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）发展、生长和扩散的重要组成部分。VEGF（血管内皮生长因子-a）是一种有效的促血管生成因子，它与皮肤的多种过程有关，包括肿瘤的发生。在皮肤中，高VEGF水平与乳头状瘤的发展、鳞状细胞癌数量的增加和淋巴结转移的发生率升高有关。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的作用完全相关。然而，越来越多的证据表明，VEGF的作用可能并不局限于内皮细胞，因为VEGF受体（VEGFR-1和VEGFR-2）可以在非内皮细胞类型中表达。最近，我们的实验室发现其中一种受体VEGFR-1是由表皮角质形成细胞表达的。我们还证明了VEGFR-1在皮肤伤口愈合增殖阶段的体外和体内角质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一部分，我们的研究结果表明，VEGF通过与VEGFR- 1的相互作用，可能通过在角质形成细胞中直接发出信号来影响皮肤肿瘤的发生。本研究的目的是确定VEGF是否可以通过VEGFR-1直接刺激角质形成细胞，以及VEGF对角质形成细胞的直接刺激是否参与皮肤癌的发生。为了进行这些研究，我们将使用新型转基因小鼠，这将允许在角化细胞中特异性地暂时删除VEGFR-1。除人类皮肤癌样本外，还将使用小鼠皮肤癌变模型来实现以下具体目的：1)确定角化细胞VEGFR-1在化学皮肤癌变中的作用；2)评估角化细胞VEGFR-1在光癌变中的作用；3)检测人角化细胞和皮肤肿瘤中VEGFR-1的表达和信号传导。这些研究可能潜在地揭示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。从这些实验中产生的数据将提供有关皮肤癌发展机制的新信息，这对每年治疗数百万被诊断患有这种疾病的患者可能很重要。

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.