MERIT Award Recipient: Kenneth W. Kinzler, Ph.D.
Genes from the FAP Locus
Colorectal cancer is a leading cause of cancer death in the United States with approximately 135,000 new cases and approximately 55,000 deaths each year. The Kinzler laboratory has previously shown that the great majority of these cases are initiated by mutations in the adenomatous polyposis coli (APC) pathway, a pathway that blocks the development of intestinal polyps. It is hoped that a better understanding of the APC pathway will lead to better treatment and prevention of colon cancer. In this regard, the Kinzler laboratory has previously exploited the role of APC in colorectal tumors to develop tests for inherited and sporadic forms of colorectal cancer. At the molecular level, the Kinzler laboratory has begun to define important components of the APC pathway, including the proteins beta-catenin, c-Myc, CDK4 and EB1. Future studies are aimed at further defining the APC pathway using genetic manipulation of human cancer cells and powerful methods for gene expression analysis.
In addition to acquiring genetic changes as described above, tumors must also subvert normal physiological processes to support their growth. Chief among these processes is the provision of a blood supply through stimulation of angiogenesis. Recently Dr. Kinzler's laboratory used SAGE, a powerful gene expression analysis tool, to study tumor angiogenesis in human colorectal tumors. Using this approach, they identified a series of proteins (TEMs) that is preferentially expressed in the vessel endothelial cells from human colorectal cancers. Ongoing studies are aimed at understanding the function of these proteins in tumor angiogenesis in hopes of exploiting them for therapy. The combination of the ongoing APC and tumor angiogenesis studies should provide important insights into the processes that drive and support colorectal tumor development.