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Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

ABSTRACT: The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a pro-tumor inflammatory microenvironment. Furthermore, in silico mutation studies and experimental validations led to a novel finding that concurrently targeting ceramide and PI3K/AKT pathway by chemical probes or marketed drugs achieves synergistic anti-cancer effects. Overall, our network model can guide further mechanistic studies on CAC and provide new insights into the design of combinatorial cancer therapies in a rational manner.

SUBMITTER: Lu J

PROVIDER: S-EPMC4597205 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

Lu Junyan J Zeng Hanlin H Liang Zhongjie Z Chen Limin L Zhang Liyi L Zhang Hao H Liu Hong H Jiang Hualiang H Shen Bairong B Huang Ming M Geng Meiyu M Spiegel Sarah S Luo Cheng C

Scientific reports 20151008

The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development ...[more]

PMID: 26446703

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Project description:The association between chronic inflammation and cancer has long been recognized. The inflammatory bowel disease ulcerative colitis frequently progresses to colon cancer; however, the underlying mechanism is still unclear. S100a9 has been emerged as an important pro-inflammatory mediator in acute and chronic inflammation, and the aberrant expression of S100a9 also contributes to tumorigenic processes such as cell proliferation, angiogenesis, metastasis, and immune evasion. We previously revealed that S100a8 and S100a9 are highly activated and play an important role in the process of colitis-associated carcinogenesis, which suggests an attractive therapeutic target for ulcerative colitis and related colon cancer. Here, we report that administration of a neutralizing anti-S100a9 antibody significantly ameliorated dextran sulfate sodium (DSS)-induced colitis and accompanied by diminished cellular infiltrate of innate immunity cells (macrophages, neutrophils, and dendritic cells) and production of pro-inflammatory cytokines (Tnf?, Il1?, Ifn?, Il6, Il17a, Il23a, Il4, and Il12a). The protective effect of anti-S100a9 antibody treatment was also observed in azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) mouse model. The inflammatory response, tumor cell proliferation, and immune cells infiltration in the colon tissues were suppressed by anti-S100a9 antibody. Gene expression profiling showed that key pathways known to be involved in CAC development, such as Wnt signaling pathway, PI3K-Akt signaling pathway, cytokine-cytokine receptor interaction, and ECM-receptor interaction pathway, were suppressed after treatment with anti-S100a9 antibody in CAC mice. In view of the protective effect of neutralizing anti-S100a9 antibody against DSS-induced colitis and AOM/DSS-induced CAC in mouse model, this study suggests that anti-S100a9 antibody may provide a novel therapeutic approach to treat ulcerative colitis and may decrease the risk for developing CAC.

Dataset Information

Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

Publications

Network modelling reveals the mechanism underlying colitis-associated colon cancer and identifies novel combinatorial anti-cancer targets.

Similar Datasets

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