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Proinflammatory CD4⁺CD45RB^hi Lymphocytes Promote Mammary and Intestinal Carcinogenesis in Apc^Min/+ Mice

¹ Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts; ² Immunology Research Division, Department of Pathology, Brigham and Women's Hospital and Division of Emergency Medicine, Children's Hospital, Boston, Massachusetts; ³ Laboratory of Pathology, Faculty of Veterinary Medicine, Aristotle University of Thessaloniki, Greece

Requests for reprints: Susan E. Erdman, Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139. Phone: 617-252-1804; Fax: 617-258-5708; E-mail: serdman{at}mit.edu.

Cancers of breast and bowel are increasingly frequent in humans. Chronic inflammation is known to be a risk factor for these malignancies, yet cellular and molecular mechanisms linking inflammation and carcinogenesis remain poorly understood. Here, we apply a widely used T-cell transfer paradigm, involving adoptive transfer of proinflammatory CD4⁺CD45RB^hi (T_E) cells to induce inflammatory bowel disease (IBD) in mice, to investigate roles of inflammation on carcinogenesis in the Apc^Min/+ mouse model of intestinal polyposis. We find that transfer of T_E cells significantly increases adenoma multiplicity and features of malignancy in recipient Apc^Min/+ mice. Surprisingly, we find that female Apc^Min/+ recipients of T_E cells also rapidly develop mammary tumors. Both intestinal polyposis and mammary adenocarcinoma are abolished by cotransfer of anti-inflammatory CD4⁺CD45RB^lo regulatory lymphocytes or by neutralization of key proinflammatory cytokine tumor necrosis factor-. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammation-driven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice. (Cancer Res 2006; 66(1): 57-61)

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