Keratinocyte responses to vascular endothelial growth factor in carcinogenesis

描述(申请人提供)：血管生成是许多类型肿瘤的发展、生长和扩散的重要组成部分，包括皮肤恶性肿瘤。血管内皮生长因子-A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，高水平的血管内皮生长因子与促进乳头状瘤发展、增加鳞状细胞癌数量和更高的淋巴转移发生率有关。一般来说，血管内皮生长因子被描述为一种内皮细胞特异性生长因子，其促进肿瘤形成的能力完全与其促血管生成作用有关。然而，随着血管内皮生长因子受体(VEGFR-1和VEGFR-2)在非内皮细胞亚型中的表达，血管内皮生长因子的作用可能不局限于内皮细胞的证据正在出现。最近，我们的实验室发现，其中一种受体VEGFR-1由表皮角质形成细胞表达。我们还证明了VEGFR-1在皮肤创伤愈合的增殖期在体外和体内角质形成细胞增殖中的功能作用。由于过度增殖与肿瘤的发展是不可分割的，我们的结果提示，通过与VEGFR-1的相互作用，VEGF可能通过直接在角质形成细胞中传递信号来影响皮肤肿瘤的发生。这项研究的目的是确定血管内皮生长因子是否能通过VEGFR-1直接刺激角质形成细胞，以及这种直接刺激角质形成细胞是否参与了皮肤癌的发生。为了进行这些研究，我们将使用新的转基因小鼠，这将允许在角质形成细胞中暂时删除VEGFR-1。除了人类皮肤癌样本外，还将使用小鼠皮肤癌模型来实现以下特定目的：1)确定角质形成细胞VEGFR-1在化学皮肤癌发生中的作用；2)评估角质形成细胞VEGFR-1在光致癌中的作用；以及3)检测VEGFR-1在人类角质形成细胞和皮肤肿瘤中的表达和信号。这些研究可能揭示血管内皮生长因子的一种新的生物学功能，并可能揭示一种新的、直接的机制，即血管内皮生长因子参与促进皮肤癌的发生。这些实验产生的数据将提供有关皮肤癌发生机制的新信息，这可能对每年治疗数百万被诊断为皮肤癌的患者很重要。 项目简介：非黑色素瘤皮肤癌是诊断出的最常见的癌症类型，美国每年报告的新病例超过100万例。在这项申请中提出的研究将检查与皮肤癌发生有关的新途径。这些研究所产生的信息可能有助于更好地了解皮肤肿瘤的发展和生长，也可能导致开发出更好的预防和治疗皮肤癌的方法。

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.