Keratinocyte responses to vascular endothelial growth factor in carcinogenesis

描述（由申请人提供）：血管生成是许多类型肿瘤（包括皮肤恶性肿瘤）发生、生长和扩散的重要组成部分。血管内皮生长因子-A（vascular endothelial growth factor-A，VEGF）是一种强有力的促血管生成因子，它参与了皮肤的多种过程，包括肿瘤的发生。在皮肤中，高VEGF水平与乳头状瘤发展增强、鳞状细胞癌数量增加和淋巴结转移发生率较高相关。一般来说，VEGF被描述为内皮细胞特异性生长因子，其促进肿瘤发生的能力与其促血管生成作用完全相关。然而，VEGF的作用可能不限于内皮细胞的证据正在出现，因为VEGF受体（VEGFR-1和VEGFR-2）可以由非内皮细胞类型的子集表达。最近，我们的实验室已经发现，这些受体之一，VEGFR-1，表皮角质形成细胞表达。我们还证明了VEGFR-1在体外和体内皮肤伤口愈合的增殖期角质形成细胞增殖中的功能作用。由于过度增殖是肿瘤发展不可或缺的，我们的研究结果表明，VEGF，通过与VEGFR- 1的相互作用，可能会影响皮肤肿瘤的信号直接在角质形成细胞。所提出的研究的目标是确定VEGF是否可以通过VEGFR-1直接刺激角质形成细胞，以及VEGF的这种直接角质形成细胞刺激是否参与皮肤致癌作用。为了进行这些研究，我们将使用新的遗传修饰小鼠，这将允许在角质形成细胞中特异性地暂时缺失VEGFR-1。除了人皮肤癌样品之外，皮肤癌发生的小鼠模型将用于实现以下特定目的：1）确定角质形成细胞VEGFR-1在化学皮肤癌发生中的作用，2）评价角质形成细胞VEGFR-1在光致癌作用中的作用，和3）检查人角质形成细胞和皮肤肿瘤中的VEGFR-1表达和信号传导。这些研究可能揭示VEGF的一种新的生物学功能，并可能揭示VEGF参与促进皮肤癌发生的一种新的直接机制。这些实验产生的数据将提供有关皮肤癌发展机制的新信息，这对于治疗每年数百万被诊断患有这种疾病的患者可能很重要。 项目叙述：非黑色素瘤皮肤癌是最常见的癌症类型，每年在美国报告超过一百万例新病例。本申请中提出的研究将检查涉及皮肤癌发展的新途径。从这些研究中获得的信息可以更好地了解皮肤肿瘤的发展和生长，也可以导致更好的方法来预防和治疗皮肤癌的发展。

DESCRIPTION (provided by applicant): Angiogenesis is an important component of the development, growth, and spread of many types of tumors, including malignancies of the skin. VEGF (vascular endothelial growth factor-A) is a potent pro-angiogenic factor, which has been implicated in a variety of processes in the skin, including tumorigenesis. In the skin, high VEGF levels are associated with enhanced papilloma development, increased squamous cell carcinoma numbers, and a higher incidence of lymph node metastasis. In general, VEGF is described as an endothelial cell-specific growth factor and its ability to promote tumorigenesis has been completely linked to its pro-angiogenic effects. However, evidence that the effects of VEGF may not be restricted to endothelial cells is emerging, as VEGF receptors (VEGFR-1 and VEGFR-2) can be expressed by a subset of non-endothelial cell types. Recently, our laboratory has discovered that one of these receptors, VEGFR-1, is expressed by epidermal keratinocytes. We have also demonstrated a functional role for VEGFR-1 in keratinocyte proliferation in vitro and in vivo during the proliferative phase of cutaneous wound healing. Because excessive proliferation is integral to tumor development, our results suggest that VEGF, through interaction with VEGFR- 1, may influence cutaneous tumorigenesis by signaling directly in keratinocytes. The goal of the proposed studies is to determine whether VEGF can directly stimulate keratinocytes through VEGFR-1, and if this direct keratinocyte stimulation by VEGF is involved in skin carcinogenesis. To carry out these studies we will use novel genetically modified mice, which will allow the temporal deletion of VEGFR-1 specifically in keratinocytes. Mouse models of skin carcinogenesis in addition to human skin cancer samples will be used to carry out the following specific aims: 1) Determine the role of keratinocyte VEGFR-1 in chemical skin carcinogenesis, 2) Evaluate the role of keratinocyte VEGFR-1 in photocarcinogenesis, and 3) Examine VEGFR-1 expression and signaling in human keratinocytes and skin tumors. These studies could potentially reveal a novel biological function for VEGF and could uncover a new, direct mechanism for the involvement of VEGF in the promotion of skin carcinogenesis. The data generated from these experiments will provide new information about the mechanisms involved in skin cancer development, which could be important for treating millions of patients diagnosed with this disease each year. PROJECT NARRATIVE: Non-melanoma skin cancer is the most common type of cancer diagnosed, with over a million new cases reported in the U.S. every year. The studies proposed in this application will examine new pathways involved skin cancer development. The information resulting from these studies could lead to a better understanding about the development and growth of skin tumors, and could also result in the development of better ways to prevent and treat skin cancer.