Several lines of evidence have shown that the development of malignant tumors requires the formation of a well developed vasculature to support the nutrition and oxygen requirements of the rapidly expanding neoplastic cells. However, this subject has not been systematically investigated in the classical models of carcinogenesis and particularly in mouse skin carcinogensis. Recently our laboratories have initiated a comprehensive research project to investigate the role of angiogenesis in the mouse skin carcinogenesis model. Based on our preliminary data we have formulated the following hypotheses: the timing and extent of the angiogenesis response is a determinant in the type of premalignant lesions (flat dysplastic vs exophytic papillomas) induced in the mouse skin by chemical protocols. In the two stage carcinogenesis protocol, angiogenesis is a very early event associated with activation of ras during initiation and essential in the histogenesis of papillomas; the angiogenesis response conditions not only the growth and size of the papillomas but also their conversion to Squamous Cell Carcinomas (SCC). Vascular endothelial growth factor (VEGF) is the major angiogenesis factor in the mouse skin carcinogenesis model but other positive angiogenesis factors are necessary to develop the changes in the stroma observed in papillomas and carcinomas. VEGF expression is driven by ras activation in this model through signaling involving the HER family of receptors and AP-1 transcription factors. Systemic angiogenesis inhibitors produced by papillomas may have an effect on tumor progression. In order to test these hypotheses we have designed the following Specific Aims: 1. Investigate the development of angiogenesis and the expression of angiogenesis factors during the carcinogenesis process of skin. 2. Define whether angiogenesis inhibitors play a role in this model. 3. Develop and characterize genetically engineered mice with altered expression of VEGF and other relevant angiogenesis regulators. 4. Investigate the mechanisms involved in the regulation of angiogenesis and angiogenesis factors in normal, preneoplastic and neoplastic keratinocytes. 5. Investigate whether a locus in mouse chromosome 6, which we have shown to be frequently deleted in chemically induced tumors, plays a role in the regulation of angiogenesis.
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