Colon cancers are highly angiogenic and were the first tumor type to demonstrate significant clinical responses to anti-angiogenic therapy. Our initial studies revealed that the genetic alterations that are commonly seen in colorectal cancer, namely mutations in the Wnt and K-ras signaling pathways, are strong regulators of vascular endothelial growth factor (VEGF) expression, both individually and synergistically. We have been interested in understanding how the microenvironment interacts with these genetic alterations to regulate angiogenesis. Hypoxia is a powerful stimulus for angiogenesis, and hypoxia inducible factor-1 (HIF-1) is the key regulator of angiogenesis in hypoxic conditions. Curiously, we discovered that angiogenesis was surprisingly well-preserved in colon cancer the absence of HIF-1. This was the consequence of the compensatory induction of an alternative angiogenic factor, the cytokine IL-8. This induction of IL-8 was mediated by NF-kB and dependent upon an activated K-ras oncogene. When HIF-1 and IL-8 were inhibited in combination, however, a potent anti-angiogenic effect was observed. The angiogenic response is therefore highly adaptable, and combination anti-angiogenesis may be the most effective therapeutic approach. Current studies seek to identify the optimal combinations of agents that target multiple independent pathways. In addition, we are interested in novel targets of the HIF transcription factor as well as differential activities of the HIF1 and HIF2 isoforms. Understanding the influence of hypoxia in tumorigenesis can provide new insights into therapeutic strategies.Molecular genetics of gastroenteropancreatic neuroendocrine tumors
Independent projects in the laboratory seek to identify key genetic alterations that underlie the pathogenesis of gastrointestinal neuroendocrine tumors. They are poorly understood on a genetic level, and we have taken a multipronged genetic and proteomic approach to define critical molecular alterations. We have assembled an unparalled collection of tumor samples and have utilized these to probe the tumor genome and proteome. Our studies have pointed to several new players: cyclin D1, a locus on chromosome 3p25, the HoxC6 gene, the RET oncogene, and PDGFR signaling. Current studies seek to define their pathogenicity and functional significance in neuroendocrine cells.Genotype-phenotype correlations in hereditary colon cancer
Masayoshi Yamamoto, M.D., Ph.D.
Liangjing Wang, M.D., Ph.D.
Eunjeong Jang, M.D.
Manish Gala, M.D.