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: 8606427
• 负责人: Kaustubh Datta
• 金额: $ 28.99万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606427
• 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; Prognostic Marker; 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; abstracting; cancer cell; cancer recurrence; cohort; deprivation; effective therapy; human FRAP1 protein; implantation; lymph nodes; meetings; men; mortality; mouse model; new growth; novel; paracrine; prognostic; prostate cancer cell; receptor; therapeutic target; therapy resistant; tissue culture; tumor

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.

项目摘要/摘要 前列腺癌在西方世界仍然是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的患者。一些出版物显示， 血管内皮生长因子-C在转移性前列腺癌中的表达 原发性前列腺癌。我们的初步结果表明，血管内皮生长因子-C在促进肿瘤存活方面发挥了直接作用。 前列腺癌细胞在应激状态下。血管内皮生长因子-C的这一功能与其已知的旁分泌明显不同 诱导新生淋巴管生长的功能。我们相信通过保护前列腺癌 来自应激诱导的细胞凋亡，血管内皮生长因子-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，血管内皮生长因子-C的表达与癌症复发有关，进一步支持了我们的 调查结果。我们推测，在应激过程中，血管内皮生长因子-C的促存活作用是必要的。 耐药和转移性前列腺癌的发展。这项建议的目标是了解 血管内皮生长因子-C作为难治性、转移性前列腺癌预后和治疗靶点的重要性。 三个具体目标将解决这一目标。在目标1中，我们将阐明血管内皮生长因子-C的分子机制 前列腺癌细胞介导的应激抗性。我们将确定血管内皮生长因子-C受体的参与， 神经匹林-2在氧化应激下调节前列腺癌细胞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 也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，特别是雄激素治疗后。 消融。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。压力- 将评估前列腺癌细胞中血管内皮生长因子-C/Neuropilin-2/m-TORC-2/AKT-1轴的耐药功能 单独或联合雄激素剥夺后的电离辐射。两种体外组织培养模型 前列腺癌动物模型(表达人前列腺癌血管内皮生长因子-C的原位移植 将使用免疫受损小鼠和转基因NKX3.1；PTEN基因敲除小鼠的细胞)。在《目标3》中，我们将 组织中血管内皮生长因子-C及其下游靶点的表达水平与复发频率的比较 前列腺癌切除后的人类前列腺癌。高水平的血管内皮生长因子-C表达与 前列腺癌切除术后的癌症复发将在大约300名患者中确定。 有局部浸润性前列腺癌和前列腺癌区域淋巴转移。角色 血管内皮生长因子-C的下游靶点(如磷酸化AKT-1(Ser473)、神经粘连蛋白-2、磷酸化c-蛋氨酸、磷酸化- FOXO-1和磷酸化mTOR在促进生存方面的作用也将得到评估。这项研究应该会提供潜在的 有效治疗干预的目标以及前列腺癌转移期的预后指标 癌症。

项目成果

Angiogenic growth factor axis in autophagy regulation.

• DOI: 10.4161/auto.23783
• 发表时间: 2013-05
• 期刊: Autophagy
• 影响因子: 13.3
• 作者: Stanton MJ;Dutta S;Polavaram NS;Roy S;Muders MH;Datta K
• 通讯作者: Datta K

Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo.

HSP90的氧化抑制会破坏超副酮复合物，并在体外和体内减弱胰腺腺癌。

• DOI: 10.1002/ijc.27687
• 发表时间: 2013-02-01
• 期刊: INTERNATIONAL JOURNAL OF CANCER
• 影响因子: 6.4
• 作者: Sarkar, Sayantani;Dutta, Devawati;Samanta, Suman Kumar;Bhattacharya, Kaushik;Pal, Bikas Chandra;Li, Jinping;Datta, Kaustubh;Mandal, Chhabinath;Mandal, Chitra
• 通讯作者: Mandal, Chitra