Calcitonin in Prostate Growth and Neoplasia

描述(由申请人提供) 细胞与细胞之间的相互作用在形态发生中起着关键作用 以及前列腺癌的发病机制。神经内分泌(NE)细胞 多种诱导增殖活性细胞有丝分裂的多肽激素 细胞。PI最近的研究表明，原代人类前列腺上皮 细胞分泌免疫活性降钙素(CT-I)及其分泌 来自前列腺癌(PC)来源的细胞的数量比 来源于细胞-来源于良性前列腺肥大(BPH)。就地 肿瘤的杂交和免疫组织化学研究表明：1)CT MRNA、CT-I和CT-R mRNA定位于良性前列腺基底层 腺体。相反，CT mRNA、CT-I、CT-R mRNA和CT结合位点被定位 在恶性前列腺上皮管腔各层的表达及其意义 随着肿瘤的进展而增加。低分化PC-3M细胞和 未分化的NRP-152细胞共表达CT和CT-R mRNAs 分化良好的LNCaP细胞只表达CT-R。外源添加的CT 刺激原代PC细胞、LNCaP和PC-3M细胞DNA合成； 抗SCT可抑制这种生长。CT还抑制了转化生长因子-b及其受体 前列腺细胞的免疫反应性。考虑转化生长因子-β在细胞中的作用 分化和凋亡，可想而知CT促进肿瘤 通过阻止分化和促进增长来进步 转化的细胞。 特指1将检验手法对CT和CT-R表达的影响 前列腺癌细胞增殖、侵袭和致瘤活性的研究。 特异性靶点2将描绘CT激活的促有丝分裂信号通路 这些细胞。具体目标3将检查CT对 转分化和转化生长因子-β在这些细胞系中的表达。建议数 研究将确定前列腺CT在调节生长和 人恶性前列腺癌的分化。

DESCRIPTION (Provided by the applicant) 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.