Prostate cancer is the most common cancer in men in North America and the second leading cause of cancer-related deaths in males. The high mortality rate of this disease is mainly due to the metastatic spread of malignant cells. Compelling evidence suggests that angiogenesis is a critical factor regulating the growth and spread of cancer. However, a significant gap exists in our understanding of the genes that impact these processes. Our preliminary data show that prostate cancer cell lines and tumors produce angiogenic CXC chemokines through a mechanism dependent on NF-kB activation. The angiogenic chemokines produced by these prostate cancer cells induce endothelial cell chemotaxis and this effect is dependent upon the angiogenic chemokine receptor CXCR2. Moreover, we also demonstrate that the Ron receptor tyrosine kinase is highly expressed in human prostate tumors and prostate cancer cell lines. In addition, we show that a blockade of Ron signaling in prostate cancer cells inhibits angiogenic CXC chemokine production and results in the stabilization of the NF-kB inhibitory protein IkB. Utilizing gene-targeted mice, we also show that a functional loss of Ron or CXCR2 significantly delays prostate tumor development in vivo. Based on our preliminary data, this proposal will test the central hypothesis that Ron signaling promotes prostate tumor growth by stimulating angiogenic chemokine production leading to CXCR2-mediated angiogenesis. The studies in this proposal will focus on the unique role of the Ron-chemokine axis in regulating prostate tumor growth by (i) delineating the mechanisms responsible for the Ron-dependent regulation of angiogenic chemokine production, (ii) determining the impact of Ron signaling in prostate tumor growth in vivo, (iii) by examining the functional significance of the chemokine receptor, CXCR2, in prostate tumor growth and angiogenesis, and (iv) by validating the significance of Ron-mediated angiogenic chemokine production in prostate cancer cells on CXCR2-regulated angiogenesis. In total, we hope to understand role of the novel Ron-chemokine axis in the development and spread of prostate cancer and provide a scientific rationale for new diagnostic or treatment modalities for this disease.
The research in this application will focus on a novel signaling pathway, driven by a protein termed the Ron receptor tyrosine kinase, in regulating the growth of prostate tumors. The goal of this proposal is to provide the scientific rationale to design new treatment strategies targeting this pathway for patients with prostate cancer.
|Stuart, William D; Brown, Nicholas E; Paluch, Andrew M et al. (2015) Loss of Ron receptor signaling leads to reduced obesity, diabetic phenotypes and hepatic steatosis in response to high-fat diet in mice. Am J Physiol Endocrinol Metab 308:E562-72|
|Vasiliauskas, Juozas; Nashu, Madison A; Pathrose, Peterson et al. (2014) Hepatocyte growth factor-like protein is required for prostate tumor growth in the TRAMP mouse model. Oncotarget 5:5547-58|
|Kulkarni, Rishikesh M; Stuart, William D; Gurusamy, Devikala et al. (2014) Ron receptor signaling is protective against DSS-induced colitis in mice. Am J Physiol Gastrointest Liver Physiol 306:G1065-74|
|Zhao, H; Chen, M-S; Lo, Y-H et al. (2014) The Ron receptor tyrosine kinase activates c-Abl to promote cell proliferation through tyrosine phosphorylation of PCNA in breast cancer. Oncogene 33:1429-37|
|Kulkarni, Rishikesh M; Stuart, William D; Waltz, Susan E (2014) Ron receptor-dependent gene regulation of Kupffer cells during endotoxemia. Hepatobiliary Pancreat Dis Int 13:281-92|
|Gurusamy, Devikala; Gray, Jerilyn K; Pathrose, Peterson et al. (2013) Myeloid-specific expression of Ron receptor kinase promotes prostate tumor growth. Cancer Res 73:1752-63|
|Cai, Yuqi; Balli, David; Ustiyan, Vladimir et al. (2013) Foxm1 expression in prostate epithelial cells is essential for prostate carcinogenesis. J Biol Chem 288:22527-41|
|Gray, Jerilyn K; Paluch, Andrew M; Stuart, William D et al. (2012) Ron receptor overexpression in the murine prostate induces prostate intraepithelial neoplasia. Cancer Lett 314:92-101|
|Kulkarni, Rishikesh M; Kutcher, Louis W; Stuart, William D et al. (2012) Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure. Hepatobiliary Pancreat Dis Int 11:383-92|
|Huitema, Leonie F A; Renn, JÃ¶rg; Logister, Ive et al. (2012) Macrophage-stimulating protein and calcium homeostasis in zebrafish. FASEB J 26:4092-101|
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