CRC risk among UC patients can be reduced by regular therapy with 5-ASA medication. Colonoscopic surveillance may be best targeted on those unable to take 5-ASAs (e.g. due to allergy) and those with a positive family history of CRC.

Recombinase-activating gene-2-deficient (Rag2 ؊/؊ ) mice lacking functional lymphocytes provide a useful model of chronic inflammatory bowel disease-emulating events in human colon cancer. Infection of Rag2 ؊/؊ mice with Helicobacter hepaticus led to accumulation of macrophages and neutrophils in the colon, a process temporally related to up-regulation of tissue inducible nitric oxide synthase (iNOS) expression at the site of infection and increased nitric oxide (NO) production, as evidenced by urinary excretion of nitrate. Progressive development of increasingly severe inflammation, hyperplasia, dysplasia, and cancer accompanied these changes. Concurrent administration of an iNOS inhibitor prevented NO production and abrogated epithelial pathology and inhibited the onset of cancer. The presence of Gr-1 ؉ neutrophils and elevated tumor necrosis factor-␣ (TNF-␣) expression in colon were required for increased iNOS expression and cancer, whereas interleukin-10 (IL-10) down-regulated TNF-␣ and iNOS expression and suppressed cancer. Anti-inflammatory CD4 ؉ regulatory lymphocytes also down-regulated iNOS and reduced cancer formation. Collectively, these results confirm essential roles for inflammation, increased TNF-␣ expression, and elevated NO production in colon carcinogenesis.colorectal cancer ͉ IBD ͉ innate immunity C hronic Helicobacter pylori infection in humans leads to gastritis and has been established as a causative agent for human gastric cancer (1). Inflammatory bowel diseases (IBDs), such as Crohn's disease and ulcerative colitis, also increase risk for colon cancer (2, 3). Generation of nitric oxide (NO) by inducible NO synthase (iNOS) is a central feature of chronic inflammatory diseases in the gastrointestinal tract (4-9), but precise mechanistic roles for NO in colon cancer development remain undefined.Colon cancer patients exhibit evidence of nitrosative and oxidative stresses that increase cancer risk (10), resulting from mutagenic reactive oxygen and nitrogen species derived from NO generated by immune cells (6,(11)(12)(13)(14)(15). Roles for chronic bacterial infection in IBD and colon cancer have been identified recently in recombinase-activating gene-2-deficient mice (Rag2 Ϫ/Ϫ ), which completely lack functional lymphocytes (16-18). We have exploited this mouse model of chronic IBDassociated cancer for studies of the role of NO and its products because it emulates naturally occurring inflammatory events in humans (16,19,20).Rag2 Ϫ/Ϫ mice have been used to assess functions of lymphocytes by adoptive transfer. Populations of CD4 ϩ T cells with low or high expression of CD45RB (17,21, 22) or CD25 (16,18,23,24) prevent or accelerate colitis in these animals. In wild-type (wt) mice, protection against inflammatory pathology induced by bacterial infection has been attributed to interleukin-10 (IL-10) and IL-10-dependent functions of CD4 ϩ cells (18,20,25,26). Collectively, this evidence forms the rationale for the hypothesis that NO overproduction comprises a linkage between Helicobacter hepaticus-i...

Activities of CD4+ regulatory (TREG) cells restore immune homeostasis during chronic inflammatory disorders. Roles for TREG cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that TREG function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that TREG cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a “hygiene hypothesis” model in which GI infections lead to changes in TREG that reduce immune-mediated diseases, here we show that gut bacteria-triggered TREG may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated TREG to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory TREG phenotype. However, under proinflammatory conditions, TREG may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and TREG-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of TREG and inflammation in cancer. Enhancing protective TREG functions may promote healthful longevity and significantly reduce risk of cancer.

Chronic inflammation contributes to the development of prostate cancer in humans. Here, we show that male ApcMin/+ mice also develop prostate carcinoma with increasing age, mimicking that seen in humans in their 5th or 6th decade of life. Proinflammatory cytokines were significantly linked with cancer and increasing age in our mouse model; however, prostate and bowel tissues lacked evidence of inflammatory cell infiltrates other than mast cells. Lymphocytes protected against cancer, and protection from prostate cancer resided in antiinflammatory CD4+CD25+ regulatory (TREG) cells that downregulated inflammatory cytokines. Supplementation with syngeneic TREG cells collected from wild-type mice reduced the levels of interleukin (IL)-6 (p < 0.05) and IL-9 (p < 0.001) and lowered prostate cancer risk (p < 0.05). Depletion of CD25+ cells in 2-month-old animals increased the expression of IL-6 (p < 0.005) within prostate and increased the frequency of high-grade prostatic intraepithelial neoplasia (p < 0.05) and microinvasive prostatic carcinoma (p < 0.05) in dorsolateral prostate. Depletion of CD25+ cells in young animals also increased the frequency of intestinal cancer in Min mice. Taken together, chronically elevated proinflammatory cytokines promoted carcinoma in ApcMin/+ mice. TREG lymphocytes downregulated inflammation-associated carcinogenic processes and contributed to immune and epithelial homeostasis.

Neoplastic epithelia may remain dormant and clinically unapparent in human patients for decades. Multiple risk factors including mutations in tumor cells or the stromal cells may affect the switch from dormancy to malignancy. Gene mutations, including p53 mutations, within the stroma of tumors are associated with a worse clinical prognosis; however, it is not known if these stromal mutations can promote tumors in genetically at-risk tissue. To address this question, ApcMin/+ and Apc Min/+ Rag2 −/− mice, which have a predilection to mammary carcinoma (as well as wild-type (wt) mice), received mesenchymal stem cells (MSC) with mutant p53 (p53MSC) transferred via tail vein injection. In the wt mouse, p53MSC circulated in the periphery and homed to the marrow cavity where they could be recovered up to a year later without apparent effect on the health of the mouse. No mammary tumors were found. However, in mice carrying the Apc Min/+ mutation, p53MSC homed to mammary tissue and signifi cantly increased the incidence of mammary carcinoma. Tumor necrosis factor (TNF)-α-dependent factors elaborated from mesenchymal cells converted quiescent epithelia into clinically apparent disease. The increased cancer phenotype was completely preventable with neutralization of TNF-α or by transfer of CD4+ regulatory T cells from immune competent donors, demonstrating that immune competency to regulate infl ammation was suffi cient to maintain neoplastic dormancy even in the presence of oncogenic epithelial and stromal mutations. The signifi cant synergy between host immunity and mesenchymal cells identifi ed here may restructure treatments to restore an anticancer microenvironment.