Graduation Date

Fall 12-17-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pathology & Microbiology

First Advisor

Dr. Rakesh K. Singh

Abstract

This dissertation examines the role of CXCR2, a seven transmembrane G- protein coupled receptor, in mediating autocrine as well as paracrine mechanisms during pancreatic cancer progression. Data presented in the initial section demonstrates the aberrant expression of the CXCR2 biological axis in human pancreatic cancer tissue specimens. A study performed within the first section of this dissertation investigates the contribution of CXCR2 signaling in pancreatic cancer initiation. These studies have identified a novel role of CXCR2 in mediating KRAS(G12D) -induced autocrine growth transformation of pancreatic cancer cells. The upregulation of the CXCR2 biological axis was found to be directly regulated by the KRAS(G12D) mutation using in vitro and in vivo model systems. Furthermore, the inhibition of CXCR2 by genetic and pharmacological tools was able to downregulate the protein level of KRAS.

The tumor microenvironment in pancreatic cancer is composed of heterogeneous populations of cells including endothelial, fibroblast and immune cells. CXCR2 is known to be expressed by a majority of these cell types. Besides, CXCR2 is also known to mediate immune responses in various diseases including cancer. The studies in the later section of this dissertation investigate the role of CXCR2 in altering local and systemic host-mediated responses in pancreatic cancer. Two experimental strategies were used: 1) Evaluating the impact of host CXCR2 depletion on tumor growth in subcutaneous versus orthotopic tumor cell implants. 2) Examining the effect of host CXCR2 deletion on the infiltration of immune cells in orthotopic pancreatic tumors. The first approach identified a pancreatic-parenchyma specific role of CXCR2 in inhibiting fibrosis in pancreatic cancer. The second strategy unraveled an important role of CXCR2 in causing local immunosuppression where CXCR2 mediates the infiltration of myeloid-derived suppressor cells (MDSCs) in pancreatic cancer. However, CXCR2 was found to be important for inhibiting extramedullary hematopoiesis and expansion of MDSCs in the spleen. Overall, the results presented in this dissertation suggest that CXCR2 signaling functions as a double-edged sword in pancreatic cancer by mediating both tumor-promoting and -inhibitory effects.

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