Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer
2016-10
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Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer
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2016-10
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The studies presented in this thesis demonstrate a novel link between activation of the FGFR pathway, alterations of the tumor microenvironment and tumor immune response in mammary tumorigenesis. These studies are the first to demonstrate that FGFR signaling in epithelial cells leads to accumulation of the ECM component hyaluronan (HA) through increased production of pro-inflammatory cytokines and activation of the STAT3 pathway. Therapeutic inhibition of STAT3 in vivo reduced HA accumulation, which correlated with reduced tumor burden. Nonetheless, STAT3 inhibition did not result in tumor regression, suggesting that additional pro-tumorigenic mechanisms are able to sustain tumor growth. Previous work has shown that FGFR1 activation leads to rapid recruitment of macrophages with pro-tumorigenic functions. We hypothesized that as TAMs differentiate in the presence of FGFR1-driven IL-6 family of cytokines, the STAT3 signaling pathway would be activated and would influence TAM differentiation. Therefore, further studies focused on delineating the STAT3-dependent phenotype and function of mammary TAMs. Utilizing a mouse model of genetic STAT3 ablation within myeloid cells demonstrated decreased tumor latency and increased tumor growth rate in conditional-STAT3∆/∆ mice compared to control animals. These results provide evidence to the hypothesis that STAT3 activation in different tumor and immune cell populations can result in both pro- and anti-tumor phenotypes, and detailed understanding of these mechanisms is necessary for developing effective therapeutic approaches.
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University of Minnesota Ph.D. dissertation. October 2016. Major: Microbiology, Immunology and Cancer Biology. Advisor: Kathryn Schwertfeger. 1 computer file (PDF); xiv, 107 pages.
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Chuntova, Polly. (2016). Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/183389.
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