PTEN- and EGFR-Dependence of CXCL12-Mediated Proliferation in the Aging Prostate

描述（由申请人提供）：前列腺良性增生性疾病（良性前列腺肥大，BPH）发生的生物学基础尚不清楚。我们实验室最近的数据表明，cxc型趋化因子CXCL12由衰老的前列腺基质分泌，并刺激未转化和转化的前列腺上皮细胞的增殖。此外，cxcl12介导的增殖反应在未转化的前列腺上皮细胞中依赖ERK，而在转化的细胞中不依赖ERK。我们现在提出PTEN的失活可能是调节下游信号和特异性cxcl12刺激的非转化和转化前列腺上皮细胞增殖反应的关键因素。本文提供的初步数据表明，CXCL12介导的增殖反应需要EGFR，并且CXCL12激活ADAMs可能催化cxcr4介导的EGFR反激活。支持人体前列腺组织免疫组化分析显示，CXCL12和CXCR4在前列腺良性和恶性增生性疾病中表达；活化的Akt与人类前列腺肿瘤的高增殖指数呈正相关，活化的ERK与高增殖指数呈负相关，Akt活化已被确定为前列腺癌不良临床预后的良好预测因子。基于这些数据，我们假设CXCL12/CXCR4轴可以在激活Raf/MEK/ERK和PI3K/PTEN/Akt通路之间“切换”以促进细胞增殖，并且通路的“选择”取决于PTEN状态。我们建议通过完成三个特定目标来验证这一假设：特定目标1：确定CXCL12激活或抑制促进非转化人前列腺上皮细胞细胞增殖的信号机制是否依赖于pten。特异性目的2：确定cxcl12刺激的增殖反应是否依赖于EGFR。特异性目的3：确定CXCL12、其受体和下游效应物的蛋白表达是否与衰老人类前列腺组织中的良性增生性疾病相关。研究意义：我们的初步数据显示，CXCL12刺激衰老相关的细胞增殖，但在未转化和转化的前列腺上皮细胞中，CXCL12利用不同的细胞内信号传导机制介导这些反应。这些机制的阐明将对开发针对CXCL12活性的治疗方法产生重大影响，从而有效治疗前列腺良性增生性疾病（BPH）和恶性增生性疾病（PCa）。公共卫生相关性：我们的初步数据显示，趋化因子CXCL12刺激衰老相关的细胞增殖，但在未转化和转化的前列腺上皮细胞中，利用不同的细胞内信号传导机制介导这些反应。这些机制的阐明将对开发针对CXCL12活性的治疗方法产生重大影响，从而有效治疗前列腺良性增生性疾病（BPH）和恶性增生性疾病（PCa）。

DESCRIPTION (provided by applicant): The biological basis for the development of benign proliferative disease (benign prostatic hypertrophy, BPH) in the prostate is poorly understood. Recent data from our laboratory shows that the CXC-type chemokine, CXCL12, is secreted by aging prostate stroma and stimulates the proliferation of both non-transformed and transformed prostate epithelial cells. Moreover, the CXCL12-mediated proliferative responses are ERK- dependent in non-transformed prostate epithelial cells, but ERK-Independent in transformed cells. We now propose that inactivation of PTEN may be the critical factor that modulates downstream signaling and the specific CXCL12-stimulated proliferative responses of non-transformed and transformed prostate epithelial cells. Preliminary data presented here shows that the CXCL12-mediated proliferative response requires EGFR, and that CXCL12 activation of ADAMs may catalyze CXCR4-mediated transactivation of EGFR. Supporting immunohistochemical analysis of human prostate tissues show that CXCL12 and CXCR4 are expressed in benign and malignant proliferative diseases of the prostate; that activated Akt has been directly correlated, and activated ERK inversely correlated, with a high proliferative index in human prostate tumors, and that Akt activation has been identified as an excellent predictor of poor clinical outcome in prostate cancer. Based on these data, we hypothesize that the CXCL12/CXCR4 axis can `switch' between activating the Raf/MEK/ERK and PI3K/PTEN/Akt pathways to promote cellular proliferation, and that the pathway `choice' depends on PTEN status. We propose to test this hypothesis through the accomplishment of three Specific Aims: SPECIFIC AIM 1: Determine whether the signaling mechanisms activated or inhibited by CXCL12 that promote cellular proliferation in non-transformed human prostate epithelial cells are PTEN-dependent. SPECIFIC AIM 2: Determine whether the CXCL12-stimulated proliferative response is EGFR- dependent. SPECIFIC AIM 3: Determine whether the protein expression of CXCL12, its receptor, and downstream effectors correlate with benign proliferative disease in aging human prostate tissues. Significance of the Proposed Research: Our preliminary data shows that CXCL12 stimulates aging- associated cellular proliferation, but utilizes different intracellular signaling mechanisms to mediate these responses in non-transformed versus transformed prostate epithelial cells. The elucidation of these mechanisms will have significant consequences for the development of therapeutics targeted against CXCL12 activity to efficaciously treat benign proliferative (BPH) versus malignant proliferative (PCa) disease in the prostate. PUBLIC HEALTH RELEVANCE: Our preliminary data shows that the chemokine CXCL12 stimulates aging-associated cellular proliferation, but utilizes different intracellular signaling mechanisms to mediate these responses in non-transformed versus transformed prostate epithelial cells. The elucidation of these mechanisms will have significant consequences for the development of therapeutics targeted against CXCL12 activity to efficaciously treat benign proliferative (BPH) versus malignant proliferative (PCa) disease in the prostate.