5 years ago

Multiscale modeling of inflammation-induced tumorigenesis reveals competing oncogenic and onco-protective roles for inflammation.

Chronic inflammation is a serious risk factor for cancer; however, the routes from inflammation to cancer are poorly understood. Based on the processes implicated by frequently mutated genes associated with inflammation and cancer in three organs (stomach, colon and liver) extracted from the GEO, TCGA and GO databases, we present a multiscale model of the long-term evolutionary dynamics leading from inflammation to tumorigenesis. The model incorporates crosstalk among interactions on several scales, including responses to DNA damage, gene mutation, cell cycle behavior, population dynamics, inflammation, and metabolism-immune balance. Model simulations revealed two stages of inflammation-induced tumorigenesis: a precancerous state and tumorigenesis. The precancerous state was mainly caused by mutations in the cell proliferation pathway; the transition from the precancerous to tumorigenic states was induced by mutations in pathways associated with apoptosis, differentiation, and metabolism-immune balance. We identified opposing effects of inflammation on tumorigenesis: mild inflammation removed cells with DNA damage through DNA damage-induced cell death, whereas severe inflammation accelerated accumulation of mutations and hence promoted tumorigenesis. These results provide insight into the evolutionary dynamics of inflammation-induced tumorigenesis and highlight the combinatorial effects of inflammation and metabolism-immune balance. This approach establishes methods for quantifying cancer risk, for the discovery of driver pathways in inflammation-induced tumorigenesis, and have direct relevance for early detection and prevention and development of new treatment regimes.

Publisher URL: http://doi.org/10.1158/0008-5472.CAN-17-1662

DOI: 10.1158/0008-5472.CAN-17-1662

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