Proinflammatory CD4+CD45RBhi Lymphocytes Promote Mammary and Intestinal Carcinogenesis in Apc Min/+ Mice

Abstract

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 ApcMin/+ 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-A. Lastly, down-regulation of cyclooxygenase-2 and c-Myc expression is observed coincident with tumor regression. These findings define a novel mouse model of inflammationdriven mammary carcinoma and suggest that epithelial carcinogenesis can be mitigated by anti-inflammatory cells and cytokines known to regulate IBD in humans and mice.

Nitric oxide and TNF-α trigger colonic inflammation and carcinogenesis in Helicobacter hepaticus -infected, Rag2 -deficient mice

“…Supplementation with proinflammatory T EFF cells increased IFN-␥-dependent and TNF-␣-dependent malignancy in inflammation-driven mouse models (41), confirmed by studies showing increased inflammatory disease after T EFF cell transfer in H. hepaticus-infected Rag2 Ϫ/Ϫ mice (18,22,42). Increased IFN-␥ secretion and NO (11,15) have been found in humans with gastrointestinal carcinoma as well (1).…”

“…Mice were euthanized at 3-4 months after infection Lymphocyte Transfer. For adoptive transfer of CD4 ϩ lymphocytes, 160 mice (treatment groups of 10 recipient mice, each with 2 replications) underwent the procedure as described previously (16,41). Single-cell suspensions of CD4 ϩ lymphocytes were prepared as described previously (56,57) from spleen and mesenteric lymph nodes from Helicobacter-free wild-type or IL10 Ϫ/Ϫ donor mice backcrossed at least 10 generations onto the 129/SvEv genetic background.…”

“…For experiments involving depletion of Gr-1 ϩ cells or neutralization of TNF-␣, 40 infected mice were subdivided into groups of 10 each, and each was dosed with 0.2 mL of anti-Gr-1 or anti-TNF antibody, or sham isotype IgG control, as described elsewhere (41). Anti-Gr-1 antibody is widely used to label mature neutrophils.…”

“…Hyperplastic and inflammatory lesions were graded on a scale of 0 to 4 with ascending severity as described previously (16,34). Macrophages and neutrophils were identified in intestinal tissue sections with standard avidin-biotin complex immunohistochemistry and were quantified as described previously (41). Immunofluorescence was performed as described elsewhere (58).…”

Mutations in Bone Marrow-Derived Stromal Stem Cells Unmask Latent Malignancy

“…Less than 1% of B6Min mice housed at MIT or UMass develop mammary carcinoma as they age (personal observation). Tumor incidence is directly linked to infl ammatory triggers [21][22][23] as tumor formation occurs with chronic infection [ 23 ]. Congenital or acquired immunodefi ciency is strongly associated with an increased incidence of tumors in both human and mice.…”