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Hepatocellular Carcinoma and Lifestyles - alcohol, coffee, diet, exercise, smoking
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" The preventive and therapeutic impact of lifestyle on cancer is remarkable and its exploitation should be further promoted. HCC is a cancer tightly linked to lifestyle.......Epidemiological studies have indicated that physical activity lowers the risk of various carcinomas (esophagus, colon, breast, bladder, lung, kidney, prostate, pancreas, endometrium and ovary)"
Journal of Hepatology Sept 1 2015
Uttara Saran1,2, Bostjan Humar3, Philippe Kolly1,2 and Jean-Francois Dufour1,2 1Hepatology, Department of Clinical Research, University of Berne, Berne, Switzerland 2University Clinic of Visceral Surgery and Medicine, Inselspital Berne, Berne, Switzerland 3Department of Visceral & Transplantation Surgery, University Hospital Zurich, Zurich, Switzerland
The majority of hepatocellular carcinoma occurs over pre-existing chronic liver diseases that share cirrhosis as an endpoint. In the last decade, a strong association between lifestyle and hepatocellular carcinoma has become evident. Abundance of energy-rich food and sedentary lifestyles have caused metabolic conditions such as obesity and diabetes mellitus to become global epidemics. Obesity and diabetes mellitus are both tightly linked to nonalcoholic fatty liver disease and also increase hepatocellular carcinoma risk independent of cirrhosis. Emerging data suggest that physical activity not only counteracts obesity, diabetes mellitus and nonalcoholic fatty liver disease, but also reduces cancer risk. Physical activity exerts significant anticancer effects in the absence of metabolic disorders. Here, we present a systematic review on lifestyles and hepatocellular carcinoma.
Cancers result from the interactions of host features with environment factors. Lifestyles, which comprise the habits by which a person chooses to live, define these interactions. Therefore, lifestyles such as dietary choices, smoking, alcohol consumption and physical activity have a profound influence on cancer development, including hepatocellular carcinoma (HCC). The capacity to survive famine was one of the strongest selection traits during evolution. This changed drastically about 50 years ago with generalization of a lifestyle characterized by abundance of food and lack of exercise. Human physiology has not changed in such a short period of time. As a consequence, we are maladapted to our new environment and this maladaptation leads to the epidemics of obesity and diabetes mellitus (DM). Obesity has been consistently associated with a 1.5-4.5 times increase of HCC risk [[1], [2], [3], [4], [5], [6], [7]]. Even an increase in body mass index (BMI) during childhood was associated with an elevated risk of HCC during adulthood [8]. DM was also linked to a 2-3-fold increase of HCC risk [[9], [10], [11]], independently of the underlying liver disease [11] and even in lean individuals [12]. Moreover, treating diabetic patients with insulin and/or insulin sensitizers may further increase the risk to develop HCC. This highlights how strongly lifestyles influence the risk of developing HCC.
Smoking is associated with the development of several types of cancers, particularly those arising in organs directly exposed to smoke. Smoking also increases the risk of developing HCC (Table 1). Tobacco smoke contains chemicals that become activated as carcinogens when metabolized in the liver [13]. A linear relation between 4-aminobiphenyl-DNA adduct levels in liver tissue and HCC risk was reported, which was also significant after adjustment for covariates, including hepatitis B surface antigen status [14]. In a large Chinese retrospective study, smokers had a higher risk ratio for HCC than nonsmokers; this concerned males as well as females and the risk correlated with the degree of cigarette consumption [15]. This was confirmed in two Asian prospective studies which adjusted for alcohol consumption [16], [17]. Data from the European Prospective Investigation into Cancer and Nutrition (EPIC) suggested that, in Europe, smoking contributes to nearly half the cases of HCC, which is actually more than hepatitis B and C viruses [18]. Moreover, smokers who underwent HCC resection had a higher rate of recurrence and liver-specific mortality [19].
Alcohol is linked to HCC via the development of cirrhosis. The published evidence does not support a role for alcohol as a direct carcinogen for HCC. Alcohol-induced liver disease is one of the most prevalent causes of cirrhosis and alcohol-induced cirrhosis is associated with a 5-year cumulative risk for HCC of 8% [20]. The odds ratios for HCC increase linearly with alcohol intake and are higher in cases of DM or infection with hepatitis B or C virus[21], [22].
Since 2002, when a protective effect of coffee against HCC was first reported [23], epidemiological studies, covering different geographical areas and different HCC etiologies and with different designs, have substantiated this observation. Three meta-analyses comprising studies from Europe and Asia found a statistically significant association between coffee consumption and an approximately 40% reduced liver cancer risk[24], [25], [26]. Prospective studies confirmed the benefit of coffee consumption. A prospective cohort that enrolled Finnish male smokers reported that coffee intake (boiled or filtered) was inversely associated with incident liver cancer [27]. Comparing high coffee consumers with low coffee consumers in the EPIC study, Bamia et al. found a decreased risk for HCC with a hazard ratio of 0.28 [28]. Finally, a large, multiethnic, population-based prospective cohort found a dose-dependent protective effect of coffee intake [29].
More than specific nutrients, it is the promotion of obesity and DM by overnutrition and energy-rich diets which increases the risk of HCC. Two case-control studies from southern Europe found a positive association between high dietary glycemic load and HCC among patients with chronic HBV or HCV infections [30], [31]. Although the latter study found that this positive association was present in patients without chronic hepatitis infection, this link was weaker and not statistically significant [31]. There is growing evidence that adherence to a healthy diet plays a role in delaying HCC development in at-risk populations. Epidemiological studies have suggested that increased consumption of fruits decreases the risk of HCC [32] and low vegetable intake was significantly associated with an increased risk of HCC [33]. An Italian case-control study reported an inverse relation between intakes of fruits, milk/yoghurt, white meats, eggs and HCC risk [34]. Higher intake of total dietary fiber and a lower intake of dietary sugar were associated with decreased risk of HCC [7]. Finally, the degree of adherence to a "Mediterranean" diet was significantly inversely related to HCC risk. Turati et al. scored adherence to a "Mediterranean" diet in 518 cases of HCC and 712 controls from Italy and Greece [35]. They found that good adherence is associated with a 50% reduction in HCC incidence and that this effect is particularly striking in patients with a chronic viral hepatitis B or C.
Physical activity
Regular exercise reduces the negative consequences associated with overconsumption of an energy-dense diet, including insulin resistance, weight gain, and obesity [[12], [36], [37]]. The recognition that physical activity can also prevent cancer has motivated growing interest in this area of research.
Preventive benefits of exercise (primary prevention)
Epidemiological studies have indicated that physical activity lowers the risk of various carcinomas (esophagus, colon, breast, bladder, lung, kidney, prostate, pancreas, endometrium and ovary). While risk reductions seem to be small for endometrial [38] and prostate cancer [39], a pronounced benefit was shown for breast [40], colon [41], and lung cancer [42]. Physical activity may even reduce lung cancer incidence in smokers [43], and breast cancer risk in BRCA1/2 mutation carriers who are genetically predisposed to the disease [44], illustrating the powerful impact of exercise. In a recent prospective study of a large Taiwanese cohort, Wen et al. observed a gradual correlation between decline in HCC risk and degree of physical activity [45], an observation which has been duplicated in an NIH study by Behrens et al. [46]. In terms of primary prophylaxis, HCC associated mortality appears to be reduced (relative risk [RR] 0.71; 95% confidence interval [CI] 0.52-0.98) in patients on moderate-to vigorous-intensity physical activity regimes (>7 h/week) before the diagnosis of cancer relative to inactive subjects [47].
Benefits of exercise post cancer diagnosis
In addition to its preventive effects, physical activity also favorably impacts on outcomes following cancer diagnosis. Mounting evidence indicates an improved quality of life, a decreased risk of recurrence, and up to 50% reduced risk of cancer-related mortality in physically active breast, prostate or colorectal cancer survivors compared with their less active peers. In men diagnosed with early prostate cancer, regular vigorous-intensity exercise (≥3 h/week) was associated with a 61% and 57% decreased risk of cancer-specific mortality and progression, respectively [48], [49]. As for liver cancer, one can consider the beneficial effects of lifestyle changes in patients with cirrhosis as secondary prevention. At the level of tertiary prevention, there is presently no evidence that exercise decreases HCC recurrence.
Hepatic effects of exercise
The benefits of physical activity have been consistently observed in a number of studies that are summarized in Table 2. Regular physical activity reduces steatosis and improves insulin sensitivity even in the absence of weight loss [[50], [51], [52], [53], [54], [55], [56], [57], [58]]. Exercise improves adipocytic insulin sensitivity, reducing the flow of fatty acids (FAs) to the liver irrespective of BMI [[59], [60], [61]]. Correspondingly, elevated physical activity is inversely associated with the onset of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) [53], [56], [57], [62], [63], [64], [65], [66], [67], [68], [69], [70]. Although currently speculative, the increased energy expenditure should further mitigate the procarcinogenic features of lipotoxicity and excess lipids, while improved insulin sensitivity should counteract the glucose-addicted phenotype of cancer cells. Kaibori et al. observed greater loss of body fat through exercise compared with dietary modification in a cohort of HCC patients, with insulin sensitivity improving only in the group with the highest exercise intensity [71].
Experimental data regarding the impact of exercise on the livers of diet-induced animal models predisposed to NAFLD, NASH, and HCC are summarized in Table 3.
Despite the heterogeneity of the experimental set-ups (particularly the composition of diets), the sum of evidence confirms the beneficial effects of exercising. Exercise programs improved adipose mass, steatosis, insulin resistance, inflammation or other parameters associated with the metabolic syndromes, which may also be improved when exercise is introduced midway through a high-fat diet regimen [[72], [73], [74], [75]], [76]. When comparing exercise with calorie restriction, Rector et al. noted elevated mitochondrial ?-oxidation, oxidative enzyme function, improved glucose tolerance, and suppression of hepatic de novo lipogenesis in the exercise group, providing support to the claim that exercise has effects superior to those of dietary modification [77]. Interestingly, halting exercise for short periods (7 days) does not appear to hamper its benefits, although longer interruptions (4 weeks) caused deterioration of the overall metabolic phenotype in hyperphagic rats [78]. In a genetic mouse model of NASH-induced HCC, regular exercise had a positive effect in delaying the onset of HCC [79].
Molecular mechanisms
Lifestyles, in particular exercise, affect several aspects of hepatocarcinogenesis. They modify the metabolism, influence the immune system and affect inflammation (Figure ure1).
Metabolic programming
Exercise reduces the cellular ATP:AMP ratio and hereby activates AMP-activated protein kinase (AMPK). AMPK inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates peroxisome proliferator-activated receptor-α (PPARα) [[80], [81]] (Figure ure2). mTORC1 is a key metabolic growth promoter, which in situations of nutrient and insulin availability activates sterol regulatory element-binding protein (SREBP), a transcription factor which controls the expression of lipogenic genes such as fatty acid synthase (FAS) [82]. In contrast, PPARα induces genes required for ?-oxidation including carnitine palmitoyltransferase I (CPT1) [[39], [83], [84], [85]]. mTORC1 stimulates glutamate dehydrogenase (GDH), possibly via the downregulation of sirtuin 4 (SIRT4) [[86], [87]]. GDH converts glutamine to α-ketoglutarate, which enters the tricarboxylic acid (TCA) cycle for ATP generation [88]. In muscle, exercise downregulates SIRT4; this releases its inhibitory effects on malonyl-CoA decarboxylase (MCD) resulting in reduced levels of malonyl-CoA, an inhibitor of ?-oxidation [[89], [90], [91]]. It remains to be investigated whether exercise has similar effects in the liver and to what extent they occur in HCC. Wang et al. reported reduced expression of SIRT4 in HCC samples [92]. In HCC, decreased AMPK activity has been associated with poor outcome and AMPK activation-induced apoptosis [93]. Likewise, mTORC1 activity has been suggested to regulate lipogenesis in hepatocarcinogenesis, with the lipogenic phenotype of HCC cells correlating to clinical aggressiveness [94]. Hence exercise could counteract HCC risk/progression in part by upregulating AMPK and downregulating mTORC1.
Interestingly, the exercise-induced changes in AMPK/Akt-mTORC1 do not require the presence of obesity/DM, indicating an independent effect of exercise on HCC inhibition [80]. Both calorie restriction and exercise have been shown to independently lower circulating insulin and insulin growth factor 1 (IGF-1) levels [95] which, apart from generally dampening PI3K-Akt-mTOR activities [[81], [96]] may also play a role in preventing the initiation and propagation of malignant tumors in the liver [97].
Immune system
Exercise is known to have immunostimulatory effects in cancer patients; however, no study has yet addressed this in HCC patients. In breast cancer survivors, regular exercise increased the percentage of CD4(+)CD69(+) cells and increased DNA synthesis after stimulation of these cells [98]. Circulating natural killer (NK) cells have key functions in the immunological defense against cancer. Brief bouts of exercise seem to be sufficient to increase the number of circulating NK cells by 4-5-fold, at least in young healthy adults [99]. Experimentally, exercise may induce relatively long-lasting changes in NK cells, with elevations sustained for up to 3 weeks following cessation of exercise in mice.
Furthermore, these exercised animals developed resistance to lung tumor formation compared with sedentary controls [100]. Significant differences in T-cell proliferation between sedentary and exercised tumor-bearing rats have been reported, with the latter demonstrating higher macrophage cytotoxic antitumor action [101].
Experimental models of diet-induced and genetic-induced obesity promote low-grade hepatic inflammation, which leads to the development of HCCs [102]. HCC progression was reversed when the hepatic inflammation was reduced by deletion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α).
Clinically,modification of diet has been shown to reduce inflammation. A study with obese individuals reported an association between caloric-restricted weight reduction and decreased plasma C-reactive protein (CRP) levels [103]. Different diets were able to decrease IL-6 levels as long as weight loss was achieved [104]. Physical activity also reduces systemic inflammation, either directly or in combination with weight loss [105]. Even in low-intensity exercise groups of cancer patients, decreased levels of oxidative DNA damage have been observed [106]. The nuclear factor erythroid 2-related factor (NRF2) system is likely to provide an important contribution to the antioxidative properties of exercising; the increased production of reactive oxygen species (ROS) during exercise leads to NRF2 activation, which in turn activates a number of antioxidant enzymes [107]. Exercise primed against exercise-unrelated oxidative stress and significantly blunted carcinogenic stimuli [[80], [106], [107], [108], [109], [110], [111], [112], [113], [114]]. Physical intervention programs can reduce serum IL-6 levels independently of BMI and DM in men [[115], [116]]. In healthy adults, high-intensity training reduces responses of blood cells to TNF-α [111], while moderate exercise in cancer patients alters inflammatory cytokine responses [113].
Physical activity may dampen inflammatory states by decreasing the circulating levels of proinflammatory cytokines such as leptin and IGF-1 levels [[95], [117]]. In rats bearing mammary tumors, both calorie restriction and/or voluntary exercise decreased serum insulin, IGF-1, and tumor burden, along with Akt pathway downregulation and increased AMPK activity in tumors as well as in other tissues such as liver [[80], [81]]. Exercise reduces circulating leptin levels independent of metabolic conditions [[109], [118]]. Leptin opposes the beneficial effects of adiponectin and AMPK in cancer patients, extending its role beyond proinflammatory signaling [[118], [119]]. Experimental studies observed that impairment of leptin signal transduction mediated by Janus-activated kinase-2 (JAK-2) and the mitogen-activated protein kinase (MAPK) pathway occurs specifically in fructose-fed rats but not in glucose-fed rats [[120], [121]].
Diet and/or genetic obesity also induces alterations of gut microbiota, resulting in increased levels of deoxycholic acid (DCA), a gut bacterial metabolite known to cause DNA damage. Enterohepatic circulation of DCA provokes senescence-associated secretory phenotype (SASP) in hepatic stellate cells (HSC), which in turn secrete various inflammatory and tumor-promoting factors. Yoshimoto et al. reported that SASP promoted obesity-associated HCC development in mice [122]. Subsequent blocking of DCA production or decreasing gut bacteria efficiently prevented HCC development in obese mice. Mice lacking SASP inducers or depleted of senescent HSCs also showed similar results, indicating that the DCA-SASP axis in HSCs plays a key role in obesity-associated HCC development [122].
The preventive and therapeutic impact of lifestyle on cancer is remarkable and its exploitation should be further promoted. HCC is a cancer tightly linked to lifestyle. We need multicenter, prospective studies on large patient cohorts with different levels of intervention. We further need more detailed experimental studies on signaling pathways involved in liver carcinogenesis that may be negatively or positively modified by lifestyles. The implementation of policies favoring the adoption of healthier lifestyles should be an integral part of our efforts against HCC.

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