VEGF Signaling and Tumor Microenvironment

描述(由申请人提供)：肿瘤微环境可以显著调节血管系统的生长速度、模式和功能，这一点已被广泛接受。我们的长期目标是获得对肿瘤微环境的分子理解，目的是抑制肿瘤血管生成。我们最近发现，一个特定的基质金属蛋白水解酶库可以处理血管内皮生长因子-A，将受体结合基序从基质结合结构域中分离出来，并从基质结合的血管内皮生长因子中释放生物活性生长因子。有趣的是，我们还发现，基质结合的血管内皮生长因子能够与可溶性血管内皮生长因子一样，对血管内皮生长因子R2进行磷酸化。然而，结合型和可溶型血管内皮生长因子启动了不同的血管扩张模式，即基质结合型血管内皮生长因子导致萌发的血管生成，有利于肿瘤生长；可溶性血管内皮生长因子导致血管增生和通透性增加。因此，肿瘤中细胞外基质及其蛋白酶的相对丰度和组成可以决定血管内皮生长因子引发的血管反应。目前，我们的研究致力于表征由可溶性和结合型血管内皮生长因子引发的交替形态发生事件的机制，以及它们与肿瘤生长和治疗的相关性。我们实验室的初步数据支持这样一种假设：“血管内皮生长因子配体的呈现方式改变了VEGFR2的磷酸化状态，并调节了细胞的不同反应”。这一假说将被三个特定的目的进一步验证：(1)确定可溶的和结合的血管内皮生长因子的信号特性；(2)表征血管内皮生长因子与细胞外基质的相互作用，并确定基质金属蛋白酶介导的生长因子处理的生物学相关性。此外，我们还将探讨自分泌血管内皮生长因子信号在肿瘤生长中的意义。根据我们使用cre-lox方法进行的初步研究，我们预测自分泌的血管内皮生长因子对内皮细胞的存活至关重要，并且可以对某些抗血管生成治疗产生抵抗。因此，在目标3中，我们将研究自分泌血管内皮生长因子信号的功能及其在抗血管生成治疗中的作用。血管生成是一种复杂的现象，涉及内皮细胞和宿主组织的信号。本申请中提出的实验信息将进一步阐明肿瘤微环境对血管内皮生长因子信号的影响。这些数据将有助于进一步完善抑制肿瘤血管生成的治疗策略。

DESCRIPTION (provided by applicant): It has been well accepted that the tumor microenvironment can significantly modulate growth rate, patterning and function of the vasculature. Our long term objective is to gain molecular understanding of the tumor microenvironment with the goal to suppress tumor angiogenesis. We have recently found that a specific pool of matrix metalloproteases can process VEGF-A severing the receptor-binding motif from the matrix-binding domain and releasing bioactive growth factor from matrix-bound VEGF. Interestingly, we also found that matrix-bound VEGF is able to phosphorylate VEGFR2 to the same degree as soluble VEGF. Nonetheless, bound and soluble VEGF initiate alternative modes of vascular expansion, namely while matrix bound VEGF leads to sprouting angiogenesis that favors tumor growth; soluble VEGF results in vascular hyperplasia and increased permeability. Thus, the relative abundance and composition of the extracellular matrix in tumors and its pool of proteases can dictate the vascular responses triggered by VEGF. Currently, our research is directed towards characterizing the mechanism that result in alternative morphogenetic events initiated by soluble and bound VEGF and their relevance to tumor growth and therapy. Preliminary data generated by our laboratory supports the hypothesis that: "The mode of VEGF ligand presentation alters VEGFR2 phosphorylation status and regulates differential cellular responses". This hypothesis will be further tested by three specific aims: (1) To define the signaling properties of soluble and bound VEGF and (2) To characterize the interactions of VEGF with the extracellular matrix and determine the biological relevance of MMP-mediated processing of this growth factor. Furthermore we will explore the significance of autocrine VEGF signaling to tumor growth. Based on our preliminary studies using a cre-lox approach, we predict that autocrine VEGF is critical to endothelial cell survival and can impose resistance to certain modalities of anti-angiogenic therapy. Thus, in Aim 3 we will investigate the function of autocrine VEGF signaling and its role in anti-angiogenic therapy. Angiogenesis is a complex phenomenon involving signals from endothelial cells and from the host tissue. Information from the experiments proposed in this application will further elucidate the influence of the tumor microenvironment in VEGF signaling. These data will aid in further refinement of therapeutic strategies to inhibit angiogenesis in tumors.