Browsing by Subject "tumor microenvironment"
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Item 3D Bone Morphology Alters Gene Expression, Motility, and Drug Responses in Bone Metastatic Tumor Cells(MDPI, 2020-09-21) Dadwal, Ushashi C.; Merkel, Alyssa R.; Page, Jonathan M.; Kwakwa, Kristin A.; Kessler, Michael; Rhoades, Julie A.; Anatomy and Cell Biology, School of MedicinePatients with advanced skeletal metastases arising from primary cancers including breast, lung, and prostate suffer from extreme pain, bone loss, and frequent fractures. While the importance of interactions between bone and tumors is well-established, our understanding of complex cell–cell and cell–microenvironment interactions remains limited in part due to a lack of appropriate 3D bone models. To improve our understanding of the influence of bone morphometric properties on the regulation of tumor-induced bone disease (TIBD), we utilized bone-like 3D scaffolds in vitro and in vivo. Scaffolds were seeded with tumor cells, and changes in cell motility, proliferation, and gene expression were measured. Genes associated with TIBD significantly increased with increasing scaffold rigidity. Drug response differed when tumors were cultured in 3D compared to 2D. Inhibitors for Integrin β3 and TGF-β Receptor II significantly reduced bone-metastatic gene expression in 2D but not 3D, while treatment with the Gli antagonist GANT58 significantly reduced gene expression in both 2D and 3D. When tumor-seeded 3D scaffolds were implanted into mice, infiltration of myeloid progenitors changed in response to pore size and rigidity. This study demonstrates a versatile 3D model of bone used to study the influence of mechanical and morphometric properties of bone on TIBD.Item A C-X-C Chemokine Receptor Type 2–Dominated Cross-talk between Tumor Cells and Macrophages Drives Gastric Cancer Metastasis(AACR, 2019-06) Zhou, Zhijun; Xia, Guanggai; Xiang, Zhen; Liu, Mingyang; Wei, Zhewei; Yan, Jie; Chen, Wei; Zhu, Jintao; Awasthi, Niranjan; Sun, Xiaotian; Fung, Kar-Ming; He, Yulong; Li, Min; Zhang, Changhua; Surgery, School of MedicinePurpose: C-X-C chemokine receptor type 2 (CXCR2) is a key regulator that drives immune suppression and inflammation in tumor microenvironment. CXCR2-targeted therapy has shown promising results in several solid tumors. However, the underlying mechanism of CXCR2-mediated cross-talk between gastric cancer cells and macrophages still remains unclear. Experimental Design: The expression of CXCR2 and its ligands in 155 human gastric cancer tissues was analyzed via immunohistochemistry, and the correlations with clinical characteristics were evaluated. A coculture system was established, and functional assays, including ELISA, transwell, cell viability assay, and qPCR, were performed to determine the role of the CXCR2 signaling axis in promoting gastric cancer growth and metastasis. A xenograft gastric cancer model and a lymph node metastasis model were established to study the function of CXCR2 in vivo. Results: CXCR2 expression is associated with the prognosis of patients with gastric cancer (P = 0.002). Of all the CXCR2 ligands, CXCL1 and CXCL5 can significantly promote migration of gastric cancer cells. Macrophages are the major sources of CXCL1 and CXCL5 in the gastric cancer microenvironment, and promote migration of gastric cancer cells through activating a CXCR2/STAT3 feed-forward loop. Gastric cancer cells secrete TNF-α to induce release of CXCL1 and CXCL5 from macrophages. Inhibiting CXCR2 pathway of gastric cancer cells can suppress migration and metastasis of gastric cancer in vitro and in vivo. Conclusions: Our study suggested a previously uncharacterized mechanism through which gastric cancer cells interact with macrophages to promote tumor growth and metastasis, suggesting that CXCR2 may serve as a promising therapeutic target to treat gastric cancer.Item A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment(Nature Publishing group, 2017-07-28) Nair, Neha; Calle, Anna Sanchez; Zahra, Maram Hussein; Prieto-Vila, Marta; Oo, Aung Ko Ko; Hurley, Laura; Vaidyanath, Arun; Seno, Akimasa; Masuda, Junko; Iwasaki, Yoshiaki; Tanaka, Hiromi; Kasai, Tomonari; Seno, Masaharu; Medical and Molecular Genetics, School of MedicineCancer-associated fibroblasts (CAFs) are one of the most prominent cell types in the stromal compartment of the tumor microenvironment. CAFs support multiple aspects of cancer progression, including tumor initiation, invasion, and metastasis. The heterogeneous nature of the stromal microenvironment is attributed to the multiple sources from which the cells in this compartment originate. The present study provides the first evidence that cancer stem cells (CSCs) are one of the key sources of CAFs in the tumor niche. We generated CSC-like cells by treating mouse induced pluripotent stem cells with conditioned medium from breast cancer cell lines. The resulting cell population expressed both CSC and pluripotency markers, and the sphere-forming CSC-like cells formed subcutaneous tumors in nude mice. Intriguingly, these CSC-like cells always formed heterogeneous populations surrounded by myofibroblast-like cells. Based on this observation, we hypothesized that CSCs could be the source of the CAFs that support tumor maintenance and survival. To address this hypothesis, we induced the differentiation of spheres and purified the myofibroblast-like cells. The resulting cells exhibited a CAF-like phenotype, suggesting that they had differentiated into the subpopulations of cells that support CSC self-renewal. These findings provide novel insights into the dynamic interplay between various microenvironmental factors and CAFs in the CSC niche.Item Identification of Topological Features in Renal Tumor Microenvironment Associated with Patient Survival(Oxford, 2018-03) Cheng, Jun; Mo, Xiaokui; Wang, Xusheng; Parwani, Anil; Feng, Qianjin; Huang, Kun; Medicine, School of MedicineMotivation As a highly heterogeneous disease, the progression of tumor is not only achieved by unlimited growth of the tumor cells, but also supported, stimulated, and nurtured by the microenvironment around it. However, traditional qualitative and/or semi-quantitative parameters obtained by pathologist’s visual examination have very limited capability to capture this interaction between tumor and its microenvironment. With the advent of digital pathology, computerized image analysis may provide a better tumor characterization and give new insights into this problem. Results We propose a novel bioimage informatics pipeline for automatically characterizing the topological organization of different cell patterns in the tumor microenvironment. We apply this pipeline to the only publicly available large histopathology image dataset for a cohort of 190 patients with papillary renal cell carcinoma obtained from The Cancer Genome Atlas project. Experimental results show that the proposed topological features can successfully stratify early- and middle-stage patients with distinct survival, and show superior performance to traditional clinical features and cellular morphological and intensity features. The proposed features not only provide new insights into the topological organizations of cancers, but also can be integrated with genomic data in future studies to develop new integrative biomarkers.Item Modeling Pancreatic Cancer Tumor Microenvironment using a Microfluidics Culture System(Office of the Vice Chancellor for Research, 2016-04-08) Ajayi, Tolulope O.; Korc, Murray; Conteh, AbassPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, with an overall five year survival rate of 7%. This is partly due to the lack of effective models that simulate the complex PDAC tumor microenvironment and allow for high throughput drug screening. Some of the key features of the PDAC tumor microenvironment are the presence of a dense stroma which impedes effective drug delivery to the pancreatic cancer cells (PCCs), as well as the presence of cancer associated fibroblasts (CAFs) that have been shown to modulate disease progression. The objective of this project is to develop an in vitro microfluidic cell culture system that allows researchers to recapitulate the PDAC tumor environment. The system, Tumor-Microenvironment-on-Chip (T-MOC) is manufactured using a replica molding technique. The chip consist of two polydimethylsiloxane (PDMS) layers separated by a porous membrane for gas exchange. This device forms an enclosed transparent device with input channel for cell entry and inner channels which mimic fluidic transport found in vivo. To analyze the potential of the device to simulate in vivo conditions, PCCs (GFP+) and CAFs (RFP+) were co-cultured with collagen and inserted into the device. Initial data analysis indicates that the device supports the growth of PCCs and allows formation of 3D tumor spheroids. In addition, analysis of GFP and RFP intensity demonstrated the effect of CAFs on PCCs growth, which diminished PCCs growth. This provides evidence that the microfluidic device can be used to replicate tumor environment allowing for future studies to screen potential drug candidates before in vivo studies.Item Molecular classification and biomarkers of clinical outcome in breast ductal carcinoma in situ: Analysis of TBCRC 038 and RAHBT cohorts(Elsevier, 2022-12-12) Strand, Siri H.; Rivero-Gutiérrez, Belén; Houlahan, Kathleen E.; Seoane, Jose A.; King, Lorraine M.; Risom, Tyler; Simpson, Lunden A.; Vennam, Sujay; Khan, Aziz; Cisneros, Luis; Hardman, Timothy; Harmon, Bryan; Couch, Fergus; Gallagher, Kristalyn; Kilgore, Mark; Wei, Shi; DeMichele, Angela; King, Tari; McAuliffe, Priscilla F.; Nangia, Julie; Lee, Joanna; Tseng, Jennifer; Storniolo, Anna Maria; Thompson, Alastair M.; Gupta, Gaorav P.; Burns, Robyn; Veis, Deborah J.; DeSchryver, Katherine; Zhu, Chunfang; Matusiak, Magdalena; Wang, Jason; Zhu, Shirley X.; Tappenden, Jen; Ding, Daisy Yi; Zhang, Dadong; Luo, Jingqin; Jiang, Shu; Varma, Sushama; Anderson, Lauren; Straub, Cody; Srivastava, Sucheta; Curtis, Christina; Tibshirani , Rob; Angelo, Robert Michael; Hall , Allison; Owzar , Kouros; Polyak , Kornelia; Maley, Carlo; Marks, Jeffrey R.; Colditz, Graham A.; Hwang, E. Shelley; West , Robert B.; Medicine, School of MedicineDuctal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We perform multiscale, integrated molecular profiling of DCIS with clinical outcomes by analyzing 774 DCIS samples from 542 patients with 7.3 years median follow-up from the Translational Breast Cancer Research Consortium 038 study and the Resource of Archival Breast Tissue cohorts. We identify 812 genes associated with ipsilateral recurrence within 5 years from treatment and develop a classifier that predicts DCIS or IBC recurrence in both cohorts. Pathways associated with recurrence include proliferation, immune response, and metabolism. Distinct stromal expression patterns and immune cell compositions are identified. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.Item Tumor microenvironment and immunology of ovarian cancer: 12th Biennial Rivkin Center Ovarian Cancer Research Symposium(BMJ, 2019) Mitra, Anirban K.; Yang-Hartwich, Yang; Medical and Molecular Genetics, School of MedicineThe 12th Biennial Ovarian Cancer Research Symposium organized by the Rivkin Center for Ovarian Cancer and the American Association for Cancer Research held on September 13–15, 2018 covered cutting edge and relevant research topics in ovarian cancer biology and therapy. Sessions included detection and prevention, genomics and molecular mechanisms, tumor microenvironment and immunology, novel therapeutics, and an education session. In this article we provide an overview of the key findings presented in the tumor microenvironment and immunology session.