GI Cancers – Daniel C. Chung Laboratory

Overview

Angiogenesis in colon cancer

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

Clinical translational studies are focused on identifying new genotype-phenotype correlations in families with hereditary cancer syndromes.  Improving the recognition of families with hereditary colon cancer and defining the specific cancer risks associated with specific mutations are our primary goals.   Using our hereditary GI cancer family registry, we have made several new observations including a higher risk than previously appreciated of thyroid cancer in Familial Adenomatous Polyposis, a subset of individuals with the MYH-Associated Polyposis syndrome that overlaps with the Lynch nonpolyposis syndrome, the impact of chemoradiation on the results of DNA microsatellite instability testing, and the role of Epithelial-to-Mesenchymal transition in tumors with or without DNA Microsatellite Instability (MSI).   The field in rapidly evolving, and we seek to enhance the use of genetic information to improve clinical management in these families.

Research Projects

• A prospective study of depressive symptoms and risk of Crohn’s disease and ulcerative colitis
• An examination of dietary factors, in particular dietary fat and fiber, on the risk of Crohn’s disease and ulcerative colitis
• Safety and efficacy of biologic therapy among older patients with inflammatory bowel disease
• Genetic predictors of severity of disease in Crohn’s disease and ulcerative colitis
• Gene-environment interactions in the pathogenesis of Crohn’s disease and ulcerative colitis
• A study of the role of vitamin D supplementation in the treatment of Crohn’s disease and ulcerative colitis
• Genetic predictors of response to therapy and adverse outcomes in inflammatory bowel diseases

Other Group Members

• Masayoshi Yamamoto, M.D., Ph.D.
• Liangjing Wang, M.D., Ph.D.
• Eunjeong Jang, M.D.
• Manish Gala, M.D.
• Audrey Ranieri

Publications

1. Zeng M, Kikuchi H, Pino MS, Chung DC. Hypoxia activates the K-Ras proto-oncogene to stimulate angiogenesis and inhibit apoptosis in colon cancer cells. PLoS One 2010 Jun 4 ;5(6):e10966. PMCID: PMC2881039.
2. Pino MS, Kikuchi H, Zeng M, Herraiz MT, Sperduti I, Berger D, Park DY, Iafrate AJ, Zukerberg LR, Chung DC. The epithelial to mesenchymal transition is impaired in colon cancer cells with microsatellite instability. Gastroenterology 2010 Apr; 138(4):1406-17. PMCID: PMC2846966.
3. Manne SL, Meropol N, Weinberg D, Vig H, Goodwin A, Catts Z, Goodwin A, Shannon KM, Chung DC. Facilitating informed decisions regarding microsatellite instability testing among high-risk individuals diagnosed with colorectal cancer. J Clin Oncol 2010 Mar 10; 28(8):1366-72. PMCID: PMC2834496.
4. Kikuchi H, Pino MS, Zeng M, Shirasawa S, Chung DC. Oncogenic KRAS and BRAF differentially regulate hypoxia-inducible factor-1alpha and -2alpha in colon cancer. Cancer Res 2009; 69:8499-506. PMCID: PMC2811371.
5. Benita Y, Kikuchi H, Smith AD, Zhang MQ, Chung DC, Xavier RJ. An integrative genomics approach identifies Hypoxia Inducible Factor-1 (HIF-1) target genes that form the core response to hypoxia. Nucleic Acids Res 2009; 37:4587-602. PMCID: PMC2724271.
6. Fujiki K, Duerr E-M, Kikuchi H, Ng A, Xavier RJ, Mizukami Y, Imamura T, Kulke MH, Chung DC. Hoxc6 is overexpressed in gastrointestinal carcinoids and interacts with JunD to regulate tumor growth. Gastroenterology 2008; 135:907-16. 
7. Imamura T, Kikuchi H, Herraiz M, Park DY, Mizukami Y, Mino-Kenudson M, Lynch MP, Rueda BR, Benita Y, Xavier RJ, Chung DC. HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer 2009; 124:763-71. PMCID: PMC2682346.
8. Pino MS, Mino-Kenudson M, Mandes Wildemore BM, Ganguly A, Batten JM, Iafrate AJ, Chung DC. Deficient DNA mismatch repair is common in Lynch syndrome-associated colorectal adenomas. J Mol Diagn 2009; 11:238-47. PMCID: PMC2671341.
9. Duerr EM, Mizukami Y, Ng A, Xavier RJ, Kikuchi H, Deshpande V, Glickman J, Warshaw AL, Kulke MH, Chung DC. Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Rel Cancer 2008; 15:243-56.
10. 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; 281:13957-63.
11. 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. Nat Med 2005; 11:992-97.
12. 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. Clin Gastroenterol Hepatol 2005; 3:1022-28.
13. Li J, Mizukami Y, Zhang X, Jo WS, Chung DC. Oncogenic K-ras stimulates Wnt signaling in colon cancer through inhibition of GSK-3beta. Gastroenterology 2005; 128:1907-18.
14. Mizukami Y, Li J, Zhang X, Zimmer MA, Iliopoulos O, Chung DC. HIF-1 independent regulation of VEGF by hypoxia in colon cancer. Cancer Res 2004; 64:1765-72.