The long-term goal of this proposal is to establish the mechanisms of ethanol (EtOH)-induced cancer in which chronic alcohol consumption with physiologically relevant doses stimulates tumor angiogenesis and matigancy. Alcohol consumption is a well-established risk factor for various types of cancer, such as cancers of the oral cavity, esophagus, liver, and breast. However, the mechanisms of EtOH-induced cancer are not clear. Growth and expansion of tumor mass are strictly dependent upon the sustained formation of new blood vessels, a process termed angiogenesis. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic factors, which is markedly up-regulated in the vast majority of human tumors. We have recently reported in Am J Physiology that physilogically relevant levels of EtOH induce VEGF expression and angiogenesis in both models of cell culture and chick chorioallantoic membrane (CAM). Furthermore, we have discovered that EtOH treatment with physiologically relevant doses increases intratumoral vascularity and VEGF expression while enhancing tumor progression and intravasantion of cancer cells in a chick CAM model. These findings suggest that EtOH-induced angiogenesis represents an important mechanism of cancer progression associated with chronic alcohol consumption in humans. We will use chronic alcohol in vivo models with administration of hysiologically relevant doses of EtOH that mimics chronic alcohol consumption in humans. This proposed work will test the hypothesis that chronic alcohol consumption with physiologically relevant loses can mediate angiogenic factors and drive a system of positive feedback between the expanding neoplasm and vasculature, wherein each promotes the growth of the other. We will use different models to address the following specific aims: 1) whether EtOH treatment with physiologically relevant doses can stimulate tumor angiogenesis and tumor progression in both in vivo models of the CAM, nude and scid mice; 2) whether administration of EtOH can alter the expression of VEGF and other regulatory factors of angiogenesis in the tumor, the circulation, and the cultured cells; and 3) how EtOH treatment can play a role in a system of positive feedback between intratumoral vasculature and tumor mass. The new information will promote cancer prevention and treatment.