Anti‐tumoral effects of exercise on hepatocellular carcinoma growth

Abstract

Regular physical exercise has many beneficial effects, including antitumor properties, and is associated with a reduced risk of developing hepatocellular carcinoma (HCC). Less is known about the impact of exercise on HCC growth and progression. Here, we investigated the effects of exercise on HCC progression and assessed whether any beneficial effects would be evident under sorafenib treatment and could be mimicked by metformin. American Cancer Institute rats with orthotopic syngeneic HCC derived from Morris Hepatoma‐3924A cells were randomly assigned to exercise (Exe) and sedentary groups, or sorafenib±Exe groups or sorafenib±metformin groups. The Exe groups ran on a motorized treadmill for 60 minutes/day, 5 days/week for 4 weeks. Tumor viable area was decreased by exercise, while cell proliferation and vascular density were reduced. Exercise increased the expression of phosphatase and tensin homolog deleted from chromosome 10 and increased the phosphorylation of adenosine monophosphate‐activated protein kinase, while the phosphorylation of protein kinase B, S6 ribosomal protein, and signal transducer and activator of transcription 3 were decreased. Transcriptomic analysis suggested major effects of exercise were on nontumoral liver rather than tumor tissue. Exercise demonstrated similar effects when combined with sorafenib. Moreover, similar effects were observed in the group treated with sorafenib+metformin, revealing an exercise‐mimicking effect of metformin. Conclusion: Exercise attenuates HCC progression associated with alterations in key signaling pathways, cellular proliferation, tumor vascularization, and necrosis. These beneficial effects are maintained when combined with sorafenib and can be mimicked by metformin. (Hepatology Communications 2018;2:607‐620)

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“…Hepatocellular carcinoma (HCC), a malignant tumor that occurs from liver cells, is the most common primary liver cancer, which is a serious hazard to human health and is one of the few cancers with rising incidence in recent decades [1,2]. Radiotherapy is effective in the treatment of many malignant tumors, but HCC is resistant to radiation [3][4][5], and a strategy to increase its radiation sensitivity is needed.…”

Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice

“…Our work complements the small number of studies that have evaluated the positive effect of lifestyle interventions on the histological features of NASH [18][19][20]. In addition, our study confirms in yet another model that exercise not only arrests the development of liver tumors [13] but attenuates progression [14]. Furthermore, we have reinforced the notion that the benefit of exercise in suppressing tumors is sustained in NAFLD well after sinusoidal capillarization, ER stress, apoptotic processes, and evidence of mitochondrial dysfunction are established.…”

“…For instance, regular physical activity significantly decreases the occurrence of tumors, from 100% down to 70%, in a model of NASH induced by the ablation of hepatocellular PTEN [13]. We also confirmed that the exercise-related mechanism was the activation of AMPK and inhibition of the mTOR/S6K pathway [13,14,37]. This mechanism holds for the current model of dietary-induced NASH.…”

“…We previously reported that in a genetic PTEN knockout mouse model of NASH, regular physical activity decreases the incidence of HCC but without a change in the NAFLD activity score (NAS) score [13]. We also reported that in a rat model of orthotopic syngeneic tumor implantation, regular physical activity downregulated the expression of hepatic genes associated with the development of HCC [14]. However, it remains unknown whether an exercise regimen can intervene at all points, or only at specific points, along the continuum from NAFL to NASH to fibrosis and HCC and change the course of the disease, especially within the context of continued nutritional overload.…”

When lifestyles sign

“…Even when drugs to treat non-alcoholic steatohepatitis will be available, lifestyle changes will remain an essential component of the therapeutic plan of these patients. In the last years, a strong association between lifestyle and hepatocellular carcinoma (HCC) has become evident (2)(3)(4). In patients with NAFLD, the annual incidence of HCC is 0.44 per 1,000 person/year and almost 50% of cases develops in a non-cirrhotic liver resulting in a diagnosis at an advanced stage with a worse prognosis (1,5).…”