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B.S. Pre-Medicine 2003
The Pennsylvania State University
Thesis Advisor: John Glod, M.D., Ph.D.
Graduate Program in Cellular and Molecular Pharmacology
RWJUH, CAB Room 3403, New Brunswick
(Behind the Cab Fare Cafeteria)
Tuesday, June 22, 2010
The co-evolution of a tumor and its microenvironment is pivotal in the progression of a malignant neoplasm. Acting through a complex signaling network, tumor cells activate neighboring stromal cells, promoting their differentiation to tumor-promoting phenotypes. Tumor-associated macrophages (TAMs) influence tumor progression through the release of pro-tumor factors involved in angiogenesis, tumor cell invasion, metastasis, immunosuppression, and chemoresistance. Specific tumor types, such as glioblastoma multiforme, are characterized by a dense macrophage infiltrate. Analyses of surgically resected glioblastomas have correlated high levels of macrophage infiltration and interleukin-6 (IL-6) expression with poor prognosis. This study aims to characterize the role of TAMs in the progression of glioblastoma. We hypothesize that upon tumor association, macrophages will orchestrate the activation of the stroma by promoting the infiltration of stem cells, secreting pro-tumor soluble factors, and increasing the immunosuppressive and chemoresistant properties of tumor cells. To demonstrate the induction of mesenchymal stromal/stem cell (MSC) migration in response to macrophage-secreted chemokines, we used an in vitro chemotaxis assay. Our results suggest that macrophages induce MSC localization through the activation of the c-Jun N-terminal kinase (JNK) signaling pathway.
MSCs selectively migrate to solid tumors, integrate into the tumor stroma, and differentiate into tumor-associated cells. In the presence of tumor-secreted factors, activated MSCs undergo differentiation to carcinoma-associated fibroblasts (CAFs) and tumor-associated pericytes. CAFs have been implicated in the progression of multiple solid tumor types. Using an in vitro model of glioblastoma, we demonstrate that macrophages and MSCs respond to glioma-secreted factors by increasing the expression of markers associated with differentiation to tumor-promoting phenotypes.
In addition, macrophages and MSCs respond to tumor signals by potentiating the secretion of pro-tumor factors, such as IL-6. Recent evidence suggests that macrophage-derived interleukin-1 beta confers chemoresistant properties to pancreatic cells. In this study, we demonstrate macrophage-induced chemoresistance in the U87 glioblastoma cell line.
This study characterizes the importance of macrophages in tumor progression and highlights the complexity of the tumor-stroma relationship. A complete understanding of the signaling mechanisms involved in stromal activation will provide the framework for the identification of novel targets for cancer therapy.