Modulation of VEGF signaling by extracellular matrix and neuropilins: impact on tumor progression, angiogenesis and anti-angiogenic therapy in prostate and pancreatic cancer

细胞外基质和神经毡蛋白调节 VEGF 信号传导：对前列腺癌和胰腺癌肿瘤进展、血管生成和抗血管生成治疗的影响

• 批准号: 227948621
• 负责人: Dr. Georg Hilfenhaus
• 金额: --
• 依托单位: Medizinische Klinik mit SP Hepatologie und Gastroenterologie (einschl. Arbeitsbereich Stoffwechselerkrankungen (CVK)
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/227948621?language=en
• 关键词: Modulation; VEGF; signaling; extracellular; matrix

It is generally accepted that the tumor microenvironment plays an active role in regulating expansion and metastatic progression. Matrix molecules serve as substrate for migration of tumor cells, as well as, provide differentiation cues for the maturation and stabilization of new vascular beds. In addition, through binding and interactions with specific growth factors, the extracellular matrix (ECM) offers a reservoir of growth regulatory signals. Previous work by Prof. Iruela-Arispe indicates that matrix-bound vascular endothelial growth factor (VEGF) is susceptible to proteolysis releasing a soluble receptor tyrosine kinase-activating fragment (N-terminal) and a smaller C-terminal matrix-bound peptide. Interestingly, this C-terminal VEGF peptide binds and activates neuropilin-1 (NRP1) in tumor and in endothelial cells, thereby possibly facilitating tumor growth and metastasis. The proposed project will test the hypothesis that: ¿Extracellular processing of VEGF results in the generation of bioactive peptides that continue to support angiogenic growth and more importantly mediate tumor progression. Furthermore, this C-terminal VEGF constitutes an untapped reservoir of growth factor that is not affected by the available VEGF-antagonist bevacizumab¿. For evaluation of the preceding hypothesis, models and human samples of prostate and pancreatic cancer will be applied, both representing tumor entities with a strong stroma/ECM reaction. In vitro experiments will address the angiogenic and tumor biological role of the C-terminal VEGF peptide and reveal the molecular signaling pathways that are activated downstream of NRP1 upon binding to C-terminal VEGF. Furthermore the impact of NRP1 blockade on tumor growth, angiogenic progression and metastatic expansion will be determined in xenograft models of prostate and pancreatic cancer overexpressing C-terminal VEGF. In addition, the presence of C-terminal and full-length VEGF will be determined in samples of human prostate and pancreatic tumors and its levels correlated with tumor progression and clinical follow-up. It is anticipated the execution of this project will expand and clarify the signaling pathways driven by VEGF in the context of ECM interactions that regulate angiogenic expansion in prostate and pancreatic cancer. This may reveal causes of present low response rates to bevacizumab in the clinic, offer a path for better stratification of patients for existing VEGF-directed therapeutic options, and potentially identifies new targets of VEGF signaling for future therapies.

人们普遍认为肿瘤微环境在调节肿瘤的扩张和转移过程中起着积极的作用。基质分子作为肿瘤细胞迁移的底物，为新生血管床的成熟和稳定提供分化线索。此外，通过与特定生长因子的结合和相互作用，细胞外基质（ECM）提供了一个生长调节信号的储存库。Iruela-Arispe教授之前的研究表明，基质结合的血管内皮生长因子（VEGF）易受蛋白水解的影响，释放可溶性受体酪氨酸激酶激活片段（n端）和较小的c端基质结合肽。有趣的是，这种c端VEGF肽结合并激活肿瘤和内皮细胞中的neuropilin-1 (NRP1)，从而可能促进肿瘤的生长和转移。拟议的项目将验证以下假设：VEGF的细胞外加工导致生物活性肽的产生，这些活性肽继续支持血管生成生长，更重要的是介导肿瘤进展。此外，这个c端VEGF构成了一个未开发的生长因子库，不受可用的VEGF拮抗剂贝伐单抗的影响。为了评估上述假设，将使用前列腺癌和胰腺癌的模型和人体样本，这两种肿瘤都具有强烈的基质/ECM反应。体外实验将探讨c端VEGF肽的血管生成和肿瘤生物学作用，揭示NRP1与c端VEGF结合后在下游被激活的分子信号通路。此外，NRP1阻断对肿瘤生长、血管生成进展和转移扩张的影响将在过表达c端VEGF的前列腺癌和胰腺癌异种移植模型中确定。此外，还将在人前列腺和胰腺肿瘤样本中检测c端和全长VEGF的存在及其与肿瘤进展和临床随访的相关水平。预计该项目的实施将扩大和阐明在前列腺癌和胰腺癌中调节血管生成扩张的ECM相互作用背景下由VEGF驱动的信号通路。这可能揭示了目前临床上对贝伐单抗反应率低的原因，为现有的VEGF导向治疗方案提供了更好的患者分层途径，并有可能为未来的治疗确定VEGF信号的新靶点。