Browsing by Subject "macrophages"
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Item Contributions Of Signal Transducer And Activator Of Transcription 3 To Tumor And Immune Cell Functions In Breast Cancer(2016-10) Chuntova, PollyThe 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.Item CONTRIBUTIONS OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION PROTEINS TO TUMOR-ASSOCIATED MACROPHAGE FUNCTION IN BREAST CANCER(2021-05) Jesser, EmilyThe Janus Kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) signaling pathway is activated in breast cancer and when hyperactive, can influence uncontrollable proliferation and inflammation. Therapies in clinical trials for breast cancer aim to inhibit JAK/STAT to turn off the “switch” in tumors signaling for growth and proliferation. The studies performed in this dissertation investigate how these inhibitors impact the tumor microenvironment. We have demonstrated that although inhibition of the JAK/STAT pathway may act on primary tumor cells directly, this alters a delicate balance in the microenvironment that leads to macrophage-mediated tumor cell therapeutic resistance and proliferation. Using genetic models of STAT3 or STAT5-specific deletion, we sought to determine the contributions of these individual transcription factors to macrophage function in the tumor microenvironment. As it has not be well-studied in breast cancer to date, we further investigated how STAT5 signaling regulates tumor-associated macrophages. We demonstrated disruption of STAT5 signaling in macrophages impedes their expression of genes associated with the anti-tumor immune response, as well as increased factors related to tissue remodeling and enhanced metastatic processes. Taken all together, these studies demonstrate the critical role macrophages play in influencing the progression or restraint of the spread of breast cancer. Further understanding how specific JAK/STAT signaling components control pro- and anti-tumor responses in these cells will be vital for determining a patient’s treatment course as well as allowing for the potential discovery of novel therapeutics.Item Microfluidic Model Systems to Evaluate Endothelial Cell Phenotype in Disease(2020-02) Hargis, GenevaMacrophages are known contributors to cancer progression in the primary site, but significantly less is known about their roles in secondary tumor formation. They are likely involved in tumor cell adhesion and transmigration of endothelial cells in the secondary site since macrophages are integral conductors of immune cell recruitment during the immune response and experimental evidence indicates that macrophages recruited to the secondary site before the arrival of tumor cells. However, current model systems are limited in their ability to observe and quantify these early interactions. We have developed a tunable, microfluidic model system consisting of an endotheilalized vessel channel perfusing a 3D collagen matrix that can be seeded with macrophages to recapitulate the basic structure of the extravasation site. We will use this model to quantify human macrophage-endothelial cell interactions in the context of metastasis by measuring permeability, tumor cell adhesion, and tumor cell transmigration. By treating devices with tumor cell conditioned media before the addition of tumor cells, we will quantify how macrophages change tumor cells extravasation phenotypes. We will also use M1 and M2 polarizing molecules to determine if macrophage polarization can create tumor-inhibitory or tumor-promoting responses. Since tumor cell adhesion and extravasation may depend on leukocyte adhesion mechanisms, we also developed a microfluidic model that can measure changes in leukocyte adhesion and velocity to endothelial cells in healthy and thrombotic states. We demonstrate that this model system may be used with endothelial and blood cells from a single patient, highlighting its utility in personalized medicine. Additionally, this model can be used to evaluate tumor cell-blood interactions and how these influence initial tumor cell adhesion in extravasation. As both these systems can probe and quantify early extravasation events, they can be used in tandem to gain a better understanding of the mechanisms driving tumor cell extravasation.