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

描述（由申请人提供）：前列腺癌仍然是西方世界最常见的非皮肤恶性肿瘤，是仅次于肺癌的第二大男性癌症死亡原因。前列腺癌死亡的主要原因是无法治愈转移性疾病的患者。许多出版物表明，与原发性前列腺癌相比，转移性前列腺癌中血管内皮生长因子- c （VEGF-C）的表达增加。我们的初步结果表明，VEGF-C在促进前列腺癌细胞在压力下的存活中起直接作用。VEGF-C的这种功能与已知的诱导新淋巴管生长的旁分泌功能明显不同。我们认为，通过保护前列腺癌细胞免受应激诱导的凋亡，VEGF-C促进前列腺癌的复发和转移。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发现。我们假设VEGF-C在应激状态下促进生存的功能对于治疗耐药和转移性前列腺癌的发展是必要的。本提案的目的是了解VEGF-C作为难治性转移性前列腺癌的预后和治疗靶点的重要性。三个具体目标将实现这一目标。在Aim 1中，我们将阐明VEGF-C介导前列腺癌细胞应激抵抗的分子机制。我们将确定VEGF-C受体、neuropilin-2在氧化应激下调控前列腺癌细胞mTOR复合物-2/AKT-1通路中的作用。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在前列腺癌尤其是雄激素消融后抗缺氧应激中的作用。在目标2中，我们将研究VEGF-C在治疗耐药前列腺癌细胞中的作用。电离辐射单独或联合雄激素剥夺后，将评估前列腺癌细胞中VEGF-C/Neuropilin-2/m-TORC-2/AKT-1轴的应激抵抗功能。体外组织培养模型和前列腺癌动物模型（免疫功能低下小鼠和转基因NKX3.1小鼠原位植入表达人前列腺癌细胞的VEGF-C；PTEN敲除小鼠）均可使用。在aim 3中，我们将比较VEGF-C及其下游靶点的组织表达水平与前列腺切除术后人类前列腺癌复发频率的关系。高VEGF-C表达水平与前列腺切除术后癌症复发的关系将在大约300名局部浸润性前列腺癌和区域淋巴结转移的前列腺癌患者中确定。VEGF-C下游靶点（如phospho- akt -1 （Ser 473）、neuropilin-2、phospho c-Met、phospho- FOXO-1和phospho- mtor）在促进生存中的作用也将被评估。这项研究将为有效的治疗干预提供潜在的靶点，并为前列腺癌转移阶段提供预后指标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This proposal will help to understand the mechanism of metastatic progression of prostate cancer and is therefore important for the development of novel and effective therapies. It will also help to predict the outcome of currently available therapies in prostate cancer patients like radiation and hormonal ablation.