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REVIEW
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.


Key words : Hepatocellular carcinoma, Immune cells, Metastasis, Regular physical activity, Tumor growth

Introduction

Different health science fields have progressively incorporated the idea that lifestyle factors, such as regular physical activity (RPA) and a healthy diet, could significantly impact the health status. Exercise has been especially reported to have a wide range of systemic effects on people, such as positive effects in weight management. Regular physical activity is inversely associated with weight gain and the incidence of obesity and also contributes to additional weight loss when coupled with dietary modifications. Exercise is a first-line intervention for patients with different chronic diseases, such as diabetes mellitus and hypertension, due to its beneficial effects on metabolism and the cardiovascular system.1-3

In the past, patients with chronic illnesses, such as cancer, were often told to rest and reduce their physical activity. This is good advice if the physical activity causes chest pain or shortness of breath. However, recent studies have shown that exercise is safe and possible during cancer treatment and can increase a patient’s quality of life and life expectancy.4-8 Thus many cancer care teams urge their patients to be as physically active as possible during cancer treatment.6

Regular physical activity is closely related to cancer in both prediagnosis and survival settings. Population-based studies have noted that the incidence of cancer decreases with increasing physical activity levels.4,6 Observational studies of breast, colon, and prostate cancer survivors have shown that cancer-specific mortality is reduced in patients who regularly exercise after a cancer diagnosis.4,6,9-11 Regular physical activity has been shown to decrease the side effects of anticancer therapy and can aid in recovery and rehabilitation following surgery, radiation, and chemotherapy.5,6,11-15 In addition, all-cause mortality in cancer survivors decreases with increasing exercise.5,7-11

A sedative lifestyle with decreased physical activity can lead to loss of body function, muscle weakness, and reduced range of motion. Regular walking and resistance training have been shown to improve physical function and skeletal muscle mass in patients with cancer.4-8 Regular exercise training is a crucial recommendation by the American College of Sports Medicine guidelines to maintain activity even in cancer patients.16

Regardless of its etiology, sarcopenia often occurs in patients with chronic liver disease, which is characterized by a loss of skeletal muscle mass and function.17,18 Patients with chronic liver disease and sarcopenia have a decline in their quality of life and physical activity.19 Sarcopenia has also been shown to associate significantly with fibrosis in the liver, and it is an independent prognostic factor for hepatocellular carcinoma (HCC).20-22

Low-intensity exercises are efficacious for improving muscle volume and strength in patients with chronic liver disease.23 Even in patients with end-stage liver disease, exercise has potential benefits in endurance and functional outcome measures.24 Recently, numerous studies have reported that cancer rehabilitation by exercise effectively improves a patient’s physical ability and muscle mass during hospitalization for advanced HCC treatment without worsened liver function.22,25,26

Regular Physical Activity Is Associated With Decreased Risk of Hepatocellular Carcinoma
The preventive impact of exercise on cancer development has been reported in many studies that document an inverse association between RPA and cancer incidence.4,6 According to epidemiological data from 73 studies conducted around the world, the risk of developing breast cancer in physically active women decreases by an average of 25% compared with inactive women.27 In a meta-analysis of 19 studies, an inverse relationship was shown between kidney cancer and physical activity.28 Similarly, some animal studies and population-based studies have suggested a protective role of exercise in decreasing the risk of developing primary liver carcinoma.29-32

A sedentary lifestyle contributes to obesity, insulin resistance, and metabolic syndrome, leading to diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Nonalcoholic steatohepatitis (NASH) is the necroinflammatory form of NAFLD and has been shown to induce HCC development even in the absence of cirrhosis.33,34 Both diabetes mellitus and obesity can increase the risk of HCC from any other cause by at least 3-fold.35,36 Hepatocellular carcinoma represents 90% of primary liver cancers and ranks third in cancer death. Because death rates in HCC are closely related to tumor incidence and effective treatment for liver cancer has not yet been developed, it is essential to prevent primary liver cancer from the very beginning.

Although we know that obesity and overnutrition increase the risk of developing primary liver cancer, the molecular mechanisms are not precise on how fatty liver contributes to the development of primary liver cancer. Despite many studies continuing to investigate the underlying mechanisms, the incidence of liver cancer continues to increase rapidly worldwide in parallel to increasing numbers of patients with diabetes and obesity.

Resultant hyperinsulinemia secondary to insulin resistance in NASH stimulates hepatic production of insulin-like growth factor 1 (IGF-1). Insulin-like growth factor 1 stimulates the growth of altered hepatocytes via activation of the Akt/mammalian target rapamycin complex 1 (mTORC1) pathway.37 However, exercise activates AMP-activated protein kinase (AMPK), which acts as a negative regulator of mTORC1.38 Therefore, it has been suggested that hepatocarcinogenesis can be prevented by suppressing mTORC1 activity via activation of AMPK with exercise.31,39 Impaired mTORC1 activity results in inhibition of cell proliferation and growth in response to growth factors and cytokines.

The tumor suppressor PTEN was identified as a functional target of exercise, by presenting as increased expression in the tumor of exercised rats. Loss of PTEN was 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.31 In addition, STAT3 expression was found to be decreased in exercised rats. STAT3 is a downstream factor of mTOR and plays a role in tumor angiogenesis and metastasis. Thus prevention of STAT3 activation will inhibit the growth of HCC.40

Piguet and colleagues31 used a NASH mouse model to show the beneficial effects of regular exercise on the development of HCC. They showed that forced treadmill running reduced liver tumor development in hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice, in which steatohepatitis and HCC develop spontaneously. In their study, the investigators divided the experimental NASH models into 2 groups. The first group was exercised on a treadmill once per day for 5 days during 32 weeks, and the second group stayed inactive. The results showed that, after the 32-week period, only 71% of exercised mice developed nodules versus 100% of mice in the inactive group. The number of tumors per liver was also reduced by exercise, as well as total tumor volume per liver and tumor cell proliferation.31

Although exercise suppressed mTORC1 in PTEN-/- mice, the exact mechanism explaining how exercise could protect against HCC development in humans with fatty liver is not yet clear.

Arfianti and colleagues29 also demonstrated that exercise reduces the incidence and progression of HCC in insulin-resistant mice. They reported other possible mechanisms on how exercise could prevent HCC development. In their study, they showed that the effect of exercise on cancer risk was independent of weight changes. In obese, insulin-resistant mice, exercise dampened the proliferation of dysplastic hepatocytes to reduce 3-month dysplastic foci and 6-month incidence of diethylnitrosamine-induced HCC.29 Exercise also significantly decreased Ki-67-positive hepatocytes and increased p53 activity in the liver. There also was increased expression of Bcl-xL and striking upregulation of the cell cycle inhibitor p27 related to p53 activity in the liver.29 These findings suggested that p53 activation and resultant p27 expression are possible pathways by which exercise decreases hepatocyte proliferation and the development of tumor growth.

The primary influence of exercise is on the tumor microenvironment rather than on the tumor itself. Exercise has been shown to attenuate the expression of numerous transcripts in the nontumoral liver microenvironment versus in the corresponding HCC microenvironment, activating several pathways in nontumor tissue, including AMPK signaling, lipid metabolism, angiogenesis, and apoptotic signaling.32 Saran and colleagues showed that RPA diminished the viable tumor volume and increased necrosis by decreasing hepatocyte proliferation and angiogenesis. Their results established the positive influence of moderate exercise on HCC growth and progression.32 Numerous angiogenesis factors, like vascular endothelial growth factor, and cytokines, such as interleukin 2 and interleukin 15, were more expressed in the nontumoral liver microenvironment than in HCC.41,42

All of these studies led us to conclude that both tumor and nontumoral microenvironments have roles in liver carcinoma progression and that RPA exerts a beneficial influence in diminishing HCC growth and progression by mechanisms involving molecular pathways in both tumoral and nontumoral liver tissue.

The beneficial effects of exercise on tumor progression are maintained and boosted when combined with sorafenib and metformin. The impact of RPA on the antitumor effect of sorafenib treatment was investigated by Saran and colleagues.32 The investigators found that cell proliferation, microvessel density, and viable tumor volume were reduced in rats that exercised and had sorafenib treatment compared with rats that only received sorafenib without exercise. In addition, they showed that RPA had a supportive effect on sorafenib treatment in terms of preventing tumor growth.

Metformin, an oral antidiabetic drug, has also been reported to have antitumor properties. Similar to the mechanism of action of RPA, metformin was also shown to induce the activation of AMPK.43 It has been suggested that metformin augments the antitumoral property of sorafenib therapy by activating the AMPK pathway.32,44 Metformin enhanced the antimetastatic effects of sorafenib in HCC by inhibiting cell migration, cell proliferation, angiogenesis, and invasion.32,45 A combination of sorafenib and metformin has been shown to prevent HCC recurrence in mice after surgical resection.46

The association of exercise and sorafenib was similar to that shown with metformin and sorafenib.32 This finding is critical because patients with liver carcinoma are often too sick to exercise regularly.19 Linden and colleagues suggested that, for patients who were too sick to perform regular exercise, metformin may provide a pharmacologic effect mimicking RPA.47

Impact of Regular Physical Activity on Cancer Survival
Although only a few studies have assessed the influence of RPA on the survival of patients after the diagnosis of cancer, most of these demonstrated that RPA reduced cancer recurrences and mortality among patients treated for different types of cancer, including HCC.5-12,22,40 Recent data showed a 40% to 50% reduction in all-cause mortality for colorectal, prostate, and breast carcinoma survivors engaging in high levels of RPA.48

Hashida and colleagues demonstrated that RPA was an independent factor for survival in patients with HCC.22 They reported that the rate of survival was higher in patients with HCC who performed RPA than in patients with HCC who did not perform RPA. In the RPA group, skeletal muscle index was increased without worsened liver function in patients with HCC.22

Loss and reduction in skeletal muscle mass have been reported to be independent prognostic factors for patients with HCC.49 Thus the significant increase in skeletal muscle mass is thought to be associated with improved prognosis of patients with HCC. Contrary to this finding, Hashida and colleagues demonstrated that RPA improves the prognosis regardless of alterations in skeletal muscle mass in patients with HCC.22 They suggested that their study is the first to report that maintaining physical activity by RPA is more critical than increasing skeletal muscle mass to improve prognosis of patients with HCC.22

Regular physical activity improves the prognosis and exerts several beneficial effects against carcinoma through different pathways. First, RPA was shown to suppress the development and proliferation of HCC by modulating the IGF-1 signal.22,37-39 Regular physical activity improved insulin resistance and decreased levels of IGF-1.50,51 In addition, RPA enhanced the expression of p21, insulin?like growth factor?binding protein 3, and PTEN, which was shown to suppress IGF-1 signaling in a cancer mouse model.37-39,52 Moreover, RPA may suppress the proliferation of liver carcinoma by suppressing the Warburg effect.22 It has been reported that aerobic exercise exerts an anti-Warburg effect, leading to increased lactate clearance capacity.53,54 Lactate is an essential molecule necessary for carcinogenesis, and it is directly associated with the prognosis of patients with carcinoma.54 Lactate is a critical component in the tumor microenvironment, especially in some of the main steps of the tumor progression, such as cell migration, angiogenesis, immune escape, metastasis, and self-sufficient metabolism.53 Therefore, the RPA-induced change in lactate metabolism of the tumor microenvironment may suppress the proliferation and progression of HCC.

In addition to the above mechanisms, myokines are reported to suppress malignant cells directly (affecting cancer cells) or indirectly (affecting other cells of the tumor microenvironment).55 Myokines were reported to influence peripheral tissues, such as skeletal muscle remodeling in response to exercise and improvements in cognitive function.56 Some in vitro studies have demonstrated that serum harvested from humans or animals following an acute exercise can directly inhibit cancer cell proliferation, viability, or survival when supplemented with cell culture media.57,58 This antitumoral impact was attributed to a few different myokines, including secreted interleukin, oncostatin M, protein acidic and rich in cysteine (SPARC), and irisin.55,56,58 In an in vivo study, interleukin augmented the mobilization of natural killer lymphocytes and decreased the liver cancer growth rate.59 Irisin is a type I transmembrane messenger protein that is synthesized in muscle cells in response to exercise. Irisin significantly reduced cancer cell viability, proliferation, and migration without influencing nonmalignant cells.57,58 Oncostatin M has an antiproliferative and apoptotic influence on cancer cells.60 Recently, Aoi and colleagues61 demonstrated that the protective effect of exercise against azoxymethane-induced colon tumourigenesis was nullified in SPARC knockout mice, and SPARC was able to induce colon cancer cell apoptosis in vitro. This finding suggested that the myokine SPARC plays an essential role in the protective effect of RPA on cancer development.

Dethlefsen and colleagues57 showed that exercise-induced catecholamines, such as epinephrine and norepinephrine, have both an indirect and a direct decreasing effect on tumor growth rate. Breast tumor cells preconditioned with exercise serum were less able to form xenograft tumors in mice, and this effect was abolished completely when the beta-blocker propranolol was also added to the pretreatment.57

The other factor that has been shown to be associated with an exercise-related delay in tumor growth is dopamine.62 Zhang and colleagues showed that moderate swimming exercise reduced tumor mass in mice, and this was mirrored by an increase in dopamine levels in the serum, tumor tissue, and prefrontal cortex. In addition, dopamine decreased tumor mass to the same extent as swimming, and a dopamine receptor 2 antagonist (domperidone) was shown to abolish the tumor growth inhibitory effect of both dopamine and swimming exercise.62

The role of RPA on the development of metastasis is not yet clear. Numerous studies have been demonstrated that RPA decreased the number or mass of metastasis.62,63 In contrast, fewer studies reported no change or increased number or mass of metastasis in patients doing RPA.62,64,65 Stress factor is suggested to play a critical role in how exercise affects metastasis. Zhang and colleagues62 found that swimming for 8 minutes/day reduced the tumor size of lung metastases in mice. However, when the mice were forced to swim for 16 or 32 minutes/day, the tumor size of metastases was found to increase.

Effect of Exercise on the Immune Microenvironment
Acute exercise is known to induce a rapid rise in circulating immune cells such as lymphocytes, monocytes, and granulocytes.66 Among all immune cells, lymphocytes and natural killer (NK) cells respond most strongly to acute exercise.67 After the cessation of exercise, the numbers of lymphocytes in the blood rapidly decrease, falling below preexercise levels within 1 hour after exercise.66 A rapid drop in lymphocyte count was previously thought to be secondary to lymphocyte apoptosis and associated with an immunosuppressive effect of exercise. However, postexercise lymphocyte apoptosis was shown to only account for a small number of the monitored lymphocytopenia. The reason for the rapid drop in lymphocyte count in circulation after exercise is stopped seems more likely because of the migration of the circulating lymphocytes into the peripheral tissues. During exercise, increased levels of catecholamines induce the recruitment of immune cells into the peripheral tissue, resulting in increased concentrations of lymphocytes, monocytes, neutrophils, and NK cells. It is thought that the mechanism underlying the increased immunity after exercise results from the margination of lymphocytes into the peripheral tissues with the induction of exercise.68 Most of the long-term studies have reported that RPA improves immune function in all age groups. Regular physical activity has been shown to be associated with augmented overall immunity, such as increased lymphocyte proliferation, improved NK cytotoxic activity, reduced T-cell senescence, and enhanced vaccine responses.69,70

Effect of Exercise on Immunity in the Tumor Microenvironment
With acute exercise, the alterations in circulating immune cells may strengthen the patient’s immune system and eliminate cancer cells from the body. Some cancer patients have shown a decrease in circulating immune cells, whereas others have shown an increase.71-73 This decreasing number of immune cells in the circulation may be the result of migration of immune cells into the tumoral and nontumoral microenvironments.73 Jönsson and colleagues reported an increase in both lymphocytes and granulocytes immediately after acute exercise in patients with chronic myeloid leukemia.73 However, other studies in patients with solid tumors have suggested that either tumor burden or cancer therapy may negatively influence immune cell mobilization in response to exercise, which may reduce immune surveillance of peripheral tissues.71,72

Although chronic exercise does not change the numbers of circulating immune cells in most studies, various studies have shown a decrease or increase in different immune cell types, such as granulocytes, leukocytes, lymphocytes, and neutrophils with RPA.74 In a previous report, RPA did not prevent a chemotherapy-associated decline in circulating immune cells.75

Rundqvist and colleagues76 demonstrated that, when mice exercised, tumor growth decreased. They suggested that this decrease in tumor growth was dependent on the levels of circulating CD8+ T cells. They also found that CD8+ T cells were made more potent by molecules that skeletal muscle cells released into the blood during exercise.76 After intense exercise, the investigators isolated immune cells and demonstrated that these CD8+ T cells alter how they use molecules for energy production after physical effort. They showed that, when immune cells from mice that exercise regularly were transferred to mice that did not exercise, they were more effective against tumor cells than the immune cells of mice who did not exercise.76 These findings suggest that CD8+ T cells alter the effects of exercise by enhancing their efficacy against tumor cells. Rundqvist and colleagues76 concluded that the ability of T cells to identify and eliminate cancer cells is essential to avoid tumor growth and progression. Thus, exercise could improve the outcome of cancer patients by augmenting the efficacy of cancer treatments through increased activation of the immune system, in which tumor-fighting cells become more effective.

Regular physical activity has been reported to decrease serum prostaglandin levels.77 Chronically increased production of prostaglandins, which are generated via cyclooxygenase 2, was shown to occur in cancer progression, apoptosis, angiogenesis, invasion, and metastases.78,79 Anti-inflammatory drugs and anti-inflammatory molecules found in some vegetables have been demonstrated to decrease the activation of prostaglandins’ cyclooxygenase 2, which could explain their reported anticancer properties.79-81 The anti-inflammatory effects of exercise were shown to be independent of achieving weight loss.82


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DOI : 10.6002/ect.2021.0456


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From the 1Pathology Department and the 2Vocational School of Health Services, Baskent University, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest. This manuscript was originally presented as part of the International Symposium on Benign and Malignant Tumors in Liver With or Without Cirrhosis held in Ankara, Turkey, June 24 and 25, 2021.
Corresponding author: B. Handan Özdemir, Baskent University, Ankara Hospital 79, Sokak 7/4 Bahçelievler Ankara 06490, Turkey
Phone: +90 312 2126591
E-mail: handan27@hotmail.com