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Colitis and cancer: a tale of inflammatory cells and their cytokines
Ezra Burstein1,2 and Eric R. Fearon1,2,3,4
1Department of Internal Medicine, 2Molecular Mechanisms of Disease Program, 3Department of Human Genetics, and 4Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Address correspondence to: Ezra Burstein or Eric R. Fearon, Molecular Mechanisms of Disease Program, University of Michigan School of Medicine, 109 Zina Pitcher Place, Biomedical Science Research Building, 1st Floor, Ann Arbor, Michigan 48109-2200, USA. Phone: (734) 764-1549; Fax: (734) 647-7950; E-mail: fearon@umich.edu (E.R. Fearon). Phone: (734) 615-1172; Fax: (734) 647-7950; E-mail: ezrab@umich.edu (E. Burstein).
Find articles by Burstein, E. in: PubMed | Google Scholar
1Department of Internal Medicine, 2Molecular Mechanisms of Disease Program, 3Department of Human Genetics, and 4Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Address correspondence to: Ezra Burstein or Eric R. Fearon, Molecular Mechanisms of Disease Program, University of Michigan School of Medicine, 109 Zina Pitcher Place, Biomedical Science Research Building, 1st Floor, Ann Arbor, Michigan 48109-2200, USA. Phone: (734) 764-1549; Fax: (734) 647-7950; E-mail: fearon@umich.edu (E.R. Fearon). Phone: (734) 615-1172; Fax: (734) 647-7950; E-mail: ezrab@umich.edu (E. Burstein).
Find articles by Fearon, E. in: PubMed | Google Scholar
Published January 24, 2008 - More info
J Clin Invest. 2008;118(2):464–467. https://doi.org/10.1172/JCI34831.
© 2008 The American Society for Clinical Investigation
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Abstract
The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-α expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55–deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55–deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-α, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-α as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-α may be useful in treating colon cancer in individuals with UC.
Authors
Boryana K. Popivanova, Kazuya Kitamura, Yu Wu, Toshikazu Kondo, Takashi Kagaya, Shiuchi Kaneko, Masanobu Oshima, Chifumi Fujii, Naofumi Mukaida
Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States, with an estimated annual cost exceeding $2 billion (1). IBD mainly consists of two disorders, ulcerative colitis (UC) and Crohn disease (CD). UC is restricted to the colon and/or rectum and always involves a continuous segment of variable length starting from the rectum. CD is a more varied disorder, which can affect essentially any segment of the gastrointestinal tract, with a preference for the terminal ileum (2). While UC causes inflammation restricted to the mucosa, CD is associated with granulomatous features and transmural inflammation that can be complicated by intestinal wall fibrosis and stenosis, internal and external fistulas, and intra-abdominal infections. The involvement of the colon and rectum, irrespective of the subtype of IBD, increases the risk for colorectal cancer (CRC), and the risk is more pronounced with early onset of the disease and greater severity and greater extent of the colitis (3). In fact, though patients with colitis-associated cancer (CAC) represent only about 1% of CRC cases, colitis patients are among those in the population at greatest risk of CRC. In patients with prolonged (>20 years) and extensive colitis involving the entire organ, the risk of CRC approaches 20%. Certain subsets of patients, such as those that have concurrent inflammation in the biliary tract (termed “primary sclerosing cholangitis”), have an even greater lifetime risk of CRC, approaching 50% (3).
The abnormal inflammatory response observed in IBD is thought to require the interplay between host genetic factors and the intestinal microbiota (4). Indeed, some patients with IBD seem to improve upon antibiotic treatment, and multiple animal models of colitis are ameliorated by the administration of antibiotics or placement of animals in germ-free conditions (4). Recently, the demonstration that a subset of CD patients carries mutations in the nucleotide-binding oligomerization domain–containing 2 (NOD2) gene (5–7), which encodes an intracellular pattern-recognition receptor for bacterial muramyldipeptides (4, 8), bolsters the notion that an abnormal balance in the immune response to gut bacteria may be a central and general feature in IBD.
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TNF-α activates an oncogenic immune response
In light of the participation of epithelial cells and inflammatory cells in the tumorigenic process, the identification of the cell population that responds to TNF-α and that promotes tumor formation was very important to address. In elegant bone marrow chimeric studies, Popivanova et al. (21) found that the deficiency of TNF-Rp55 was only relevant when it involved immune system cells and not when it involved the epithelium. This indicates that TNF-α production in the mucosa, presumably initiated by resident cells, is required for activation of immune cells, which in turn are important in the subsequent development of cancer (Figure 1). TNF-α did not appear to behave as a trophic factor for the epithelium, but was needed to activate a tumor-promoting immune response. In addition, an intriguing result reported by Popivanova et al., albeit one that lacks clear mechanistic insights at present, was the authors’ finding that TNF-α blockade by etanercept may have had inhibitory effects on the outgrowth and/or persistence of neoplastic colon epithelial cells harboring β-catenin mutations. Mutational defects abrogating regulation of β-catenin signaling (e.g., adenomatous polyposis coli gene inactivation) have been suggested to be a late event in the pathogenesis of CAC in humans (24). As such, it remains to be determined whether the association that Papivanova et al. observed between TNF blockade and a reduced β-catenin mutation frequency in neoplastic lesions in the mice reflects a direct stimulatory interaction between TNF signaling and β-catenin or the fact that loss of TNF signaling inhibited progression of neoplastic cells to the state at which they might acquire β-catenin dysregulation.
Figure 1Role of TNF-α in inflammation associated with colorectal carcinogenesis. Injury to the intestinal epithelium can result in DNA damage and altered gene expression and function, the initial step required for neoplastic transformation. In addition, this is accompanied by activation of NF-κB within epithelial cells, which promotes prosurvival pathways that are required for the initial growth of the resulting neoplastic cells. NF-κB activation also promotes proinflammatory gene expression. TNF-α originating from the mucosa or possibly the epithelium itself, participates in orchestrating the activation of immune cells. Production of various proinflammatory factors by the activated immune system participates in the ensuing inflammatory response but additionally plays a role in tumor growth by providing trophic signals to the early neoplastic lesions. Loss of TNF-α signaling in immune cells, and not the mucosa, stops this cascade by aborting the mucosal inflammatory response, and this can be achieved by pharmacologic blockade of TNF-α with etanercept and possibly other agents (21).
In closing, it is worth emphasizing that the observations reported in the Popivanova et al. (21) study have potentially significant clinical ramifications. While etanercept is approved for clinical use for rheumatoid arthritis, it lacks the efficacy that monoclonal antibodies against TNF have in inducing clinical remission in IBD. Nevertheless, it is likely that monoclonal antibodies against TNF would recapitulate the effect of etanercept in this model. Given the time course for development of CAC in humans, it will be some time before we know whether TNF blockade has a significant effect on inhibiting tumor formation in IBD patients, but the rationale for the potential efficacy of TNF blockade in CAC is now well supported by the findings in the current study.
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