The Ron receptor tyrosine kinase in prostate cancer.

Prostate cancer is a leading cause of cancer related death among men in the United States, and despite current therapies, once the cancer progresses and metastasizes, the mortality rate is dramatically increased. Therefore, advances in our understanding of prostate cancer signaling pathways involved in prostate tumor progression are critical for the development of new therapeutic options. Prostate tumor angiogenesis has been shown to be critical for prostate tumor growth and metastasis, and the production of angiogenic chemokines is important for tumor vascularization. Angiogenic chemokines are a group of cytokines that act as chemoattractants for endothelial cells, and have been implicated in the pathogenesis of prostate cancer. A receptor tyrosine kinase termed Ron has also been implicated in several human cancers, including prostate cancer. In our studies, we sought to determine the impact of Ron receptor signaling in prostate cancer cells on the production of angiogenic chemokines. Our data show that Ron is highly expressed in human prostate cancer specimens compared to normal prostate tissue, and is also highly expressed in PC-3 and DU145 prostate cancer cell lines. Interestingly, Ron expression correlated with angiogenic chemokine production in prostate cancer cells. Inhibition of Ron in PC-3 or DU145 cells resulted in decreased angiogenic chemokine production, with no effect on VEGF or on the angiostatic chemokine CXCL10. The impact of Ron on the production of angiogenic chemokines is at least partially dependent on the activation of the NF-kappaB transcription factor, which has previously been shown to regulate angiogenic chemokine production in prostate cancer cells. Additionally, overexpression of Ron in LNCaP prostate cancer cells is sufficient to induce production of the angiogenic chemokine CXCL8, and these levels can be abrogated using an inhibitor of NF-kappaB. Furthermore, compared with control PC-3 cells, Ron-knockdown PC-3 cells orthotopically transplanted into the prostates of nude mice resulted not only in decreased prostate tumor growth, but also in decreased prostate microvessel density, further validating our hypothesis that Ron is indeed a regulator of prostate tumor angiogenesis. These data are further discussed in Chapter 3. We also sought to determine the role of the Ron receptor tyrosine kinase in vivo, by utilizing the Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mouse model. We found that prostate tumors taken from TRAMP mice have overexpression of Ron compared to wild-type mouse prostate. Furthermore, TRAMP mice crossed with mice lacking functional Ron exhibited decreased prostate tumor size correlating with reduced prostate vasculature. Utilizing cell lines derived from TRAMP mouse prostates lacking functional Ron or cells derived from TRAMP mouse prostates expressing Ron, we found Ron-deficient TRAMP cells to be less viable than Ron-expressing TRAMP cells. Interestingly, there is no difference in apoptosis between cell lines, however our data suggests Ron-expressing TRAMP cells have a survival advantage. These results are discussed in further detail in Chapter 4. Taken together, our studies demonstrate for the first time that Ron receptor signaling is critical for angiogenic chemokine production in prostate cancer cells. Additionally, Ron is necessary for prostate tumor growth and angiogenesis in vivo, and is a regulator of cellular viability in cells derived from TRAMP mouse prostates. These studies provide novel insight into how the Ron receptor impacts prostate cancer, and enhances our understanding of Ron receptor signaling in tumor angiogenesis.