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The Weight of Diet & Obesity on Hepatocellular Carcinoma

Oct 13, 2022 1:51:00 PM / by Champions Oncology

Hepatocellular Cell Image

Obesity has been linked to numerous comorbidities, including insulin resistance, type 2 diabetes, chronic inflammation, and hepatocellular carcinoma (HCC). Non-alcoholic fatty liver disease (NAFLD) is an obesity comorbidity that is closely linked to the development of HCC and is independent of other HCC risk factors like chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or heavy alcohol consumption[1]. HCC is one of the leading causes of cancer and cancer-related deaths, especially in men, and here we highlight current research linking obesity and lifestyle choices to HCC.


Improvements in treating HBV and HCV have reduced the incidence of HCC caused by these chronic infections. Nonetheless, HCC has been increasing annually and has been closely linked to increased incidences of NAFLD, including the development of nonalcoholic steatohepatitis (NASH), which has pathological hallmarks of hepatitis and is associated with liver fibrosis and HCC development[2]. Strikingly, numerous studies and meta-analyses have shown that obese individuals are at a much greater risk of HCC-related mortality than normal weight individuals[3]. Numerous factors appear to be driving mortality, including chronic inflammation, metabolic syndrome, and dysbiosis of gut microbiota, which ultimately contribute liver and organ failure and HCC progression.


Mouse studies are critical to examining the link between poor diet and liver disease. In epidemiological studies, the direct contribution of diet is difficult to distinguish from other factors that contribute to HCC, including heavy alcohol or aflatoxin-contaminated food consumption[4]. Studies in obese mice on high-fat diets have shown that NASH development is mediated by activation of liver-resident immune cells, especially Kupffer cells, which recruit B cells, T cells, NK cells and macrophages to the liver and drives inflammation and fibrosis[5]. These studies have begun to reveal the innate and adaptive immune responses that lead to liver inflammation and oncogenesis.

Liver Failure Diagram

Although NASH mouse models resemble human disease, not all patients with NASH develop HCC. HCC can also develop in NAFLD patients with no evidence of liver fibrosis[6]. In this regard, genomic studies in patients have been critical to understanding other factors that contribute to HCC progression. Thousands of somatic mutations have been identified in HCC samples, with many of these mutations altering signaling pathways that regulate tumor growth including JAK/STAT signaling, and especially STAT3 activation[7]. These findings have been validated in rodent models, and a recent study in mouse models of NASH and obesity suggested that obesity triggers changes in the liver microenvironment that both drive STAT1 activation, which causes NASH, and STAT3 activation, which promotes HCC[8].


Sedentary lifestyles are also linked to NASH and HCC, and a recent study showed that regular aerobic exercise can decrease tumor development in a spontaneous steatohepatitis and HCC model[9]. Other studies have suggested that some healthy dietary patterns may reduce HCC risk, although further investigation is needed to validate these findings[10].


The incidence of and mortality associated with HCC is likely to rise due to the ongoing obesity pandemic, and insights into lifestyle choices that contribute to liver disease and HCC are critical to shaping medical treatment and the development of novel therapies.


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[1] Singal AG, El-Serag HB. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 2015 Nov 1;13(12):2140-51.

[2] Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-33.

[3] Gupta A, Das A, Majumder K, Arora N, Mayo HG, Singh PP, Beg MS, Singh S. Obesity is independently associated with increased risk of hepatocellular cancer-related mortality: a systematic review and meta-analysis. Am. J. Clin. Oncol. 2018 Sep;41(9):874.

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[7] Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat. Genet. 2015 May;47(5):505-11.

[8] Grohmann M, Wiede F, Dodd GT, Gurzov EN, Ooi GJ, Butt T, Rasmiena AA, Kaur S, Gulati T, Goh PK, Treloar AE. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell. 2018 Nov 15;175(5):1289-306.

[9] Piguet AC, Saran U, Simillion C, Keller I, Terracciano L, Reeves HL, Dufour JF. Regular exercise decreases liver tumors development in hepatocyte-specific PTEN-deficient mice independently of steatosis. J. Hepatol. 2015 Jun 1;62(6):1296-303.

[10] Yang WS, Zeng XF, Liu ZN, Zhao QH, Tan YT, Gao J, Li HL, Xiang YB. Diet and liver cancer risk: a narrative review of epidemiological evidence. Br. J. Nutr. 2020 Aug;124(3):330-40


Tags: Solid Tumor Oncology