Carcinogenesis Advance Access originally published online on August 27, 2007
Carcinogenesis 2007 28(12):2614-2623; doi:10.1093/carcin/bgm180
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Rapid reversal of interleukin-6-dependent epithelial invasion in a mouse model of microbially induced colon carcinoma
1 Division of Comparative Medicine
2 Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
3 Department of Medicine and Microbiology, Columbia University, 1130 St Nicholas Avenue, Room 918, New York, NY 10032
4 Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Avenue, Boston, MA 02115, USA
5 Present address: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Thessaloniki 54006, Greece
6 Present address: Unit for Molecular Pathology, Center for Cancer Research, Massachusetts General Hospital, Bldg 149, Rm 7148, 13th Street, Charlestown, MA 02129, USA
7 Present address: Feinstein Institute for Medical Research, 350 Community Drive, Manhasset NY 11030, USA
* To whom correspondence should be addressed. Tel: +1 617 252 1804; Fax: +1 617 258 5708; Email: serdman{at}mit.edu
Chronic inflammation of mucosal surfaces renders them increasingly susceptible to epithelial cancers both in humans and mice. We have previously shown that anti-inflammatory CD4+CD45RBloCD25+ regulatory (Treg or TR) lymphocytes down-regulate inflammation and block development of bacteria-triggered colitis and colorectal cancer (CRC) in 129/SvEv Rag2–/– mice. Interestingly, TR cells collected from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma with a strong gender bias expressing in male mice. We found we show that peritoneal invasion in this model is dependent on pleiotropic cytokine IL-6. Mucinous carcinoma arose rapidly and consistently after treatment with IL10–/– TR cells, which were found to express Foxp3+ and localize throughout tumor tissue. Carcinogenesis was rapidly reversible with transfer of wild type IL10-competent TR cells. Likewise, treatment with IL10-Ig fusion protein was sufficient to revert the lesions histologically, and restore inflammatory cytokine and oncogene expression to base line levels. These studies indicate an essential role for IL 6 in this CRC phenotype. Furthermore, immune-competent TR cells were important not only for preventing pathology but also for constructive remodeling of bowel following tumorigenic microbial insults. These data provide insights into etiopathogenesis of inflammation-associated epithelial invasion and maintenance of epithelial homeostasis.
Abbreviations: IBD, inflammatory bowel disease; Ig, immunoglobulin; IL, interleukin; PCR, polymerase chain reaction; PI, post-infection; Tgf, transforming growth factor; TNF-
, tumor necrosis factor ; TR or Treg, CD4+CD45RBloCD25+; wt, wild-type; CRC, colorectal cancer
Received July 5, 2007; revised July 26, 2007; accepted July 27, 2007.