Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer.
Inflammatory bowel disease (IBD) is a disorder of chronic inflammation with increased susceptibility to colorectal cancer. The etiology of IBD is unclear but thought to result from a dysregulated adaptive and innate immune response to microbial products in a genetically susceptible host. Toll-like receptor (TLR) signaling induced by intestinal commensal bacteria plays a crucial role in maintaining intestinal homeostasis, innate immunity and the enhancement of intestinal epithelial cell (IEC) integrity. However, the role of TLR2 in the development of colorectal cancer has not been studied. We utilized the AOM-DSS model for colitis-associated colorectal cancer (CAC) in wild type (WT) and TLR2(-/-) mice. Colons harvested from WT and TLR2(-/-) mice were used for histopathology, immunohistochemistry, immunofluorescence and cytokine analysis. Mice deficient in TLR2 developed significantly more and larger colorectal tumors than their WT controls. We provide evidence that colonic epithelium of TLR2(-/-) mice have altered immune responses and dysregulated proliferation under steady-state conditions and during colitis, which lead to inflammatory growth signals and predisposition to accelerated neoplastic growth. At the earliest time-points assessed, TLR2(-/-) colons exhibited a significant increase in aberrant crypt foci (ACF), resulting in tumors that developed earlier and grew larger. In addition, the intestinal microenvironment revealed significantly higher levels of IL-6 and IL-17A concomitant with increased phospho-STAT3 within ACF. These observations indicate that in colitis, TLR2 plays a protective role against the development of CAC.
Lowe
Emily L
EL
Division of Pediatric Infectious Diseases and Immunology, Cedars-Sinai Medical Center and David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.
Crother
Timothy R
TR
Rabizadeh
Shervin
S
Hu
Bing
B
Wang
Hanlin
H
Chen
Shuang
S
Shimada
Kenichi
K
Wong
Michelle H
MH
Michelsen
Kathrin S
KS
Arditi
Moshe
M
D058739:Aberrant Crypt Foci / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D003092:Colitis / Q000150:complications* / Q000235:genetics / Q000276:immunology; D015179:Colorectal Neoplasms / Q000209:etiology / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009385:Neoplastic Processes; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology*
D015850:Interleukin-6; D051195:Toll-Like Receptor 2