NERVE GROWTH FACTOR RECEPTORS & HUMAN PROSTATE NEOPLASIA

前列腺癌和良性前列腺增生症 在老年人的发病率和死亡率中扮演了突出的角色 成年男性，预计发病率将在 在接下来的几十年里，北美的模范男性人口 逐渐变老。因此，调控植物生长的机制 前列腺癌的管理和治疗尤其重要。 前列腺瘤。在这方面，旁分泌之间的相互作用 间质细胞和前列腺上皮细胞被认为在 在调节前列腺生长中的基础作用。在过去的几年里 多年来，该实验室已经发现了一种新的神经生长因子样物 基质细胞分泌的蛋白质(神经营养因子)和相应的 邻近上皮细胞上介导旁分泌的受体系统 人类前列腺的生长。低亲和力p75 NGF受体和 NGF受体高亲和力trk酪氨酸激酶家族成员 发生在人类的前列腺中。最近，这个实验室报告说， P75神经生长因子受体在肿瘤进展过程中逐渐丢失 人的前列腺癌，所以它在转移中完全不存在 前列腺癌细胞株。因为在其他细胞系统中，p75受体 被认为可以调节trk受体的活性，我们建议 测试假设，在人类肿瘤进展过程中 前列腺癌p75表达缺陷消除trk的调节 酪氨酸激酶受体，导致前列腺不受控制的生长 上皮细胞。为了充分研究NGF的作用 前列腺瘤中的受体被建议检测免疫球蛋白。 Trk受体在正常人皮肤上皮细胞中的定位 人类前列腺癌的良恶性。作为这些研究的后续行动， 上皮性Trk受体的自磷酸化反应 神经营养素的刺激将通过免疫沉淀法检测 Trk受体，并用抗磷酸酪氨酸抗体进行探测。 随后，与生长因素无关的生长因素的影响 神经营养因子对神经生长因子受体表达的影响有待研究。最后，我们 将直接检验p75受体缺失的假说 消除trk受体的调节，导致不受控制的生长 通过将p75基因转回前列腺癌 我们之前已经证明的肿瘤细胞缺乏p75的表达。 然后我们将测试p75转染体的trk自动还原情况- 磷酸化和生长速度减慢。这些研究应该提供 神经营养因子介导的神经生长因子旁分泌作用的确凿证据 人类前列腺生长过程中的受体信号。

Prostate neoplasia in the form of cancer and benign prostatic hyperplasia have assumed a prominent role in the morbidity and mortality of the aging adult male, and is projected to further increase in incidence over the next several decades as the modal male population in North America progressively ages. Hence, the mechanisms which regulate growth of the prostate are of particular relevance to the management and treatment of prostate neoplasia. In this context, paracrine interactions between stromal cells and epithelial of the prostate are thought to play a fundamental role in the regulation of prostate growth. Over the last few years this laboratory has identified a novel nerve growth factor-like protein (neurotrophin) secreted by stromal cells and a corresponding receptor system on the adjacent epithelial cells that mediates paracrine growth of the human prostate. Both low affinity p75 NGF receptors and a member of the high affinity trk tyrosine kinase family of NGF receptors occur in the human prostate. Recently, this laboratory reported that the p75 NGF receptor is progressively lost during neoplastic progression of the human prostate, so that it is completely absent in metastatic prostate tumor cell lines. Since in other cell systems, the p75 receptor is thought to modulate the activity of the trk receptors, we propose to test the hypothesis that during neoplastic progression of the human prostate a defect in p75 expression eliminates modulation of the trk tyrosine kinase receptor, leading to uncontrolled growth of the prostatic epithelial cells. In order to fully investigate the role of NGF receptors in prostate neoplasia it is proposed to examine the immuno- localization of the trk receptor in epithelial cells of the normal, benign and malignant human prostate. As a follow up to these studies the autophosphorylation of the epithelial trk receptor in response to neurotrophin stimulation will be examined by immunoprecipitation of the trk receptor and probing with an antiphosphotyrosine antibody. Subsequently, the effect of growth factors not related to the neurotrophins on NGF receptor expression is to be examined. Finally, we will directly test the hypothesis that loss of the p75 receptor eliminates modulation of the trk receptor leading to uncontrolled growth of the epithelial cells by transfecting the p75 gene back into prostatic tumor cells which we have previously demonstrated lack p75 expression. We will then test the p75 transfectants for reduced trk auto- phosphorylation and reduced growth rate. These studies should provide definitive evidence for the paracrine role of neurotrophin mediated NGF receptor signalling in the growth of the human prostate.