The role of tissue damage in hepatic cancer development and outgrowth
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Hepatocellular cancer (HCC) is the most common primary hepatic cancer and is overall the 5th most common cancer with 748,300 new liver cancer cases in 2008, and the 3rd most lethal cancer in the developed world with 695,900 fatalities in 2008. Chronic liver injury, inflammation, and fibrosis have been clearly linked to liver carcinogenesis through epidemiological studies. Various etiologies are known to be able to induce this chronic state of liver injury, fibrosis and inflammation of the liver, including chronic drug abuse or alcohol consumption, autoimmune disorders, toxins, bacterial infections and the most important cause, chronic infection of the liver with viruses. It has been estimated that over 80% of HCC cases are caused by chronic liver infections with hepatitis B and hepatitis C viruses. Besides the clear causative relationship between chronic liver injury and carcinogenesis, liver injury has also been linked to increased outgrowth of preexisting primary and secondary liver tumors. Secondary liver tumors are even more common than primary liver tumors, which can be explained by the physiology of the organ. High volumes of blood pass the liver from a dual supply, the systemic circulation and the portal vein, increasing the chance of transporting tumor forming cells (TFCs) to the liver. Fenestrations in the hepatic sinusoidal epithelium then allow relatively easy penetration of TFCs, enabling TFCs to settle into the hepatic parenchyma, causing secondary tumors in the liver. Especially colorectal, lung, and breast tumors are known to have a high potency to metastasize to the liver. Primary and secondary liver tumors are notoriously difficult to treat with chemotherapy. For the majority of hepatic malignancies surgical resection is considered the only real curative option. In many patients surgery is not possible due to the bad condition of the liver, tumor size, number of tumors and or location of the tumors. In these cases ablative techniques are used to destroy tumor tissue for palliative or curing purposes. These methods however, also cause damage to the liver that can lead to increased outgrowth of tumor cells that have survived the treatment, or probably cause development of new tumors. In this review, the current knowledge of underlying mechanisms of liver tissue damage leading to carcinogenesis and cancer outgrowth will be discussed.