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Mouse model of MCC deficiency reveals novel pathways altered by colon barrier destruction in colitis-associated cancer

ABSTRACT: Chronic inflammation is a well-known risk factor but the early events by which inflammation promotes colitis-associated cancer (CAC) are still poorly understood. Here we developed a new model to profile early carcinogenesis, using mice deficient for the tumor suppressor ‘Mutated in colorectal cancer’ (MCC). We generated mice with loss of MCC expression in colonic/intestinal epithelial cells (MccΔIEC) and gave them a diet containing the drug sulindac, which acts as a mild irritant in the mouse proximal colon causing foci of tissue damage with chronic inflammation. The genomic expression profiles were analyzed by Mouse Transcriptome Arrays (10 weeks) and tissue by histopathology at 20 weeks. MccΔIEC mice exposed to sulindac developed colon lesions with adenocarcinoma (59%) and down-regulation of E2F targets, such as the DNA mismatch repair genes. MCC-proficient mice also developed lesions, but these showed up-regulation of E2F pathways and progressed to cancer less frequently (19%). The most highly activated pathway in both groups was Interferon-Gamma-Response, in particular the p47-GTPase family of anti-microbial host defense genes that are homologs of the Crohn’s Disease susceptibility gene IRGM.

ORGANISM(S): Mus musculus

PROVIDER: GSE84391 | GEO | 2019/05/01

REPOSITORIES: GEO

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Project description:Background & Aims: Cirrhosis and chronic inflammation precede development of hepatocellular carcinoma (HCC) in approximately 80% of cases. We investigated immune-related gene expression patterns in liver tissues surrounding early-stage HCCs and chemopreventive agents that might alter these patterns to prevent liver tumorigenesis. Methods: We analyzed gene expression profiles of non-tumor liver tissues from 392 patients with early-stage HCC (training set, n=167 and validation set, n=225) and liver tissue from patients with cirrhosis without HCC (n=216, controls) to identify changes in expression of genes that regulate the immune response that could contribute to hepatocarcinogenesis. We defined 172 genes as markers for this deregulated immune response, which we called the immune-mediated cancer field (ICF). We analyzed the expression data of liver tissues from 216 patients with cirrhosis without HCC and investigated the association between this gene expression signature and development of HCC and outcomes of patients (median follow-up 10 years). Human liver tissues were also analyzed by histology. C57BL/6J mice were given a single injection of N-nitrosodiethylamine followed by weekly doses of carbon tetrachloride to induce liver fibrosis and tumorigenesis. Mice were then given orally the multiple tyrosine inhibitor nintedanib or vehicle (controls); liver tissues were collected and histology, transcriptome, and protein analyses were performed. We also analyzed transcriptomes of liver tissues collected from mice on a choline-deficient high-fat diet, which developed chronic liver inflammation and tumors, given orally aspirin and clopidogrel or the anti-inflammatory agent sulindac vs mice on a chow (control) diet. Results: We found the ICF gene expression pattern in 50% of liver tissues from patients with cirrhosis without HCC and in 60% of non-tumor liver tissues from patients with early-stage HCC. The liver tissues with the ICF gene expression pattern had 3 different features: increased numbers of effector T cells; increased expression of genes that suppress the immune response and activation of transforming growth factor beta signaling; or expression of genes that promote inflammation and activation of interferon gamma signaling. Patients with cirrhosis and liver tissues with the immunosuppressive profile (10% of cases) had a higher risk of HCC (hazard ratio, 2.41; 95% 1.21–4.80). Mice with chemically-induced fibrosis or diet-induced steatohepatitis given nintedanib or aspirin and clopidogrel downregulated the ICF gene expression pattern in liver and developed fewer and smaller tumors than mice given vehicle. Conclusions: We identified an immune-related gene expression pattern in liver tissues of patients with early-stage HCC, called the ICF, that associates with risk of HCC development in patients with cirrhosis. Administration of nintedanib or aspirin and clopidogrel to mice with chronic liver inflammation caused loss of this gene expression pattern and developed fewer and smaller liver tumors. Agents that alter immune regulatory gene expression patterns associated with carcinogenesis might be tested as chemopreventive agents in patients with cirrhosis. To assess the impact of sulindac or aspirin/clopidogrel treatment on the immune-mediated cancer field, we collected samples from a choline-deficient high-fat diet fed mouse model developing NASH, HCC and fibrosis, previously published (Malehmir M et al, Nat Med, 2019) . We analyzed gene expression profiling of non-tumor liver samples from mice fed a CD-HFD for 12 weeks treated with vehicle that presented HCC and fibrosis (considered as high-risk group) (n=4); as well as mice fed a CD-HFD for 12 weeks treated with sulindac (n=10) or aspirin/clopidogrel (n=6). As controls, we analyzed samples from mice fed a chow-diet for 12 weeks (considered as healthy group) (n=5).

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Mouse model of MCC deficiency reveals novel pathways altered by colon barrier destruction in colitis-associated cancer

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