Unknown,Transcriptomics,Genomics,Proteomics

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Thrombospondin 1 in a model of colorectal carcinogenesis

ABSTRACT: By using a model of inflammation-induced carcinogenesis the effects of TSP-1 in induced tumors were analyzed. Mice received a single injection of azoxymethane (AOM) and multiple cycles of dextran sodium sulfate (DSS) for inducing chronic inflammation-related cancers. Proliferation and angiogenesis status were analyzed as well as their transcript profile by using a gene microarray approach. We used Affymetrix GeneChips to determine the changes in the genetic profile between WT and TSP-1 deficient tumors in a model of colorectal carcinogenesis. We identified differentially expressed genes between WT and TSP-1 deficient tumors. WT and TSP-1 deficient mice were with a single injection of AOM and were drinking 1.5%DSS (dextran sulfate sodium) to induce colitis in four cycles. Wt mice drinking water only was used as reference. Mice were sacrificed and tumors excised for these studies and morphological analyses

ORGANISM(S): Mus musculus

SUBMITTER: Sridar Chittur

PROVIDER: E-GEOD-60805 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:MUC1 is a tumor-associated antigen that is aberrantly expressed in cancer and inflammatory bowel disease (IBD). Even though immune cells express low MUC1 levels, their modulations of MUC1 are important in tumor progression. Consistent with previous clinical data that show increased myeloid-derived suppressor cells (MDSCs) in IBD, we now show that down-regulation of MUC1 on hematopoietic cells increases MDSCs in IBD, similar to our data in tumor-bearing mice. We hypothesize that MDSC expansion in IBD is critical for tumor progression. In order to mechanistically confirm the linkage between Muc1 down-regulation and MDSC expansion, we generated chimeric mice that did not express Muc1 in the hematopoietic compartment (KOM-bM-^FM-^RWT). These mice were used in 2 models of colitis and colitis-associated cancer (CAC) and their responses were compared to wildtype chimeras (WTM-bM-^FM-^RWT). KOM-bM-^FM-^RWT mice show increased levels of MDSCs during colitis that was responsible for the larger colon tumors that eventually developed in these mice. Using microarray and qRT-PCR analysis, we observed increased pro-tumorigenic signaling in the colons of KOM-bM-^FM-^RWT mice during colitis as compared to WTM-bM-^FM-^RWT mice. Our RNA (microarray and qRT-PCR analysis) and protein analysis demonstrate increased up-regulation of metalloproteinases, collagenases, defensins, complements, growth factors, cytokines and chemokines in KOM-bM-^FM-^RWT mice as compared to WTM-bM-^FM-^RWT mice. Antibody-mediated depletion of MDSCs in mice during colitis reduced colon tumor formation during CAC. Development of CAC is a serious complication of colitis and our data highlight MDSCs as a targetable link between inflammation and cancer. A total of 12 samples were analysed. RNA was made from the mucosa of the colon of WTM-bM-^FM-^RWT and KOM-bM-^FM-^RWT mice that were either untreated or treated with azoxymethane (AOM) and dextran sodium sulfate (DSS). There are 4 groups, n=3 for each group: untreated WTM-bM-^FM-^RWT mice, untreated KOM-bM-^FM-^RWT mice, AOM+DSS treated WTM-bM-^FM-^RWT mice, AOM+DSS treated KOM-bM-^FM-^RWT mice = 12 samples in total.

Project description:Nonresolving inflammation is correlated to carcinogenesis. Ulcerative colitis-associated colorectal cancer (UC-CRC), one of the typical carcinoma generated by inflammation that cannot be resolved properly, has been widely believed to involve a multistep process contains M-bM-^@M-^\inflammation-dysplasia-cancerM-bM-^@M-^] sequence. The exact molecular mechanisms underlying the step-wise development of UC-CRC is still not fully understood. Detecting the changes in gene expression profiles may help to reveal why and how does the prolonged inflammatory response lead to carcinogenesis, and to characterize potential diagnostic/prognostic markers or additional therapeutic targets for UC-CRC. There for, we performed temporal genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with the development of colitis-associated cancer, based on an AOM/DSS induced mouse model of UC-CRC. 6-week-old male ICR mice were given a single intraperitoneal injection of AOM (10mg/kg) at Day 1, followed by three cycles of DSS administration (cycle 1: 2%, Day 8~14; cycle 2: 1.5%, Day 29~33; cycle 3: 1.5%, Day 50~54) in the drinking water. Instead, control group of mice were given a single intraperitoneal injection of saline (10mg/kg) at Day 1 and distilled water drinking from the beginning to the end without DSS. Colorectal tissues were collected at days 14, 28, 42, 56 and 140 (at the end of the 2nd, 4th, 6th, 8th and 20th week) from the AOM/DSS group and at day 14 from the control group. Pathological changes of each sample were identified under microscope. Samples collected at the end of the 2nd week were inflamed mucosae, the 4th week were low grade dysplasias, the 6th week were high grade dysplasias, the 8th week were high grade dysplasias with active inflammation, the 20th week were carcinomas, and the control sample were normal mucosae. Total RNA were extracted and detected by Affymerix GeneChip Mouse Genome 430 2.0 Array.

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Thrombospondin 1 in a model of colorectal carcinogenesis

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