Daniel C. Chung, MD
Molecular Genetics of Colon Cancer; Angiogenesis in Colon Cancer; Neuroendocrine Tumors
There are two major ongoing projects. A primary focus of the laboratory is to define the roles of the Wnt and K-ras signaling pathways in the regulation of angiogenesis. The genetic events in colorectal cancer development are well described, and the challenge is to determine the functional consequences of these genetic defects. The Wnt and K-ras pathways are critical regulators of early tumorigenesis, and identifying the relevant biological processes affected by these pathways can provide clues into strategies for preventing or arresting growth at this early pre-malignant stage. 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, and we have provided insights into the importance of the PI3K effector pathway. Interestingly, K-ras functions synergistically with Wnt signaling to upregulate VEGF, and we have identified the PI3K-dependent inhibition of GSK-ß as an important molecular mechanism for this interaction. Hypoxia is also a critical stimulus for VEGF upregulation, and our studies have defined a unique role for oncogenic Kras signaling in the hypoxic induction of VEGF that does not depend upon the classical hypoxia-inducible factor-1 (HIF-1) pathway. However, in the absence of HIF-1, tumor angiogenesis is preserved. Current studies are aimed at elucidating the compensatory pathways that maintain angiogenesis in the absence of HIF-1. Collectively, these studies highlight the importance of angiogenesis in premalignant as well as malignant disease, and focus attention on potential anti-angiogenic approaches for the prevention of colon cancer.
The second focus of the laboratory is to identify the genetic events that underlie the development of gastroenteropancreatic neuroendocrine tumors. Human neuroendocrine tumors exhibit unique biological properties, and defining the molecular genetic alterations that underlie these distinctive features remains an important challenge. In addition to the MEN1 tumor suppressor gene, the cyclin D1 oncogene has demonstrated a role in the pathogenesis of these neuroendocrine tumors. Upregulation of cyclin D1 is observed early in tumor formation, implying a possible role in tumor initiation. Our goal is to take a genome-wide approach to identify additional genetic events that may provide new insights into tumor pathogenesis and ultimately, therapy.