Understanding Prostate Cancer Pathogenesis
Prostate cancer is the most prevalent type of cancer in men. However, there is no cure for relapsed androgen withdrawal-refractory prostate cancer which is fatal due to metastasis. Many studies have demonstrated the existence of cancer cells with stem cell properties (aka cancer propagating cells (CPCs)) within the cancer cell population. CPCs may cause cancer recurrence due to resistence to conventional therapies. Understanding molecular and cellular mechanisms governing normal prostate stem cells and CPCs may improve our understanding and provide new opportunities for the design of therapeutics acting specifically on CPCs. Two of such mechanisms, p53/microRNA-34/Met network and neuroendocrine (NE) signaling are the topic of my dissertation. microRNA-34 (miR-34) family has been proposed to play a tumor suppressor role in various cancers, including the prostate cancer. However, direct genetic evidence for the tumor suppressor functions of miR-34 under physiologically relevant settings has been lacking. By using newly generated mice carrying conditional alleles of mir-34, we have shown that miR-34 cooperates with p53 in suppression of prostate carcinogenesis by joint control of MET-dependent prostate stem/progenitor cells. Thus, therapeutic targeting of MET is likely to affect CPCs, particularly in p53 and miR-34 deficient patients. NE signaling has been shown to be one of the features in advanced prostate cancer. However, the roles of NE cells in prostate carcinogenesis and development are insufficiently elucidated. By using bacterial artificial chromosome (BAC) we have generated a mouse model for conditional NE cell ablation, and shown that prostate epithelium-specific ablation of NE cells results in prostate hypotrophy, suggesting NE cells play an important role in prostate development. Moreover, we have studied effects of neuropeptide in membrane metallo-endopeptidase (Mme) null mice, and shown that Mme cooperates with Pten to suppress prostate carcinogenesis in the control of prostate stem/progenitor cells. Gastrin-releasing peptide (GRP), a substrate of MME, showed similar effects on mouse prostate stem/progenitor cells and human prostate CPCs. These effects were effectively abrogated by GRP receptor (GRPR) antagonist or knockdown of GRPR expression. Taken together, these findings show critical role of NE signaling in prostate development and carcinogenesis and GRPR is a potential therapeutics targeting prostate CPCs.
prostate cancer; miR-34; Neuroendocrine
Schimenti, John C.; Tumbar, Tudorita
Ph. D., Environmental Toxicology
Doctor of Philosophy
dissertation or thesis