Cell-to Cell interactions are known to play a critical role in morphogenesis and pathogenesis of the prostate gland. Neuroendocrine (NE) cells secrete numerous peptide hormones which induce mitogenesis in proliferation-competent cells. Recent studies by the PI suggest that primary human prostate epithelial cells secrete immunoreactive calcitonin (CT-I) in culture, and its secretion from prostate carcinoma (PC)-derived cells is several-fold greater than that from the cells-derived from benign prostatic hypertrophy(BPH). In situ hybridization and immunohistochemistry studies of tumors have shown that 1) CT mRNA, CT-I and CT-R mRNA are localized in the basal layer of benign prostate gland. In contrast, CT mRNA, CT-I, CT-R mRNA and CT binding sites are localized in luminal layers of malignant prostate epithelium, and their expression increases with tumor progression. Poorly differentiated PC-3M cells and undifferentiated NRP-152 cells co-express CT and CT-R mRNAs and well-differentiated LnCaP cells express only CT-R. Exogenously added CT stimulates DNA synthesis of primary PC cells, LnCaP and PC-3M cells; and anti-sCT inhibits this growth. CT also inhibited TGF-b and TGF-b receptor immunoreactivity in prostate cells. Considered with the role of TGF-b in cell differentiation and apoptosis, it is conceivable that CT promotes tumor progression by arresting differentiation, and increasing the growth of transformed cells.
Specific Aim 1 will test the effect of manipulation of CT and CT-R expression on proliferative, invasive and tumorigenic activities of prostate cancer cells.
Specific Aim 2 will delineate mitogenic signaling pathway activated by CT in these cells.
Specific Aim 3 will examine the effect of CT on transdifferentiation and TGF-b expression in these cell lines. The proposed studies will define the role for prostatic CT in regulation of growth and differentiation in malignant human prostate gland.
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