Unknown,Transcriptomics,Genomics,Proteomics

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Deletion of TNF in Winnie-ApcMin/+ mice reveals its dual role in the onset and progression of colitis-associated colorectal cancer

ABSTRACT: Colorectal cancer (CRC) is among the best examples depicting the relationship between inflammation and increased cancer risk. The introduction of new therapeutic options targeting the inflammatory mediators has been shown to markedly decrease the overall risk of CRC even though their chemopreventive potential is still under debate [1,2]. Specifically, conflicting reports exist concerning the relationship between Infliximab, a monoclonal antibody that specifically blocks Tumor Necrosis Factor (TNF), and an increased risk of CRC in patients with Inflammatory Bowel Disease (IBD). To address the axis between TNF and CRC development and progression, we depleted the Tnf from our previously established murine model of colitis-associated cancer (CAC), the Winnie-ApcMin/+ line. Surprisingly, a detailed histological characterization, demonstrated that the deletion of Tnf in Winnie-ApcMin/+ mice resulted in an initial reduction of dysplastic lesions incidence in 5-week-old mice, followed by faster disease progression with a unique molecular pattern at 8 weeks. Our results highlight that TNF could exert a dual role in CAC supporting the promotion of neoplastic lesions onset at the early stage of the disease and inducing their reduction during disease progression.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

SUBMITTER: Genomix4Life Genomix4Life

PROVIDER: E-MTAB-12356 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, Î±6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of Î±6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old Î±6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).

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Deletion of TNF in Winnie-ApcMin/+ mice reveals its dual role in the onset and progression of colitis-associated colorectal cancer

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