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Timothy C. Wang, M.D.
Dorothy L. and Daniel H. Silberberg Professor of Medicine
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Research
Summary
Dr. Timothy C. Wang is the Silberberg Professor of Medicine and Chair of the Division of Gastroenterology. He received his MD from Columbia University, followed by clinical and research training at Washington University and Harvard/MGH. His main interest is in murine models of gastrointestinal cancer, and the role of stem cells in nflammation-associated cancer. Dr. Wang’s laboratory reported that gastric cancer in murine models can originate from bone marrow-derived stem cells. A separate project has identified markers for human gastric cancer stem cells. As the leader of the Columbia University Tumor Microenvironment Network, he has investigated the importance of the stem cell niche in governing stem cell differentiation, and how this niche is altered in chronic inflammatory states that predispose to cancer. He is currently investigating the role of both fibroblasts and myeloid cells in carcinogenesis. Dr. Wang is a recipient of the AGA Funderberg Gastric Cancer Award and is the Editor of the first textbook on gastric cancer, “The Biology of Gastric Cancer” (Springer 2008). He is the Chair of the GCMB NIH study section, Chair of the AGA Future Trends Committee, Associate Editor for Gastroenterology, Editor in Chief of Therapeutic Advances in Gastroenterology. He is the author of more than 160 peer-reviewed publications.
Research Activities
Dr. Wang began his research career in the area of gastrin biology, and his research has continued to explore the role of gastrin peptides in diverse diseases including peptic ulcer disease, gastric cancer, and colorectal cancer. His laboratory was the first to generate gastrin-deficient mice through targeted gene disruption, and to identify in vivo roles for incompletely processed gastrins such as glycine-extended gastrin (G-gly) and progastrin. With respect to colon cancer, his laboratory demonstrated a direct link between Wnt signaling and gastrin gene regulation, and between progastrin expression and an increased susceptibility to colon cancer in animal models. He has been a leader in the field of gastrin biology, and his work in the field of gut hormones has included organizing the International Conference on Gastrin (1999) and the International Regulatory Peptide Conference (2002). He current serves on the International Steering Committee for Regulatory Peptides. Other areas of investigation include gastrin-regulated transcription, the regulation of protein stability and degradation, and the role of the trefoil peptide SP/TFF2 in gastric disease. His lab was the first to develop a knockout of the TFF2 gene, and more recently to show a role for TFF2 in innate immunity.
The major current focus of his laboratory is the nature of the association between inflammation and cancer. He was the first to show in vivo oncogenic roles for cyclin D1, able to induce neoplasia when overexpressed in mammary epithelium (Wang et al, Nature 1994). His laboratory has worked extensively with mouse models of Helicobacter infection, and was the first to describe a murine model of Helicobacter-dependent gastric carcinogenesis. Studies from Dr. Wang’s group has demonstrated the critical importance for Th1-mediated inflammation in the progression through atrophy/metaplasia and cancer in the mouse stomach, and he has also identified co-factor roles for hormones, nutrients and host factors in the development of cancer. However, the most exciting work currently underway in Dr.Wang’s laboratory relates to studies on the cellular origins of gastric cancer. Dr. Wang was the first to propose the hypothesis that epithelial cancers might possibly originate from a circulating stem cell. Studies were undertaken in Dr. Wang’s laboratory in 2001 that led to the remarkable observation that, in mice transplanted with GFP- or lacZ-tagged bone marrow and then infected with Helicobacter, gastric cancers originated not from gastric stem cells but from bone marrow-derived stem cells. Dr. Wang is the senior author of this paper, published in Science (Science 2004; 306:1568-71), and his lab is now highly focused on follow-up investigations related to this remarkable discovery. The landmark paper provides the first clear understanding of the link between inflammation and cancer, and in fact offers a new paradigm for the multistep model of cancer progression.
http://asp.cpmc.columbia.edu/facdb/profile_list.asp?uni=tcw21&DepAffil=Medicine
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Selected Publications:
1. Wang TC, Cardiff RD, Zuckerberg L, Lees E, Arnold A, Schmidt EV. (1994) Mammary hyperplasia and carcinoma in MMTV-Cyclin D1 transgenic mice. Nature
369:669-671
2. Wang TC, Koh TJ, Varro A, Cahill R, Dangler CA, Fox JG, Dockray GJ. (1996) Processing and proliferative effects of human progastrin in transgenic mice. J. Clin. Invest.
98:1918-1929
3. Koh TJ, Dockary GJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Wang TC. (1999) Overexpression of glycine-extended gastrin in transgenic mice results in increased colonic proliferation. J. Clin. Invest.
103:1119-1126
4. Wang TC, Dangler C, Chen C, Goldenring JR, Koh TJ, Raychowdhury R, Coffey RJ, Ito S, Varro A, Fox JG. (2000) Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric carcinoma. Gastroenterology
118:36-47
5. Fox JG, Beck P, Dangler CA, Whary MT, Wang TC, Shi HN, Anderson CN. (2000) Concurrent enteric helminth infection modulates inflammation, gastric immune responses, and reduces Helicobacter-induced gastric atrophy. Nature Medicine
6:536-542
6. Fox JG, Wang TC. (2001) Helicobacter pylori--not a good bug after all! New England Journal of Medicine
345(11):829-832
7. Wang TC, Goldenring, JR. (2002) Inflammation intersection: gp130 balances gut irritation and stomach cancer. Nature Medicine
8(10):1080-1082
8. Houghton JM, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR, Wang TC. (2004) Gastric cancer originating from bone marrow derived cells. Science
306:1568-1571
9. Fox JG, Rogers AB, Whary MT, Ge Z, Ohtani M, Jones EK, Wang TC. (2007) Accelerated progression of gastritis to dysplasia in the pyloric antrum of TFF2 -/- C57BL6 x Sv129 Helicobacter pylori-infected mice. American Journal Pathology
171(5):1520-1528
10. Takaishi S, Okumura T, Wang TC. (2008) Gastric Cancer Stem Cells. Journal Clinical Oncology
26(17):2876-2882
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Honors and Awards
AGA Funderberg Gastric Cancer Award
Committees
Chair - GCMB NIH Study Section
Chair - AGA Future Trends Committee
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