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Carcinogenesis Advance Access published online on August 27, 2007
Carcinogenesis, doi:10.1093/carcin/bgm180
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cytokine –mediated rapid reversal of epithelial invasion in a mouse model of microbially-induced colon carcinoma

Theofilos Poutahidis1,*, Kevin M. Haigis2, Varada P. Rao1, Prashant R. Nambiar1, Christie L. Taylor1, Zhongming Ge1, Koichiro Watanabe1, Anne Davidson3, Bruce H. Horwitz4, James G. Fox1 and Susan E. Erdman1

1 Division of Comparative Medicine . Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139
2 Center for Cancer Research, Massachusetts Institute of Technology
3 Department of Medicine and Microbiology, Columbia University, 1130 St. Nicholas Ave., Rm. 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

Corresponding author: Susan E. Erdman serdman{at}mit.edu, ph 617-252-1804, fax 617-258-5708

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 carcinoma (CRC) in 129/SvEv Rag2-/- mice. Interestingly, CD4+CD25+ cells from Interleukin (IL)-10-deficient cell donors not only failed to suppress carcinogenesis but instead promoted invasive mucinous colonic carcinoma in male mice. Here we show that peritoneal invasion by 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 dependent on IL-6 and rapidly reversible by 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 levels to base line levels. These studies indicate an essential role for IL-6 in this male predominant CRC phenotype. Interleukin-10-competent TR cells are important 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.

Key Words: IL6 • epithelial homeostasis • colorectal cancer • regulatory cells • IL10

* current address: Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece, 54006

Received June 5, 2007; revised July 26, 2007; accepted July 27, 2007.


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