The role of VEGF-C in resisting stress in prostate cancer

项目概要/摘要 前列腺癌仍然是西方世界最常见的非皮肤恶性肿瘤， 男性癌症死亡的第二大原因，仅次于肺癌。前列腺癌死亡率的主要原因是 无法治愈转移性疾病患者。一些出版物表明， 血管内皮生长因子-C（VEGF-C）在转移性前列腺癌中的表达， 原发性前列腺癌。我们的初步结果提示VEGF-C在促进肿瘤细胞存活中的直接作用。 前列腺癌细胞在压力下。VEGF-C的这种功能与其已知的旁分泌功能明显不同。 诱导新淋巴管生长的功能。我们相信通过保护前列腺癌 应激诱导细胞凋亡，VEGF-C促进前列腺癌复发和转移。有趣的是， 在最近的许多临床研究中，VEGF-C表达与癌症复发相关，进一步支持了我们的研究。 调查结果。我们推测VEGF-C在应激过程中的生存促进功能是必要的， 治疗抗性和转移性前列腺癌的发展。本提案的目的是了解 VEGF-C作为难治性、转移性前列腺癌预后和治疗靶点的重要性。 三个具体目标将实现这一目标。目的1：阐明VEGF-C在肿瘤细胞中的作用机制 介导的前列腺癌细胞的应激抗性。我们将确定VEGF-C受体的参与， neuropilin-2在氧化应激下调节前列腺癌细胞中的mTOR复合物-2/AKT-1通路。 因此，我们的研究将提供有关mTOR复合物-2激活的上游机制的信息。我们 还将确定VEGF-C在前列腺癌中抵抗缺氧应激的作用，特别是在雄激素治疗后， 消融术在目标2中，我们将研究VEGF-C在治疗抗性前列腺癌细胞中的作用。压力- 将评价前列腺癌细胞中VEGF-C/神经纤毛蛋白-2/m-TORC-2/AKT-1轴的抗性功能 在单独的电离辐射或与雄激素剥夺组合之后。两种体外组织培养模型 和前列腺癌的动物模型（表达VEGF-C的人前列腺癌的原位植入 免疫受损小鼠和转基因NKX3.1;PTEN敲除小鼠中的细胞）。在目标3中，我们 比较VEGF-C及其下游靶点的组织表达水平与复发频率 前列腺切除术后的人类前列腺癌高VEGF-C表达水平与 将在大约300名患者的队列中确定直肠癌切除术后的癌症复发 局部浸润性前列腺癌和区域淋巴结转移的前列腺癌。的作用 VEGF-C的下游靶点（例如磷酸化-AKT-1（Ser 473）、神经纤毛蛋白-2、磷酸化c-Met、磷酸化 还将评估FOXO-1和磷酸化-mTOR）在促进存活中的作用。这项研究将提供潜在的 有效治疗干预的目标以及前列腺转移阶段的预后指标 癌

Project summary/Abstract Prostate cancer remains the most common non- cutaneous malignancy in the Western world and is the second highest cause of cancer death in men after lung cancer. The main reason for prostate cancer mortality is the failure to cure patients with metastatic disease. A number of publications have demonstrated an increase in expression of vascular endothelial growth factor-C (VEGF-C) in metastatic prostate cancer when compared to primary prostate cancer. Our preliminary results suggest a direct role of VEGF-C in promoting survival of prostate cancer cells during stress. This function of VEGF-C is distinctly different from its known paracrine function of inducing the growth of new lymphatic vessels. We believe that by protecting the prostate cancer cells from stress-induced apoptosis, VEGF-C promotes prostate cancer recurrence and metastasis. Interestingly, in many recent clinical studies, VEGF-C expression is correlated with cancer recurrence, further supporting our findings. We hypothesize that the survival promoting function of VEGF-C during stress is necessary for the development of therapy-resistant and metastatic prostate cancer. The goal of this proposal is to understand the importance of VEGF-C as a prognostic as well as a therapeutic target for refractory, metastatic prostate cancer. Three specific aims will address this goal. In Aim 1, we will elucidate the molecular mechanism of VEGF-C mediated stress resistance of prostate cancer cells. We will determine the involvement of VEGF-C receptor, neuropilin-2 in regulating the mTOR complex-2/AKT-1 pathway in prostate cancer cells under oxidative stress. Our study will therefore provide information about the upstream mechanisms of mTOR complex-2 activation. We will also determine the role of VEGF-C in resisting hypoxic stress in prostate cancer especially after androgen ablation. In aim 2, we will investigate the role of VEGF-C in therapy resistant prostate cancer cells. The stress- resistant function of the VEGF-C/Neuropilin-2/m-TORC-2/AKT-1 axis in prostate cancer cells will be evaluated following ionizing radiation alone or in combination with androgen deprivation. Both in vitro tissue culture models and animal models of prostate cancer (Orthotopic implantation of VEGF-C expressing human prostate cancer cells in immunocompromised mice and transgenic NKX3.1;PTEN knock-out mice) will be used. In aim 3, we will compare the tissue expression levels of VEGF-C and their down-stream targets with the frequency of recurrence of human prostate cancer following prostatectomy. The association of high VEGF-C expression levels with cancer recurrence following prostatectomy will be determined in a cohort of approximately three hundred patients with locally invasive prostate cancer and prostate cancer with metastases in the regional lymph nodes. The role of downstream targets of VEGF-C (e.g. Phospho-AKT-1 (Ser 473), neuropilin-2, phospho c-Met, phospho- FOXO-1 and phospho-mTOR) in promoting survival will also be evaluated. This study should provide potential targets for effective therapeutic interventions as well as prognostic indicators for the metastatic stage of prostate cancer.