The goals of the laboratory are: (1) to define the molecular pathogenesis of endocrine tumors of the GI tract. Genome-wide allelotyping studies have identified several novel tumor suppressor loci on chromosomes 3p, 3q, 11p, 16p, and 22q, and current studies are aimed at characterizing these loci further. In addition, we are exploring the role of cyclin D1 in tumor pathogenesis by defining the mechanisms of oncogene upregulation as well as the cell cycle and non-cell cycle functions of cyclin D1 in these tumors. (2) to understand the molecular mechanisms that regulate angiogenesis in early colonic neoplasia. In particular, a primary focus of the laboratory is to define the roles of the Wnt and K-ras signaling pathways in the regulation of angiogenesis. Vascular endothelial growth factor (VEGF) is the critical stimulus for tumor angiogenesis, and we have demonstrated the novel upregulation of VEGF by the Wnt pathway. Oncogenic Ras can also up-regulate VEGF, but we have provided the first insights into the importance of the PI3K/Akt effector pathway in colon tumorigenesis. Interestingly, K-ras functions synergistically with Wnt signaling to upregulate VEGF, and we have identified the PI3K-dependent inhibition of GSK-3β as an important molecular mechanism for the interaction between these two critical pathways.