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Inflammation in Primary and Metastatic Liver Tumorigenesis-Under the Influence of Alcohol and High-Fat Diets.

ABSTRACT: The liver plays an outsized role in oncology. Liver tumors are one of the most frequently found tumors in cancer patients and these arise from either primary or metastatic disease. Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer and the 6th most common cancer type overall, is expected to become the 3rd leading cause of cancer mortality in the US by the year 2030. The liver is also the most common site of distant metastasis from solid tumors. For instance, colorectal cancer (CRC) metastasizes to the liver in two-thirds of cases, and CRC liver metastasis is the leading cause of mortality in these patients. The interplay between inflammation and cancer is unmistakably evident in the liver. In nearly every case, HCC is diagnosed in chronic liver disease (CLD) and cirrhosis background. The consumption of a Western-style high-fat diet is a major risk factor for the development of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), both of which are becoming more prevalent in parallel with the obesity epidemic. Excessive alcohol intake also contributes significantly to the CLD burden in the form of alcoholic liver disease (ALD). Inflammation is a key component in the development of all CLDs. Additionally, during the development of liver metastasis, pro-inflammatory signaling is crucial in eliminating invading cancer cells but ironically also helps foster a pro-metastatic environment that supports metastatic seeding and colonization. Here we review how Westernized high-fat diets and excessive alcohol intake can influence inflammation within the liver microenvironment, stimulating both primary and metastatic liver tumorigenesis.

SUBMITTER: Strathearn LS

PROVIDER: S-EPMC7230665 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Inflammation in Primary and Metastatic Liver Tumorigenesis-Under the Influence of Alcohol and High-Fat Diets.

Strathearn Lauren S LS Stepanov Afanasii I AI Font-Burgada Joan J

Nutrients 20200327 4

The liver plays an outsized role in oncology. Liver tumors are one of the most frequently found tumors in cancer patients and these arise from either primary or metastatic disease. Hepatocellular carcinoma (HCC), the most prevalent form of primary liver cancer and the 6th most common cancer type overall, is expected to become the 3rd leading cause of cancer mortality in the US by the year 2030. The liver is also the most common site of distant metastasis from solid tumors. For instance, colorect ...[more]

PMID: 32230953

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Project description:Previous studies demonstrated that diet-induced obese mice fed a semi-purified high-fat diet (HFD) had greater liver tumorigenesis than mice fed a non-semi-purified diet. Because ingredients present in standard unpurified diets may elicit potential chemopreventive properties that are not present in semi-purified diets, the present study evaluated hepatic tumorigenic effects of dietary fat by replacing it with refined carbohydrates [digestible saccharides; high-carbohydrate diet (HCD)] in a semi-purified diet without altering other components. Two-wk-old C57Bl/6J male mice were randomly injected i.p. with either the liver-specific carcinogen diethylnitrosamine (25 mg/kg body weight) to induce liver cancer or saline as the nontumor control. At age 6 wk, mice with or without cancer initiation were further randomly assigned to an HFD (26% and 60% energy from carbohydrates and fat, respectively) or an HCD (66% and 12% energy from carbohydrates and fat, respectively) and consumed food ad libitum for 24 wk. Results showed that HCD-fed mice had a comparable degree of hepatic tumorigenesis (tumor number and volume) as HFD-fed mice, despite having significantly reduced body weights. HCD feeding induced greater hepatic endoplasmic reticulum (ER) stress-mediated protein kinase RNA-activated-like kinase (PERK) activation and oncogenic interleukin-6/signal transducer and activator of transcription 3 signaling than HFD feeding. HCD-stimulated PERK signaling was associated with elevated expression of prosurvival markers in tumors, including induced protein kinase B activation, increased extracellular signal-regulated kinases 1/2 phosphorylation, and elevated cyclin D1 protein expression. However, HCD-mediated PERK activation in tumors was also positively associated with markers of proapoptosis, which included elevated CCAAT/enhancer-binding protein homology protein expression and increased cleaved caspase-3. HCD-fed mice had greater severity in hepatic steatosis than HFD-fed mice. HCD-induced steatosis exacerbation was associated with increased expression in hepatic de novo lipogenic markers that can promote ER stress. Together, these data indicated that chronic HCD consumption by mice can produce comparable severity of hepatic tumorigenesis as HFD consumption, potentially through upregulating PERK-mediated ER stress.

Dataset Information

Inflammation in Primary and Metastatic Liver Tumorigenesis-Under the Influence of Alcohol and High-Fat Diets.

Publications

Inflammation in Primary and Metastatic Liver Tumorigenesis-Under the Influence of Alcohol and High-Fat Diets.

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