Daniel Chung's Laboratory

The overall goal of the laboratory is to better elucidate the genetic events in gastrointestinal tumorigenesis. 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. Interistingly, K-ras functions synergistically with Wnt signaling to upregulate VEGF, and we have identified the PI3K-dependent inhibition of GSK-3beta 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.

Past Lab Members

• Suzanne Brown
• John Gaspard
• Won-Seok Jo, MD
• Jingnan Li, MD, PhD
• Karina Lund
• Yusuke Mizukami, MD, PhD

Recent Lab Publications

• Bertagnolli MM, Eagle CJ, Zauber AG, Redston M, Solomon SD, Kim KM, Tang J, Rosenstein RB, Wittes J, Corle D, Hess TM, Woloj GM, Boisserie F, Anderson WF, Viner JL, Bagheri D, Burn J, Chung DC, Dewar T, Foley TR, Hoffman N, MacRae F, Pruitt RE, Saltzman JR, Salzberg B, Sylwestrowicz T, Gordon GB, Hawk ET, for the APC Study Investigators. Celecoxib for the prevention of sporadic colorectal adenomas. New England Journal of Medicine, 2006, 355:873-84.


• Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC. Hypoxic regulation of vascular endothelial growth factor through the induction of PI3K/Rho/ROCK and c-Myc. Journal of Biological Chemistry, 2006, 281:13957-63.


• Mizukami Y, Jo WS, Duerr EM, Gala M, Li J, Zhang XB, Zimmer MA, Iliopoulos O, Zukerberg LR, Lynch MP, Rueda BR, Chung DC. Induction of interleukin-8 preserves the angiogenic response in HIF-1 deficient colon cancer cells. Nature Medicine, 2005, 11:992-97.


• Gostjeva EV, Zukerberg L, Chung D, Thilly WG. Bell-shaped nuclei dividing by symmetrical and asymmetrical nuclear fission have qualities of stem cells in human colonic embryogenesis and carcinogenesis. Cancer Genetics and Cytogenetics, 2006, 164:16-24.


• Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, Chung DC. Hypoxic regulation of vascular endothelial growth factor through the induction of PI3K/Rho/ROCK and c-Myc. J Biol Chem. 2006 Mar 16, epub.


• Jo WS, Mizukami Y, Duerr EM, Zukerberg LR, Chung DC. Wnt signaling can repress thrombospondin-1 expression in colonic tumorigenesis. Cancer Biology and Therapy, 2005, 4:1361-66.


• Jo WS, Bandipalliam P, Shannon KM, Niendorf KB, Chan-Smutko G, Hur C, Syngal S, Chung DC. Correlation of polyp number and family history of colon cancer with germline MYH mutations. Clinical Gastroenterology and Hepatology, 2005, 3:1022-28.


• Jo WS, Chung DC. Genetics of hereditary colon cancer. Seminars in Oncology, 2005, 32:11-23.


• Li J, et al. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta. Gastroenterology, 2005, 128:1907-18.


• Velayos FS, et al. Low rate of microsatellite instability in young patients with adenomas: Reassessing the Bethesda Guidelines. American Journal of Gastroenterology, 2005, 100:1143-49.


• Costa-Guda J, et al. Mutational analysis of PPARG as a candidate tumor suppressor gene in enteropancreatic endocrine tumors. Clinical Endocrinology, 2005, 62:603-6.


• Zhang X, et al. Overexpression of cyclin D1 in pancreatic beta-cells in vivo results in islet hyperplasia without hypoglycemia. Diabetes, 2005, 54:712-19.


• Chung DC. Cyclin D1 in human neuroendocrine tumorigenesis, in Gastroenteropancreatic neuroendocrine tumor disease: molecular and cell biological aspects. Annals of NY Academy of Sciences 2004, 1014:209-217.


• Willett CG, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nature Medicine, 2004, 10:145-47.


• Mizukami Y, et al. HIF-1 independent regulation of VEGF by hypoxia in colon cancer. Cancer Research 2004, 64:1765-72.

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