VEGF receptor Flk-1 was significantly increased in the trachea. These results establish the existence of vascular remodeling in the airways in a mouse model of allergic asthma and support a key role for the expression of unique VEGF isoform genes as mediators of structural changes.
- Published
- 2008
40. Association of Dietary Vitamin A and β-Carotene Intake with the Risk of Lung Cancer: A Meta-Analysis of 19 Publications
- Author
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Na Yu, Bing Dai, Jian Kang, Zan-feng Wang, and Xinming Su
- Subjects
Vitamin ,medicine.medical_specialty ,Lung Neoplasms ,Databases, Factual ,medicine.medical_treatment ,lcsh:TX341-641 ,Review ,Dietary vitamin ,Sensitivity and Specificity ,vitamin A ,chemistry.chemical_compound ,beta-Carotene ,Risk Factors ,Internal medicine ,β-carotene ,medicine ,Animals ,Humans ,Lung cancer ,Nutrition and Dietetics ,business.industry ,Carotene ,medicine.disease ,beta Carotene ,Surgery ,Diet ,meta-analysis ,Disease Models, Animal ,lung cancer ,chemistry ,Meta-analysis ,Relative risk ,business ,lcsh:Nutrition. Foods and food supply ,Food Science ,Cohort study - Abstract
Whether dietary β-carotene and vitamin A intake protect against lung cancer risk is not clear. Therefore, we performed this meta-analysis to investigate the association between them. The related articles were searched using the databases PubMed and the Web of Knowledge up to May 2015. We used the random-effect model to estimate the relative risk (RR) and their 95% CI. Small-study effect was assessed using Egger’s test. In total, 19 studies comprising 10,261 lung cancer cases met the inclusion criteria. The pooled RR and their 95% CI was 0.855 (0.739–0.989) for higher category of dietary vitamin A intake and lung cancer risk, especially among Asian populations and in the cohort studies. Evidence from 18 studies suggested that higher category of dietary β-carotene intake could reduce lung cancer risk (0.768 (0.675–0.874)).The associations were also significant in American and Asian populations. In conclusions, higher category of dietary β-carotene and vitamin A intakes could reduce the risk of lung cancer. However, the dose-response analysis was not performed due to the limited data in each individual study. Due to this limitation, further studies with detailed dose, cases and person-years for β-carotene and vitamin A of each category are wanted to assess this dose-response association.
- Published
- 2015
41. Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types
- Author
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Daniel J. Serie, Pengyuan Liu, Xinming Su, Michael H. Tomasson, Graham A. Colditz, Michelle A. Hurchla, William C. Wilson, Katherine N. Weilbaecher, Dingyan Wang, Anthony O. Gramolini, Lan Lu, Julie O'Neal, Xiao-Yan Wen, Liang Chu, Yalin Xu, Ravi Vij, Celine M. Vachon, and Sarah R. Amend
- Subjects
Paraproteinemia ,Somatic cell ,lcsh:Medicine ,Genome-wide association study ,Bone Marrow Cells ,Biology ,Malignancy ,Polymorphism, Single Nucleotide ,Receptors, Tumor Necrosis Factor ,Mice ,medicine ,Animals ,Humans ,Point Mutation ,lcsh:Science ,Exome ,Multiple myeloma ,B-Lymphocytes ,Multidisciplinary ,Macrophages ,lcsh:R ,medicine.disease ,Molecular biology ,Neoplasm Proteins ,Adaptor Proteins, Vesicular Transport ,lcsh:Q ,Stromal Cells ,Multiple Myeloma ,Monoclonal gammopathy of undetermined significance ,SNP array ,Genome-Wide Association Study ,Research Article - Abstract
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy of antibody-producing plasma B-cells. The genetic basis of MGUS and its progression to MM remains poorly understood. C57BL/KaLwRij (KaLwRij) is a spontaneously-derived inbred mouse strain with a high frequency of benign idiopathic paraproteinemia (BIP), a phenotype with similarities to MGUS including progression to MM. Using mouse haplotype analysis, human MM SNP array data, and whole exome and whole genome sequencing of KaLwRij mice, we identified novel KaLwRij gene variants, including deletion of Samsn1 and deleterious point mutations in Tnfrsf22 and Tnfrsf23. These variants significantly affected multiple cell types implicated in MM pathogenesis including B-cells, macrophages, and bone marrow stromal cells. These data demonstrate that multiple cell types contribute to MM development prior to the acquisition of somatic driver mutations in KaLwRij mice, and suggest that MM may an inherently non-cell autonomous malignancy.
- Published
- 2015
42. Abstract 2963: Inhibition of stromal p38MAPK abrogates breast cancer metastasis
- Author
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Kathleen Weilbaecher, Sheila A. Stewart, Roberta Faccio, Yujie Fu, Bhavna Murali, Joseph B. Monahan, Kathlees Leahy, Jasmine Sponagel, Kevin Flannagan, Qiaho Ren, Xianmin Luo, Elise Alspach, and Xinming Su
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Stromal cell ,business.industry ,Internal medicine ,medicine ,Breast cancer metastasis ,business - Abstract
Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that its inhibition significantly reduced breast cancer bone metastases by specifically targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone. Citation Format: Sheila A. Stewart, Bhavna Murali, Qiaho Ren, Xinming Su, Kevin Flannagan, Xianmin Luo, Jasmine Sponagel, Yujie Fu, Elise Alspach, Kathlees Leahy, Roberta Faccio, Kathleen Weilbaecher, Joseph Monahan. Inhibition of stromal p38MAPK abrogates breast cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2963. doi:10.1158/1538-7445.AM2017-2963
- Published
- 2017
43. Abstract 2198: Integrin αvβ3-targeted lipase-labile docetaxel-prodrug micelles preferentially treat breast cancer bone metastases
- Author
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Alison K. Esser, Michael H. Ross, Dipanjan Pan, Anne H. Schmieder, Gregory M. Lanza, Katherine N. Weilbaecher, Xiaoxia Yang, Xinming Su, and Grace Cui
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,business.industry ,Integrin ,Cancer ,Prodrug ,medicine.disease ,Metastatic breast cancer ,Metastasis ,Breast cancer ,Docetaxel ,Internal medicine ,Cancer research ,biology.protein ,Medicine ,business ,Ex vivo ,medicine.drug - Abstract
Background: Bone metastases occur in 70% of metastatic breast cancer patients and are a leading cause of morbidity. Current therapies are often palliative, in part due to a lack of specificity for tumor targets within the bone. Integrin αvβ3 is overexpressed on neo-angiogenic blood vessels, tumor-promoting macrophages, osteoclasts, and more aggressive breast cancer cells, making it an attractive therapeutic target. Objective: The goal of this study was to use Sn2 lipase-labile docetaxel-prodrug nanoparticle, targeted against activated integrin αvβ3, to attenuate breast cancer metastases. Methods: A novel phospholipid-based micelle (∼12.5 nm) was functionalized with a peptidomimetic for activated integrin αvβ3, and designed to carry either rhodamine for fluorescent labeling or Sn2 lipase-labile prodrug of docetaxel (DTX-PD) for drug delivery. For microscopic localization studies, fluorescently labeled micelles were prepared with or without integrin αvβ3-targeting. C57BL/6 female mice received MMTV-PyMT breast cancer cell line (luciferase-labeled) via intracardiac (IC) injection to achieve tumor metastasis in all major organs. On day 8 post-IC injection, micelle preparations were administered i.v. and circulated within C57BL/6 mice for 3 hours prior to sacrifice and tissue collection. For drug efficacy studies, Sn2 lipase-labile docetaxel-prodrug was incorporated into αvβ3-micelles (αvβ3-DTX-PD). C57BL/6 female mice IC injected with MMTV-PyMT cells (luciferase-labeled) were treated with αvβ3-DTX-PD, or molar equivalent dose of free-DTX, or saline. Beginning on day 4 post-IC injection, mice were treated 3 times, once every 3 days (1.85mg/kg DTX per treatment). On day 12 post-IC injection, metastatic burden in the major organs was analyzed via ex vivo bioluminescent imaging. Results: Fluorescent histological analysis of the tibiofemoral bone region showed significant colocalization of αvβ3-micelles with breast cancer bone metastases, as compared with non-targeted micelles (6.5-fold increase, p Conclusion: These findings suggest that the unique elevated expression of integrin αvβ3 within breast cancer bone metastases could be exploited with αvβ3-DTX-PD micelles for effective therapy. Citation Format: Michael H. Ross, Alison K. Esser, Anne H. Schmieder, Grace Cui, Xiaoxia Yang, Xinming Su, Dipanjan Pan, Gregory M. Lanza, Katherine N. Weilbaecher. Integrin αvβ3-targeted lipase-labile docetaxel-prodrug micelles preferentially treat breast cancer bone metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2198.
- Published
- 2016
44. Abstract LB-270: Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases
- Author
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Kevin C. Flanagan, Bhavna Murali, Kathleen M. Leahy, Sheila A. Stewart, Xianmin Luo, Xinming Su, Yujie Fu, Jasmin Sponagel, Elise Alspach, Katherine Weilbeacher, and Joseph B. Monahan
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Stromal cell ,business.industry ,Bone metastasis ,Cancer ,medicine.disease ,Metastatic breast cancer ,Primary tumor ,Metastasis ,Breast cancer ,Zoledronic acid ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Bone metastasis is a devastating and fatal complication of breast cancer for which we lack effective therapies. Thus, identifying therapies that effectively limit metastases will significantly reduce comorbidities and improve long-term survival. Recently we demonstrated that the p38MAPK pathway sustains the pro-tumorigenic senescence-associated secretory phenotype (SASP) and targeting this pathway limits the tumor-promoting capabilities of senescent cells and cancer-associated fibroblasts (CAFs). Because we found that a significant percentage of p38MAPK-dependent SASP factors are expressed in the stroma associated with breast cancer lesions, we asked whether targeting p38MAPK could limit primary and metastatic breast cancer growth. While p38MAPK inhibition modestly limited primary tumor growth, we found that this inhibition significantly reduced breast cancer bone metastases by targeting the stromal compartment. Further, p38MAPK inhibition was as effective as paclitaxel at limiting tumor growth in the bone but in contrast to paclitaxel, which failed to protect from cancer-induced bone loss, p38MAPK inhibition also protected against devastating bone loss. This contrasts our p38MAPK approach from zoledronic acid, which limits bone loss but fails to slow tumor growth in already engrafted tumors. Analysis of the mechanism(s) responsible for this reduced metastasis suggests that p38MAPK inhibition specifically targets reactive and/or senescent osteoblasts within the bones of animals harboring metastatic lesions. Because we find that senescent osteoblasts are present in human bone, we postulate that they promote metastatic outgrowth and thus p38MAPK inhibition limits the pro-metastatic activities of these cells. Finally, we will present recent data from our clinically relevant preclinical model that demonstrates that inhibition of the p38MAPK pathway can drastically reduce metastasis from the primary site. We propose that p38MAPK is an important stromal-specific therapy for breast cancer metastasis to the bone. Citation Format: Sheila A. Stewart, Bhavna Murali, Xinming Su, Kevin Flanagan, Jasmin Sponagel, Xianmin Luo, Yujie Fu, Elise Alspach, Kathleen Leahy, Joseph Monahan, Katherine Weilbeacher. Inhibition of the stromal p38MAPK pathway abrogates breast cancer metastases. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-270.
- Published
- 2016
45. Prevalence of Comorbidities in Asthma and Nonasthma Patients
- Author
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Menglu Li, Jian Kang, Lingfei Kong, Xuan Zhao, Yuan Ren, and Xinming Su
- Subjects
medicine.medical_specialty ,Urinary system ,Prevalence ,Comorbidity ,Endocrine System Diseases ,Global Health ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Diabetes mellitus ,medicine ,Humans ,030212 general & internal medicine ,Asthma ,business.industry ,General Medicine ,Odds ratio ,medicine.disease ,Obesity ,Cerebrovascular Disorders ,030228 respiratory system ,Cardiovascular Diseases ,Meta-analysis ,Physical therapy ,business ,Systematic Review and Meta-Analysis ,Research Article - Abstract
This study compares the prevalence rates of comorbidities between asthma and nonasthma control patients reported in the literature. Literature was searched in several electronic databases. After the selection of studies by following précised eligibility criteria, meta-analyses of odds ratios were carried out with subgroup and sensitivity analyses. Eleven studies studying 117,548 asthma patients compared with 443,948 non-asthma controls were included in the meta-analysis. The prevalence of cardiovascular comorbidities (odds ratio (OR): [95% CI] 1.90 [1.70, 2.14]; P
- Published
- 2016
46. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer
- Author
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Andrea Wang-Gillam, Biancamaria Ricci, David G. DeNardo, Lucia D'Amico, Roberta Faccio, David B. Bumpass, Aude Helene Capietto, Ali Zamani, Sheila A. Stewart, Melissa A. Meyer, Zhengfeng Yang, Sahil Mahajan, Katherine N. Weilbaecher, and Xinming Su
- Subjects
musculoskeletal diseases ,0301 basic medicine ,T-Lymphocytes ,T cell ,Immunology ,Biology ,medicine.disease_cause ,Article ,Mice ,03 medical and health sciences ,Immune system ,0302 clinical medicine ,Stroma ,Pancreatic cancer ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Immunology and Allergy ,Myeloid Cells ,beta Catenin ,Research Articles ,030304 developmental biology ,Mice, Knockout ,Tumor microenvironment ,0303 health sciences ,Neoplasms, Experimental ,Cell Biology ,medicine.disease ,3. Good health ,Pancreatic Neoplasms ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Carcinogenesis - Abstract
D’Amico et al. show that Dkk1 exerts immune-suppressive effects by directly targeting β-catenin in murine and human MDSCs and promoting their activation in cancer., Tumor–stroma interactions contribute to tumorigenesis. Tumor cells can educate the stroma at primary and distant sites to facilitate the recruitment of heterogeneous populations of immature myeloid cells, known as myeloid-derived suppressor cells (MDSCs). MDSCs suppress T cell responses and promote tumor proliferation. One outstanding question is how the local and distant stroma modulate MDSCs during tumor progression. Down-regulation of β-catenin is critical for MDSC accumulation and immune suppressive functions in mice and humans. Here, we demonstrate that stroma-derived Dickkopf-1 (Dkk1) targets β-catenin in MDSCs, thus exerting immune suppressive effects during tumor progression. Mice bearing extraskeletal tumors show significantly elevated levels of Dkk1 in bone microenvironment relative to tumor site. Strikingly, Dkk1 neutralization decreases tumor growth and MDSC numbers by rescuing β-catenin in these cells and restores T cell recruitment at the tumor site. Recombinant Dkk1 suppresses β-catenin target genes in MDSCs from mice and humans and anti-Dkk1 loses its antitumor effects in mice lacking β-catenin in myeloid cells or after depletion of MDSCs, demonstrating that Dkk1 directly targets MDSCs. Furthermore, we find a correlation between CD15+ myeloid cells and Dkk1 in pancreatic cancer patients. We establish a novel immunomodulatory role for Dkk1 in regulating tumor-induced immune suppression via targeting β-catenin in MDSCs.
- Published
- 2016
47. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment
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Jochen G. Schneider, Sara Chen, Xinming Su, Leah Goldberg, Marcos Vidal, Emanuela Heller, Jingyu Xiang, Michelle A. Hurchla, Hongju Deng, Fanxin Long, Julie L. Prior, Mary C. Hornick, David Piwnica-Worms, Kyu Sang Joeng, Ross L. Cagan, and Katherine N. Weilbaecher
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Patched ,Patched Receptors ,Cancer Research ,medicine.medical_specialty ,Heterozygote ,Stromal cell ,Mice, Nude ,Osteoclasts ,Bone Neoplasms ,Receptors, Cell Surface ,Biology ,Bone and Bones ,Article ,Cell Line ,Receptors, G-Protein-Coupled ,Paracrine signalling ,Mice ,Osteoclast ,Internal medicine ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Animals ,Humans ,Hedgehog Proteins ,Tumor microenvironment ,Mice, Inbred BALB C ,Veratrum Alkaloids ,Neoplasms, Experimental ,Smoothened Receptor ,Hedgehog signaling pathway ,Patched-1 Receptor ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Cancer research ,Female ,Smoothened ,Signal Transduction - Abstract
Hedgehog (Hh) signaling is implicated in bone development and cellular transformation. Here we show that inhibition of Hh pathway activity inhibits tumor growth through effects on the microenvironment. Pharmacologic inhibition of the Hh effector Smoothened (Smo) increased trabecular bone in vivo and inhibited osteoclastogenesis in vitro. In addition, enhanced Hh signaling due to heterozygosity of the Hh inhibitory receptor Patched (Ptch1+/−) increased bone resorption, suggesting direct regulation of osteoclast (OC) activity by the Hh pathway. Ptch1+/− mice had increased bone metastatic and subcutaneous tumor growth, suggesting that increased Hh activation in host cells promoted tumor growth. Subcutaneous growth of Hh-resistant tumor cells was inhibited by LDE225, a novel orally bioavailable SMO antagonist, consistent with effects on tumor microenvironment. Knockdown of the Hh ligand Sonic Hh (SHH) in these cells decreased subcutaneous tumor growth and decreased stromal cell production of interleukin-6, indicating that tumor-derived Hh ligands stimulated tumor growth in a paracrine fashion. Together our findings show that inhibition of the Hh pathway can reduce tumor burden, regardless of tumor Hh responsiveness, through effects on tumor cells, OCs, and stromal cells within the tumor microenvironment. Hh may be a promising therapeutic target for solid cancers and bone metastases. Cancer Res; 72(4); 897–907. ©2011 AACR.
- Published
- 2011
48. Tumor microenvironments direct the recruitment and expansion of human Th17 cells
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Guangyong Peng, Daniel F. Hoft, Jian Ye, Yanping Zhang, Xinming Su, and Eddy C. Hsueh
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CD4-Positive T-Lymphocytes ,Immunology ,Cell ,chemical and pharmacologic phenomena ,Breast Neoplasms ,Cell Communication ,Biology ,Cancer Vaccines ,Proinflammatory cytokine ,Pathogenesis ,Lymphocytes, Tumor-Infiltrating ,Immunity ,Cell Movement ,Cell Line, Tumor ,medicine ,Immunology and Allergy ,Humans ,Melanoma ,Tumor microenvironment ,Interleukin-17 ,Cancer ,hemic and immune systems ,Cell Differentiation ,Fibroblasts ,medicine.disease ,Coculture Techniques ,Cell biology ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Colonic Neoplasms ,Female ,Ovarian cancer - Abstract
Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their prevalence among tumor-infiltrating lymphocytes (TILs) and function in human tumor immunity remains largely unknown. We have recently demonstrated high percentages of Th17 cells in TILs from ovarian cancer patients, but the mechanisms of accumulation of these Th17 cells in the tumor microenvironment are still unclear. In this study, we further showed elevated Th17 cell populations in the TILs obtained from melanoma and breast and colon cancers, suggesting that development of tumor-infiltrating CD4+ Th17 cells may be a general feature in cancer patients. We then demonstrated that tumor microenvironmental RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells. In addition to their recruitment, we found that tumor cells and tumor-derived fibroblasts produce a proinflammatory cytokine milieu as well as provide cell–cell contact engagement that facilitates the generation and expansion of Th17 cells. We also showed that inflammatory TLR and nucleotide oligomerization binding domain 2 signaling promote the attraction and generation of Th17 cells induced by tumor cells and tumor-derived fibroblasts. These results identify Th17 cells as an important component of human TILs, demonstrate mechanisms involved in the recruitment and regulation of Th17 cells in tumor microenvironments, and provide new insights relevant for the development of novel cancer immunotherapeutic approaches.
- Published
- 2009
49. Inherited Loss of Samsn1 Contributes to Increased Risk of MGUS and MM through Effects on Multiple Cell Types, Including B-Cells, Transformed Myeloma Cells, and Macrophages
- Author
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Dingyan Wang, Pengyuan Liu, Celine M. Vachon, Sarah R. Amend, Michael H. Tomasson, Michelle A. Hurchla, Lan Lu, Ravi Vij, Xinming Su, Liang Chu, Daniel J. Serie, Graham A. Colditz, William C. Wilson, and Katherine N. Weilbaecher
- Subjects
Macrophage colony-stimulating factor ,Stromal cell ,Immunology ,Plasma cell dyscrasia ,Cell Biology ,Hematology ,Plasma cell ,Biology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,medicine ,Cancer research ,Macrophage ,Bone marrow ,Monoclonal gammopathy of undetermined significance ,Interleukin 4 - Abstract
Multiple myeloma (MM) is a malignancy of plasma B-cells that is invariably preceded by monoclonal gammopathy of undetermined significance (MGUS), a pre-neoplastic plasma cell proliferative disorder. C57Bl/KaLwRij (KaLwRij) is a spontaneous inbred mouse strain predisposed to benign idiopathic paraproteinemia (BIP), a plasma cell dyscrasia that parallels many features of human pathology including progression to myeloma. In both humans and mice, the genetic basis for MGUS/MM risk is unknown. We sought to identify the genetic basis for MGUS/MM risk in KaLwRij mice to shed light on genes or pathways that mediate disease risk in humans. Using an integrative approach, we combined KaLwRij x B6 haplotype analysis (418 genes) and a MM patient association study (180 genes) to identify five candidate genes likely to contribute to both murine BIP-susceptibility and human MM risk. Surprisingly, we found KaLwRij mice had homozygous germline deletion of one of the five candidate genes, Samsn1, a putative negative regulator of B-cell activation. Consistent with the reported inhibitory function of SAMSN1 in B-cells, KaLwRij mice had enhanced naïve B-cell response in vitro following stimulation with IL4 and LPS and in vivo following immunization. We found that re-expression of Samsn1 in KaLwRij-derived myeloma cell line 5TGM1 decreased MM tumor growth in vitro, suggesting that loss of Samsn1 contributes to tumor growth in part through a cell intrinsic mechanism. Importantly, germline risk alleles may also influence cell types beyond the pre-malignant B-cells. It is established that the host environment also plays a critical role in supporting myeloma growth in KaLwRij mice. We found that Samsn1 is highly expressed in macrophages, but not in other MM-supportive cell types including osteoclasts and bone marrow stromal cells. Myeloma-associated macrophages play critical roles in supporting tumor growth and are broadly classified as anti-tumor M1 macrophages and tumor-promoting M2 macrophages. Microarray analysis of macrophages from B6 and KaLwRij mice prior to onset of BIP revealed three differentially expressed genes, but only one, Samsn1, is conserved in the human genome. We found that both unpolararized primary peritoneal and MCSF cultured bone marrow macrophages from healthy KaLwRij mice had markedly elevated expression of pro-tumorigenic M2 macrophage markers FIZZ1 and YM1 compared to B6 controls, despite the absence of activating cytokines. To confirm that loss of Samsn1 influenced macrophage activation and M2 polarization, we obtained bone marrow macrophages from mice with a targeted deletion of Samsn1 and found that unpolarized Samsn1-/- cells had similarly increased pro-tumor M2 macrophage marker expression. To evaluate the biologic significance of Samsn1 loss in macrophages on MM tumor growth, we established 5TGM1 MM tumors and injected M2 polarized macrophages from B6, KaLwRij, or Samsn1-/- mice. We found that MM tumor burden was markedly enhanced by the addition of a Samsn1-/- or KaLwRij macrophages compared to wild type macrophages. Thus, we found that loss of Samsn1 in macrophages enhances M2 polarization, prior to MGUS/MM development and can promote established myeloma tumor growth. Together, this data suggests that Samsn1 is a gene contributing to BIP-susceptibility in KaLwRij mice through mutually exclusive functions in multiple cell types including B-cells and macrophages. It is likely that SAMSN1 and its pathway members contribute to human MM progression, and may represent a point for preventative therapeutic intervention. Disclosures No relevant conflicts of interest to declare.
- Published
- 2014
50. Whole Genome Sequence of Multiple Myeloma-Prone C57BL/KaLwRij Mouse Strain Suggests the Origin of Disease Involves Multiple Cell Types
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Dingyan Wang, Liang Chu, Michael H. Tomasson, Michelle A. Hurchla, Celine M. Vachon, Ravi Vij, Xinming Su, Anthony O. Gramolini, Daniel J. Serie, Yalin Xu, Sarah R. Amend, Graham A. Colditz, William C. Wilson, Katherine N. Weilbaecher, Pengyuan Liu, and Lan Lu
- Subjects
Genetics ,Whole genome sequencing ,Cell type ,Mouse strain ,medicine ,Disease ,Biology ,medicine.disease ,Molecular Biology ,Biochemistry ,Multiple myeloma ,Biotechnology
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