Inflammatory responses to the microbiota are proposed as contributory to the initiation and/or progression of human colorectal cancer (CRC). However, molecular links between members of the microbiota and colon carcinogenesis are poorly defined. The human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), is a molecular subtype of B. fragilis that produces a potent metalloprotease toxin called the B. fragilis toxin (BFT). ETBF is a potent inducer of colon tumorigenesis in a murine model through induction of a selective procarcinogenic intracolonic Th17 immune response. ETBF colon tumorigenesis requires BFT expression. BFT activates several procarcinogenic signaling pathways in colonic epithelial cells (CEC) by binding to a specific receptor localized to CECs. However, the BFT CEC receptor and its relationship to BFT-induced oncogenic signaling, colitis and colon tumorigenesis remain to be elucidated. Through subtraction array and shRNA strategies, GPR35, a G protein-coupled receptor (GPCR), is now identified as the putative BFT receptor. This proposal will test the hypothesis that GPR35, known to be highly expressed in the colon and previously linked to gastric cancer induction, is the CEC receptor hijacked by BFT and a critical contributor to colon carcinogenesis, thereby, providing a direct molecular link between a common microbiota member and CRC pathogenesis. We will test this hypothesis and further define how GPR35 contributes to BFT-induced CEC oncogenic signaling using knockout and knock-in CEC strategies plus GPR35 and ?-arrestin KO murine models. GPRCs represent the largest family of cell surface receptors within the human genome and powerful targets for new drug discovery. Thus, establishing a role for GPR35 or its isoforms in colon carcinogenesis may advance the prevention and/or therapy of human CRC.

Public Health Relevance

Colon cancer is the second leading cause of cancer death for women and men. We show that a single protein toxin (BFT) released by a newly recognized common human stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) causes colon tumor formation. This project will identify whether a protein in the colon cells called GPR35 binds BFT to stimulate colon tumor formation. GPR35 may be a new target for colon cancer prevention and treatment.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA179440-02
Application #
8693979
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Daschner, Phillip J
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Sears, Cynthia L; Geis, Abby L; Housseau, Franck (2014) Bacteroides fragilis subverts mucosal biology: from symbiont to colon carcinogenesis. J Clin Invest 124:4166-72
Sears, Cynthia L; Garrett, Wendy S (2014) Microbes, microbiota, and colon cancer. Cell Host Microbe 15:317-28