Regulatory Pathways and Role of VPF/VEGF in Renal Cancer

VPF/VEGF 在肾癌中的调控途径和作用

• 批准号: 7661839
• 负责人: DEBABRATA MUKHOPADHYAY
• 金额: $ 30.25万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-11 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7661839
• 关键词: Angiogenesis Inhibitors; Animal Model; Antibodies; Antineoplastic Agents; Avastin; Biology; Blood Vessels; Cancer Biology; Carcinogenesis Mechanism; Carcinoma; Cell Line; Clear Cell; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Data; Dependency; Differentiation Antigens; Disease Progression; Drug resistance; Elements; Erinaceidae; Event; Exhibits; Experimental Designs; FDA approved; Genes; Grant; Growth; Intervention; Kidney Neoplasms; Knock-out; Lead; Ligands; Light; Maintenance; Malignant Epithelial Cell; Mediating; Molecular; Nature; Neoplasm Metastasis; Neuropilin-1; Neuropilins; Outcome; Pathway interactions; Patients; Phenotype; Phosphotransferases; Play; Process; Progression-Free Survivals; Property; Quality of life; Reagent; Receptor Protein-Tyrosine Kinases; Regulation; Regulatory Pathway; Renal Cell Carcinoma; Renal carcinoma; Resistance; Role; Signal Pathway; Signal Transduction; Staging; Testing; Transfection; Tumor Biology; Tumor Suppressor Genes; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Vascular Permeabilities; Von Hippel-Lindau Syndrome; Xenograft Model; angiogenesis; base; cancer cell; clinical effect; design; extracellular; in vivo; independency; jagged1 protein; kinase inhibitor; loss of function; mRNA Stability; neoplastic cell; notch protein; novel; novel therapeutic intervention; novel therapeutics; overexpression; promoter; public health relevance; receptor; research study; tissue culture; tumor; tumor growth; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Most of the cases, the clear-cell renal cell carcinoma (RCC) express strikingly elevated baseline levels of vascular permeability factor also known as vascular endothelial growth factor (VEGF) rationalized their vascular nature. We originally described the regulation of VEGF A in RCC that is both transcriptional and has mRNA stability and later defined the molecular mechanisms of those pathways. Moreover, it has been shown by our group as well as others that transfection of wild type-VHL (wt-VHL) into RCC cell lines down-regulates VEGF expression that lead to suppression of tumor growth in xenograft models. Despite the positive impact of several anti-angiogenic drugs and multi-kinase inhibitors on progression-free survival and quality of life, disease progression eventually occurs and that leads to rationalize for more studies for better understanding of VEGF biology and its interconnection with tumor biology. Furthermore, several tumors including RCC cells also express high level of neuropilin (NRPs; the non-tryrosine kinase receptor of VEGF) but the downstream signaling events and the subsequent effects on tumor survival, metastasis and progression are poorly understood. Nonetheless, our preliminary data suggest a novel function of VEGF on tumor cells via NRP-1 and that leads to generate a new hypothesis that VEGF/NRP-1 axis can play an important role to maintain the tumor niche or tumorigenic properties of cancer cells. To test our hypothesis, in this competitive renewal application, we have proposed three specific aims. Aim 1 will elucidate the role of VEGF A as a regulator to maintain the dedifferentiated phenotype of RCC cells. Experiments will be performed to examine the importance of VEGF A/NRP-1 axis in tumorigenesis of RCC. Aim 2 will clarify the regulations of downstream effector genes of NRP-1 in RCC tumorigenesis such as: Shh and Notch-1. We will also evaluate the consequences of Np63 null RCC cells on tumorigenesis. Finally, Aim 3 will examine the dependency of renal tumor growth on VEGF/NRP-1 axis in vivo. In this regard, we will extend the tissue culture data and reagents to animal models of renal tumors, seeking to understand the importance of VEGF/NRP1 axis as well as the mechanisms by which it plays an important role in the tumorigenesis. Overall, the proposed experiments will provide new and important information on the mechanisms of carcinogenesis and suggest new targets for intervention in RCC, a common, highly vascular, angiogenesis-dependent carcinoma that is resistant to currently available therapies. PUBLIC HEALTH RELEVANCE: Clear-cell renal cell carcinoma (RCC) arising sporadically or in the von Hippel Lindau (VHL) syndrome, exhibit loss of function of a tumor suppressor gene, VHL. RCC characteristically overexpress VEGF A, and we originally described the regulation of VEGF A in RCC that is both transcriptional and has mRNA stability and later defined the molecular mechanisms of those pathways. Based upon those studies and several clinical trials, a humanized version of anti-VEGF antibody, Avastin, is now approved by the FDA as the first line of anti-angiogenic drugs to battle against patients afflicted with advanced RCC; however, the overall clinical outcome is not encouraging. During the current grant cycle, we have hypothesized that VEGF/NRP-1 axis plays an unusual role to maintain dedifferentiated stages of tumor cells through: sonic hedgehog and notch signaling and that leads to highly aggressive cancer and drug resistance. The experiments proposed herein are designed to investigate the detailed signaling pathways that will explain a new role of VEGF A on RCC tumorigenesis and eventually will shed new light on the mechanisms of carcinogenesis in a common, highly aggressive carcinoma which is resistant to current therapy.

描述（由申请人提供）：大多数情况下，透明细胞肾细胞癌（RCC）明显升高的血管通透性因子的基线水平也被称为血管内皮生长因子（VEGF）合理化其血管性质。我们最初描述了RCC中VEGF A的调节，该调节既是转录且具有mRNA稳定性，后来又定义了这些途径的分子机制。此外，我们的组以及其他将野生型VHL（WT-VHL）转染到RCC细胞系下调的VEGF表达，从而导致异种移植模型中肿瘤生长抑制。尽管几种抗血管生成药物和多激酶抑制剂对无进展生存和生活质量的积极影响，但疾病的进展最终会发生，这导致了更多的研究，以更好地了解VEGF生物学及其与肿瘤生物学的相互联系。此外，包括RCC细胞在内的几种肿瘤还表达了高水平的神经肽（NRP； VEGF的非肌动蛋白激酶受体），但下游信号事件以及随后对肿瘤存活，转移和进展的影响很少。尽管如此，我们的初步数据表明，VEGF通过NRP-1的新功能在肿瘤细胞上的新功能，这导致了一个新的假设，即VEGF/NRP-1轴可以在维持癌细胞的肿瘤生殖裂或肿瘤特性方面发挥重要作用。为了检验我们的假设，在这种竞争性更新应用中，我们提出了三个具体目标。 AIM 1将阐明VEGF A作为调节剂的作用，以维持RCC细胞的去分化表型。将进行实验以检查VEGF A/NRP-1轴在RCC肿瘤发生中的重要性。 AIM 2将阐明NRP-1下游效应基因在RCC肿瘤发生中的法规，例如：SHH和Notch-1。我们还将评估NP63 NULL RCC细胞对肿瘤发生的后果。最后，AIM 3将检查体内肾脏肿瘤生长对VEGF/NRP-1轴的依赖性。在这方面，我们将将组织培养数据和试剂扩展到肾脏肿瘤的动物模型，以寻求了解VEGF/NRP1轴的重要性以及它在肿瘤发生中起重要作用的机制。总体而言，提出的实验将提供有关致癌机制的新的重要信息，并提出了干预RCC的新目标，RCC是一种常见的，高度血管，血管生成依赖性癌，对当前可用的疗法具有抗性。公共卫生相关性：偶尔出现或在von Hippel-Lindau（VHL）综合征中引起的清晰细胞肾细胞癌（RCC），表现出肿瘤抑制基因的功能损失，VHL。 RCC具有过表达的VEGF A，我们最初描述了RCC中VEGF A的调节，该调节既是转录且具有mRNA稳定性，后来又定义了这些途径的分子机制。根据这些研究和几项临床试验，抗VEGF抗体Avastin的人源化版本现在已被FDA批准为抗血管生成药物的第一线，以与患有晚期RCC的患者作斗争；但是，总体临床结果并不令人鼓舞。在当前的赠款周期中，我们假设VEGF/NRP-1轴通过通过：Sonic Hedgehog和Notch信号传导来维持肿瘤细胞的去分化阶段起着与众不同的作用，这会导致高度攻击性的癌症和耐药性。本文提出的实验旨在研究详细的信号通路，这些详细信号通路将解释VEGF A在RCC肿瘤发生中的新作用，并最终将在常见的，高度侵略性的癌中对癌发生的机制进行新的启示，这对当前治疗具有抗性。