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The Innate Immune Receptor Nod1 Protects the Intestine from Inflammation-Induced Tumorigenesis

Division of Hematology and Oncology, Departments of ¹ Internal Medicine and ² Pathology, ³ University of Michigan Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan

Requests for reprints: Gabriel Núñez, University of Michigan Comprehensive Cancer Center, Room 4215, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5938. Phone: 734-764-8514; Fax: 734-647-9654; E-mail: bclx{at}umich.edu.

Key Words: colon cancer • colitis • inflammation, NLR

There is growing evidence that the host innate immune system has a critical role in regulating carcinogenesis, but the specific receptors involved and the importance of their interaction with commensal bacteria need to be elucidated. Two major classes of innate immune receptors, the Toll-like receptors and Nod-like receptors, many of which are upstream of nuclear factor-B, are involved in the detection of intestinal bacteria. The Toll-like receptors have been implicated in promoting colon tumorigenesis, but the role of Nod-like receptors in regulating tumorigenesis remains unclear. Using an established mouse model system of colitis-associated colon tumorigenesis, we show that Nod1 deficiency results in the increased development of both colitis-associated and Apc tumor suppressor–related colon tumors. In the absence of Nod1 signaling, there is a greater disruption of the intestinal epithelial cell barrier due to chemically induced injury as manifested by increased surface epithelial apoptosis early on during chemically induced colitis and increased intestinal permeability. The increased intestinal permeability is associated with enhanced inflammatory cytokine production and epithelial cell proliferation in Nod1-deficient mice as compared with wild-type mice. Depletion of the gut microbiota suppressed tumor development in Nod1-deficient mice, thus highlighting a link between the commensal bacteria within the intestine and the host innate immune Nod1 signaling pathway in the regulation inflammation-mediated colon cancer development. [Cancer Res 2008;68(24):10060–7]