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率、模式和功能，这一点已被广泛接受。 我们的长期目标是获得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，一个特定的池基质金属蛋白酶可以处理VEGF-A切断受体结合基序从基质结合域和释放生物活性的生长因子从基质结合的VEGF。 有趣的是，我们还发现基质结合的VEGF能够将VEGFR 2磷酸化至与可溶性VEGF相同的程度。 尽管如此，结合的和可溶性VEGF启动血管扩张的替代模式，即，基质结合的VEGF导致有利于肿瘤生长的萌芽血管生成;可溶性VEGF导致血管增生和渗透性增加。 因此，肿瘤中细胞外基质的相对丰度和组成及其蛋白酶库可以决定VEGF触发的血管反应。 目前，我们的研究是针对表征的机制，导致替代形态发生事件启动的可溶性和结合VEGF及其相关性肿瘤生长和治疗。 我们实验室产生的初步数据支持以下假设：“VEGF配体呈递的模式改变VEGFR 2磷酸化状态并调节差异细胞反应”。 这一假设将通过三个具体目的进一步检验：（1）确定可溶性和结合VEGF的信号传导特性和（2）表征VEGF与细胞外基质的相互作用，并确定MMP介导的该生长因子加工的生物学相关性。 此外，我们将探讨自分泌VEGF信号转导对肿瘤生长的意义。 基于我们使用cre-lox方法的初步研究，我们预测自分泌VEGF对内皮细胞存活至关重要，并且可以对某些抗血管生成疗法产生抗性。 因此，在目标3中，我们将研究自分泌VEGF信号传导的功能及其在抗血管生成治疗中的作用。 血管生成是一个复杂的现象，涉及来自内皮细胞和宿主组织的信号。 来自本申请中提出的实验的信息将进一步阐明肿瘤微环境在VEGF信号传导中的影响。 这些数据将有助于进一步完善治疗策略，以抑制肿瘤血管生成。

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.