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Sustained proliferation leads to Liver Cancer
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
Key Event Relationship Description
Every time a cell divides, there is a small chance that a mutation might occur. Because hepatocytes are polyploid, there is an increased rate of error-prone division due to multipolar mitotic spindles, which can result in aneuploidy in daughter cells (Stanger 2015). The risk for mutation is further increased when these cells are under stress (e.g., by a chemical exposure or increased oxidative stress). While it is generally understood that increased cellular proliferation is a predisposing factor to chemical carcinogenesis— ‘sustained proliferative signaling’ is one of the Hallmarks of Cancer (Hanahan and Weinberg 2000, Hanahan and Weinberg 2011) and IARC identifies altered cell proliferation as a key characteristic of a carcinogen (Smith, et al. 2015)—the exact mechanism for how one leads to the other is not altogether clear. There will be many steps in between observations of overt cellular proliferation leading to hepatocellular carcinoma. Thus, we describe this as an indirect KER with the hopes that additional empirical data to support the intervening steps will be available in the future, and that these additional KE(R)s can be developed at that time.
Evidence Supporting this KER
It is broadly accepted that pro-proliferative signaling is activated in an attempt to compensate for increases in cell death (Stanger 2015). Increased hepatocyte proliferation on a background of polyploidy, elevated cell death and oxidative DNA damage has the effect of increasing the likelihood of fixing harmful mutations, which are necessary for malignant transformation (Celton-Morizur and Desdouets 2010, Shi and Line 2014). However, the precise mechanistic processes defining this relationship have not been mapped out.
Uncertainties and Inconsistencies
Not all cases where there is sustained cellular proliferation produce tumours (some simply regenerate the liver to its healthy form). For instance Barash et al. (2010) demonstrate that increased background levels of inflammation and genomic instability are required for the progression from sustained cellular proliferation following PHx to tumourigenesis. Therefore, it is clear that malignant transformation must be accompanied by some sort of abnormal cellular signaling or impaired homeostasis. It is well understood that ‘context’ plays an important, albeit poorly understood, role in malignant transformation (Bissell and Hines 2011). More work is needed in this field to determine the additional modifying factors that predict whether a chemical that induces hepatocellular proliferation will cause cancer.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Any species that has a liver.
Barash, H., Gross, E.R., Edrei, Y., Ella, E., Israel, A., Cohen, I., Corchia, N., Ben-Moshe, T., Pappo, O., Pikarsky, E., Goldenberg, D., Shiloh, Y., Galun, E., Abramovitch, R., 2010. Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks. Proc. Natl. Acad. Sci. U. S. A. 107, 2207-2212.
Bissell, M.J., Hines, W.C., 2011. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17, 320-329.
Celton-Morizur, S., Desdouets, C., 2010. Polyploidization of liver cells. Adv. Exp. Med. Biol. 675, 123-135.
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Moser, G.J., Foley, J., Burnett, M., Goldsworthy, T.L., Maronpot, R., 2009. Furan-induced dose–response relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology 61, 101-111.
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Shi, J.-., Line, P.-., 2014. Effect of liver regeneration on malignant hepatic tumors. World J. Gastroenterol. 20, 16167-16177.
Smith, M.T., Guyton, K.Z., Gibbons, C.F., Fritz, J.M., Portier, C.J., Rusyn, I., DeMarini, D.M., Caldwell, J.C., Kavlock, R.J., Lambert, P., Hecht, S.S., Bucher, J.R., Stewart, B.W., Baan, R., Cogliano, V.J., Straif, K., 2015. Key Characteristics of Carcinogens as a Basis for Organizing Data on Mechanisms of Carcinogenesis. Environ. Health Perspect.
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Stanger, B.Z., 2015. Cellular homeostasis and repair in the mammalian liver. Annu. Rev. Physiol. 77, 179-200.
Templin, M.V., Jamison, K.C., Sprankle, C.S., Wolf, D.C., Wong, B.A., Butterworth, B.E., 1996. Chloroform-induced cytotoxicity and regenerative cell proliferation in the kidneys and liver of BDF1 mice. Cancer letters 108, 225-231.