How Exercise Affects the Development and Progression of Hepatocellular Carcinoma by Changing the Biomolecular Status of the Tumor Microenvironment.

Abstract

A sedentary lifestyle contributes to the development of nonalcoholic fatty liver disease. This disease is associated with hepatocellular carcinoma, even in the absence of cirrhosis. Nonalcoholic steatohepatitis mouse models have shown the benefits of regular exercise on hepatocellular carcinoma development. These models showed that total tumor volume per liver and tumor cell proliferation were reduced by exercise. Exercise also decreased the Ki-67-positive hepatocytes and increased p53 activity in the liver. In addition, an increased expression of Bcl-xL and the striking upregulation of p27 related to p53 activity were found in the liver. These findings suggest that p53 activation and resultant p27 expression are possible pathways by which exercise decreases hepatocyte proliferation and the development of tumor growth. Exercise could counteract hepatocellular carcinoma progression by activating adenosine monophosphate-activated protein kinase and thereby impairing mTORC1 activity. Impaired mTORC1 activity results in inhibition of cell proliferation in response to growth factors. The tumor suppressor PTEN was identified as a target of exercise by presenting increased expression in tumors of exercised rats. Loss of PTEN is shown to result in cell proliferation, growth, and invasion; therefore, increased expression of PTEN in a tumor will abate the cell proliferation and tumor growth. In addition, STAT3, a downstream factor of the mechanistic target of rapamycin that plays a role in tumor angiogenesis and metastasis, has been shown to be decreased in exercised rats. Thus, prevention of its activation will inhibit growth of hepatocellular carcinoma. In clinical studies, exercise was positively associated with improved recurrence-free survival in patients with hepatocellular carcinoma. Exercise may slow cancer progression by direct action on tumor-intrinsic factors and signaling pathways, thus possibly improving the efficacy of the anticancer treatment. This review explains the potential anticancer benefits of exercise by highlighting the tumor-intrinsic factors and signaling pathways of hepatocellular carcinoma associated with exercise.