Prevention of Colitis- Associated Colon Cancer
Prevention of Colitis- Associated Colon Cancer
By M.L.Clapper, PhD; H. S. Cooper, MD; and S. Murthy, PhD
Inflammatory bowel disease (ibd) continues to affect approximately one million individuals in the United States.1 Although the high incidence of colorectal cancer among these IBD patients has been well established, the molecular basis for this increased risk remains unknown. The animal model of dextran sulfate sodium (DSS)-induced colitis provides a unique opportunity to evaluate the sequence of biochemical and histological changes that lead to dysplasia and cancer. The similarity of DSS-induced colitis to human disease makes this model a valuable resource with which to develop strategies for the chemoprevention of colitis-associated colon cancer.
The incidence of colorectal cancer in the United States is among the highest in the world, with an estimated 129,400 new cases diagnosed each year. Patients with inflammatory bowel disease (specifically ulcerative colitis) face a significantly increased risk of developing colonic malignancies. This risk begins approximately 10 years after the onset of colitis and increases with each decade of life, reaching as high as 25-40% after 40 years in patients who have not had a prophylactic colectomy.2 Duration of disease and extent of tissue involvement are the most significant determinants of colon cancer risk in this population. Use of conventional screening endoscopy for the early detection of colitis-associated neoplasms has been compromised by the characteristic flat morphology of both precancerous and cancerous lesions. It is unfortunate that colectomy remains the only definitive treatment for the prevention of colorectal cancer in patients with ulcerative colitis.
The molecular basis for the colonic dysplasias and cancers among ulcerative colitis patients remains unknown. Much attention has focused on the contribution of inflammation and highly reactive oxygen species to cellular damage and neoplasia, including the anticipated increased incidence of mutations under these conditions. Although several common colon cancer genes (APC, p53, DCC, MCC, Rb) are mutated in colitis-associated neoplasms,3,4 neither a defined sequence of genetic events nor germline mutations have been identified to explain their development. These data, when combined with additional supportive observations: 1) suggest that colonic dysplasias progress to colon cancers via a pathway that is distinct from that of both sporadic and heritable colon cancers; and 2) provide little insight into the identity of potential risk factors and molecular targets for intervention.
Preclinical Animal Models
Relevant and reproducible animal models of colitis-associated neoplasms are required to elucidate the molecular pathways involved in the progression of colitis to dysplasia. Subsequent evaluation of agents with known chemopreventive activity (i.e., DFMO [difluoromethylornithine], oltipraz, sulindac sulfone) in these preclinical models should facilitate the establishment of a nontoxic, efficacious regimen for the prevention of colitis-associated colon cancer. Although many animal models of colitis have been established, few are appropriate to study the dysplasia-cancer sequence. Cotton top tamarins spontaneously develop colitis and colon cancer when maintained in captivity. However, cancers do not arise from dysplasias in these animals and take several years to develop.5 More recently, Interleukin-106 and G protein7 knockout mice have been generated which develop colitis and adenocarcinomas. The relevance of these mouse models to human disease has not been established.
Adaptation of the hamster model of DSS-induced colitis8 to mice by this group9 and others10 has provided a unique opportunity to evaluate the spectrum of biochemical and histological changes that lead to colitis and subsequent dysplasia/cancer. In this model, Swiss Webster mice are administered DSS (4%) in the drinking water for seven days. Recovery for 14 days on untreated drinking water results in the establishment of acute colitis and the development of histological ulcerations and erosions. Clinical symptoms of colitis are preceded by progressive loss of the epithelial crypts. Inflammation is secondary to loss of the entire crypt on Day 5, with subsequent erosions.
Chronic colitis is induced by repeating the administration of DSS and water (one cycle = 7 days DSS and 14 days water) for two to four cycles. Animals with chronic disease exhibit lymphocyte and plasma cell infiltration, crypt distortion, and focal erosions similar to those found in human patients with ulcerative colitis. By the end of the fourth cycle, approximately 15% of the animals develop neoplastic lesions that are morphologically identical to dysplasias and/or cancers in humans. Non-neoplastic background mucosa show changes of classic chronic ulcerative colitis. Inflammation is more extensive in animals with dysplasia and cancer as compared to those without lesions.
A detailed characterization of the pathology of DSS-induced colitis suggests that this is a reliable and relevant model for the future development of strategies for the chemoprevention of human colitis-associated colon cancer. Similar to humans with ulcerative colitis, DSS-treated animals: 1) experience periods of clinical activity and inactivity; 2) possess varying degrees of inflammation many months after DSS;9 and 3) develop both flat and polypoid dysplasias and flat and polypoid cancers. The resulting dysplasias and carcinomas exhibit patterns of immunohistochemical staining for lectins and b-catenin that are similar to those of human colon tumors.11
Chemoprevention
Recent advances in the area of cancer chemoprevention have provided new opportunities for the development of therapeutic regimens for the prevention of colitis-associated colon cancer. Chemoprevention refers to the use of natural or synthetic agents to delay the formation of precancerous lesions or inhibit their progression to invasive cancers. Although several clinical chemoprevention trials have been performed in individuals at increased risk for sporadic colorectal cancer, none have targeted patients with IBD. Retrospective analyses in patients with long-standing ulcerative colitis suggest that daily folate supplementation may inhibit tumor formation.12,13 The ability of routine maintenance therapy for colitis (sulphasalazine or 5-aminosalicylic acid) to delay the development of colon cancer remains equivocal. The long-term benefit of treatment with nonsteroidal anti-inflammatory agents has not been assessed in this population. Prospective, randomized, clinical trials in patients with ulcerative colitis are needed to definitively assess the chemopreventive activity of each of these agents.
Preclinical development of chemopreventive regimens for individuals with ulcerative colitis continues to be challenged by our inability to identify a target population at increased risk of disease. Treatment of high-risk individuals with chemopreventive agents prior to the establishment of disease, a conventional approach to chemoprevention, is thus not practical and dictates the need to identify early biomarkers of risk for colon cancer. Previous studies have suggested that the activity of the Phase II detoxication enzyme glutathione S-transferase (GST) is significantly decreased in blood lymphocytes from individuals at increased risk for colorectal cancer (individuals without IBD, but with a personal or family history of colon cancer or personal history of polyps) as compared to cancer-free, healthy controls.14 A direct correlation between the GST activity of blood lymphocytes and colonic mucosa from the same individual was also established. Application of these findings to individuals with IBD has been precluded by the potential effect of routine colitis therapy on detoxication enzyme activity. The mouse model of DSS-induced colitis represents a relevant system in which to assess colon cancer risk.
We have recently characterized Phase II detoxication enzyme expression during acute and chronic colitis in the DSS mouse model.15 Examination of colon tissue after each cycle of DSS revealed significant reductions in GST, g-glutamylcysteine synthetase, the rate-limiting enzyme of glutathione synthesis, and glutathione levels after two cycles of treatment. Levels continued to decrease with each subsequent cycle of DSS exposure. In the case of GST, reductions in enzymatic activity were confirmed at both the protein and RNA level. Immunohistochemical analyses revealed that the loss of GST was not specific to any particular cell type, but instead was present in all cellular compartments (epithelium, smooth muscle, and endothelial cells) of the colon. These data suggest that Phase II detoxication enzyme inducers may be efficacious in the prevention of colitis-associated colon cancer.
Oltipraz is a Phase II enzyme inducer that was marketed previously for the treatment of schistosomiasis. Its observed ability to significantly elevate the detoxication potential of the host while depleting glutathione levels within the schistosome provided the first evidence that oltipraz may be effective in increasing cellular protection. One of the most exciting attributes of this compound is its ability to protect numerous target organs from a variety of structurally diverse carcinogens. Its effectiveness in inhibiting colon carcinogenesis in animal models16 and inducing the transcription of Phase II detoxication enzymes within the colonic mucosa of high-risk individuals (non-IBD)17 has been reported. Based upon these findings, we have initiated an evaluation of the effect of oltipraz on the formation of colitis-associated neoplasms. Preliminary studies in the DSS model of induced colitis indicate that oltipraz can inhibit the development of carcinomas in this model.18
Commentary
Several opportunities currently exist for developing clinical chemopreventive interventions for colitis patients at increased risk for colorectal cancer. The mouse model of DSS-induced colitis exhibits many characteristics of the human disease and represents a valuable system in which to examine both the molecular events associated with colitis and the inhibition of them by chemopreventive agents. Translation of these preclinical findings to a clinical setting will be facilitated by focusing on promising agents such as oltipraz for which the optimal dosage and schedule for administration have been established. (Dr. Clapper is Member, Division of Population Science, and Dr. Cooper is Senior Member, Department of Pathology, Fox Chase Cancer Center; Dr. Murthy is Professor of Medicine, Associate Vice President for Research, Krancer Center for Inflammatory Bowel Disease Research, MCP Hahnemann University, Philadelphia.)
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