Proinflammatory CD4+ CD45RB(hi) lymphocytes promote mammary and intestinal carcinogenesis in Apc(Min/+) mice.
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-alpha. 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.
Rao
Varada P
VP
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Poutahidis
Theofilos
T
Ge
Zhongming
Z
Nambiar
Prashant R
PR
Horwitz
Bruce H
BH
Fox
James G
JG
Erdman
Susan E
SE
D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology; D000236:Adenoma / Q000235:genetics / Q000276:immunology; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology; D005260:Female; D017491:Genes, APC; D016259:Genes, myc / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000276:immunology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000276:immunology*; D007417:Intestinal Polyps / Q000235:genetics / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology
D014409:Tumor Necrosis Factor-alpha; D017493:Leukocyte Common Antigens