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: 8018658
• 负责人: Kaustubh Datta
• 金额: $ 29.89万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018658
• 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; Proto-Oncogene Proteins c-akt; 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(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，是男性癌症死亡的第二大原因，仅次于肺癌。前列腺癌死亡的主要原因是未能治愈转移性疾病患者。多篇文献报道转移性前列腺癌与前列腺癌相比，血管内皮生长因子-C(VEGF-C)表达增加。我们的初步结果表明，在应激状态下，血管内皮生长因子-C在促进前列腺癌细胞存活方面发挥了直接作用。血管内皮生长因子-C的这种功能与其已知的诱导新生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，血管内皮生长因子-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，血管内皮生长因子-C的表达与癌症复发相关，进一步支持了我们的发现。我们假设，在应激状态下，血管内皮生长因子-C的生存促进功能在耐药和转移性前列腺癌的发生发展中是必要的。这项建议的目的是了解血管内皮生长因子-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。三个具体目标将解决这一目标。目的1，阐明血管内皮生长因子-C介导前列腺癌细胞抗应激反应的分子机制。我们将确定在氧化应激条件下，血管内皮生长因子-C受体、神经粘连蛋白-2在调节前列腺癌细胞mTOR复合体-2/AKT-1通路中的作用。因此，我们的研究将提供有关mTOR复合体-2激活的上游机制的信息。我们还将确定血管内皮生长因子-C在前列腺癌抵抗低氧应激中的作用，特别是在雄激素消融后。在目标2中，我们将研究血管内皮生长因子-C在前列腺癌耐药细胞中的作用。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轴的抗应激功能。将使用体外组织培养模型和前列腺癌动物模型(免疫低下小鼠原位移植表达血管内皮生长因子-C的人前列腺癌细胞和转基因NKX3.1；PTEN基因敲除小鼠)。在目标3中，我们将比较组织中血管内皮生长因子-C及其下游靶点的表达水平与前列腺癌切除后复发的频率。在大约300名局部浸润性前列腺癌和前列腺癌区域淋巴结转移患者中，将确定前列腺癌切除术后高水平的血管内皮生长因子-C表达与癌症复发的关系。此外，还将评估血管内皮生长因子-C下游靶点(如磷酸化AKT-1(Ser473)、神经匹林-2、磷酸化c-Met、磷酸化FOXO-1和磷酸化mTOR)在促进生存方面的作用。这项研究应该为有效的治疗干预提供潜在的靶点，以及前列腺癌转移阶段的预后指标。 公共卫生相关性：这项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非常重要。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，如放射治疗和激素消融。