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

VEGF-C在前列腺癌抗应激中的作用

• 批准号: 7899319
• 负责人: Kaustubh Datta
• 金额: $ 31.35万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899319
• 关键词: Ablation; Address; Androgens; Animal Model; Apoptosis; Cancer Etiology; Cancer Patient; Cellular Stress; Cessation of life; Clinical Research; Complex; Cutaneous; Development; Disease; Failure; Frequencies; Goals; Hormonal; Human; Hypoxia; Immunocompromised Host; In Vitro; Ionizing radiation; Knockout Mice; Lymphangiogenesis; Lymphatic vessel; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Mus; NKX3-1 gene; Neoplasm Metastasis; Neuropilin-2; Outcome; Oxidative Stress; PTEN gene; Pathway interactions; Patients; Process; Prostatectomy; Publications; Radiation; Radiation therapy; Recurrence; Refractory; Resistance; Role; Specimen; Staging; Stream; Stress; Therapeutic Intervention; Tissues; Transgenic Mice; Transgenic Organisms; Vascular Endothelial Growth Factor C; Western World; cancer cell; cancer recurrence; cohort; deprivation; effective therapy; human FRAP1 protein; implantation; lymph nodes; meetings; men; mortality; mouse model; new growth; novel; paracrine; prognostic; prognostic indicator; public health relevance; receptor; therapeutic target; therapy resistant; tissue culture; tumor

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.

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，是仅次于肺癌的男性癌症死亡的第二大原因。前列腺癌死亡率的主要原因是未能治愈转移性疾病患者。许多出版物已经证明，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。我们的初步研究结果表明，VEGF-C在促进前列腺癌细胞在应激过程中的存活中发挥直接作用。VEGF-C的这种功能明显不同于其已知的诱导新淋巴管生长的旁分泌功能。我们认为VEGF-C通过保护前列腺癌细胞免于应激诱导的凋亡，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。我们推测，VEGF-C在应激过程中的生存促进功能对于治疗抗性和转移性前列腺癌的发展是必要的。该提案的目标是了解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。目的1：阐明VEGF-C介导前列腺癌细胞抗应激的分子机制。我们将确定VEGF-C受体，神经纤毛蛋白-2在氧化应激下调节前列腺癌细胞中mTOR复合物-2/AKT-1通路的参与。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，特别是在雄激素消融后。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。将在单独电离辐射或与雄激素剥夺组合后评价前列腺癌细胞中VEGF-C/神经纤毛蛋白-2/m-T0 RC-2/AKT-1轴的抗应激功能。将使用前列腺癌的体外组织培养模型和动物模型（在免疫受损小鼠和转基因NKX3.1;PTEN敲除小鼠中原位植入表达VEGF-C的人前列腺癌细胞）。在目标3中，我们将比较VEGF-C及其下游靶标的组织表达水平与前列腺癌切除术后人类前列腺癌复发的频率。将在大约300名患有局部浸润性前列腺癌和前列腺癌伴区域淋巴结转移的患者的队列中确定高VEGF-C表达水平与前列腺切除术后癌症复发的相关性。还将评价VEGF-C的下游靶标（例如磷酸化-AKT-1（Ser 473）、神经纤毛蛋白-2、磷酸化c-Met、磷酸化- FOXO-1和磷酸化-mTOR）在促进存活中的作用。这项研究将为有效的治疗干预提供潜在的靶点，并为前列腺癌的转移阶段提供预后指标。 公共卫生关系：这一建议将有助于了解前列腺癌转移进展的机制，因此对于开发新的有效治疗方法具有重要意义。它还将有助于预测前列腺癌患者目前可用的治疗方法的结果，如放射和激素消融。