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

描述（由申请人提供）：对前列腺良性增生性疾病（良性前列腺肥大，BPH）发生的生物学基础了解甚少。我们实验室的最新数据表明，CXC型趋化因子CXCL 12由老化的前列腺基质分泌，并刺激非转化和转化的前列腺上皮细胞的增殖。此外，CXCL 12介导的增殖反应在非转化的前列腺上皮细胞中是ERK依赖性的，但在转化的细胞中是ERK非依赖性的。我们现在提出，失活的PTEN可能是调节下游信号和特定的CXCL 12刺激的非转化和转化的前列腺上皮细胞的增殖反应的关键因素。本文提供的初步数据表明，CXCL 12介导的增殖反应需要EGFR，CXCL 12激活亚当斯可能催化CXCR 4介导的EGFR反式激活。对人前列腺组织的支持性免疫组织化学分析显示，CXCL 12和CXCR 4在前列腺的良性和恶性增殖性疾病中表达;激活的Akt与人前列腺肿瘤中的高增殖指数直接相关，激活的ERK与人前列腺肿瘤中的高增殖指数负相关，并且Akt激活已被鉴定为前列腺癌中不良临床结果的极好预测因子。基于这些数据，我们假设CXCL 12/CXCR 4轴可以在激活Raf/MEK/ERK和PI 3 K/PTEN/Akt途径之间“切换”以促进细胞增殖，并且途径“选择”取决于PTEN状态。我们建议通过实现三个特定目的来测试这一假设：特定目的1：确定CXCL 12激活或抑制的促进非转化人前列腺上皮细胞增殖的信号传导机制是否是PTEN依赖性的。具体目的2：确定CXCL 12刺激的增殖反应是否是EGFR依赖性的。具体目标3：确定CXCL 12、其受体和下游效应物的蛋白表达是否与衰老的人前列腺组织中的良性增生性疾病相关。拟议研究的意义：我们的初步数据表明，CXCL 12刺激衰老相关的细胞增殖，但利用不同的细胞内信号传导机制来介导非转化与转化前列腺上皮细胞中的这些反应。这些机制的阐明将对靶向CXCL 12活性的治疗剂的开发具有重要意义，以有效地治疗前列腺中的良性增殖性（BPH）与恶性增殖性（PCa）疾病。公共卫生相关性：我们的初步数据表明，趋化因子CXCL 12刺激衰老相关的细胞增殖，但利用不同的细胞内信号传导机制来介导这些反应，在非转化与转化的前列腺上皮细胞。这些机制的阐明将对靶向CXCL 12活性的治疗剂的开发具有重要意义，以有效地治疗前列腺中的良性增殖性（BPH）与恶性增殖性（PCa）疾病。

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.