Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG et al.. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 140: 197-208

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 01/2010; 140(2):197-208. DOI: 10.1016/j.cell.2009.12.052
Source: PubMed


Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity among all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor-promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.

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Available from: Christoph Oesterreicher, Jul 22, 2014
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    • "Furthermore, the source of cytokines in kidney disease (Spoto et al., 2012) may not be the same as in obesity or metabolic disease where adipose tissues are believed to be a major source (Fruhbeck et al., 2001). In other inflammation/infection models, other tissues such as spleen and liver can be a major source of cytokines (Arsenijevic et al., 1998; Park et al., 2010). "
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    ABSTRACT: The role of mild kidney dysfunction in altering lipid metabolism and promoting inflammation was investigated in uninephrectomized rats (UniNX) compared to Sham-operated controls rats. The impact of UniNX was studied 1, 2, and 4 weeks after UniNX under mild food restriction at 90% of ad libitum intake to ensure the same caloric intake in both groups. UniNX resulted in the reduction of fat pad weight. UniNX was associated with increased circulating levels of beta-hydroxybutyrate and glycerol, as well as increased fat pad mRNA of hormone sensitive lipase and adipose triglyceride lipase, suggesting enhanced lipolysis. No decrease in fat pad lipogenesis as assessed by fatty acid synthase activity was observed. Circulating hormones known to regulate lipolysis such as leptin, T3, ghrelin, insulin, corticosterone, angiotensin 1, and angiotensin 2 were not different between the two groups. In contrast, a select group of circulating lipolytic cytokines, including interferon-gamma and granulocyte macrophage-colony stimulating factor, were increased after UniNX. These cytokine levels were elevated in the spleen, but decreased in the kidney, liver, and fat pads. This could be explained by anti-inflammatory factors SIRT1, a member of the sirtuins, and the farnesoid x receptor (FXR), which were decreased in the spleen but elevated in the kidney, liver, and fat pads (inguinal and epididymal). Our study suggests that UniNX induces adipose tissue lipolysis in response to increased levels of a subset of lipolytic cytokines of splenic origin.
    Full-text · Article · Jul 2015 · Frontiers in Physiology
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    • "In addition, recent studies have shown that chronic pancreatitis is required for KRAS-induced pancreatic ductal adenocarcinomas in adult mice (Guerra et al., 2007). Therefore, nongenetic events associated with HCD feeding could modulate tumor initiation when the latter is driven by a defined oncogenic mutation including KRAS (Guerra et al., 2007; Park et al., 2010a). Notably, lungs of SD or HCD-pretumor-onset Kras G12D mice treated with doxy for 4 weeks had no differences in tumor size and multiplicity (Figure S1I). "
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    ABSTRACT: Dietary effects on tumor biology can be exploited to unravel cancer vulnerabilities. Here, we present surprising evidence for anti-proliferative action of high-calorie-diet (HCD) feeding on KRAS-driven lung tumors. Tumors of mice that commenced HCD feeding before tumor onset displayed defective unfolded protein response (UPR) and unresolved endoplasmic reticulum (ER) stress. Unresolved ER stress and reduced proliferation are reversed by chemical chaperone treatment. Whole-genome transcriptional analyses revealed FKBP10 as one of the most downregulated chaperones in tumors of the HCD-pre-tumor-onset group. FKBP10 downregulation dampens tumor growth in vitro and in vivo. Providing translational value to these results, we report that FKBP10 is expressed in human KRAS-positive and -negative lung cancers, but not in healthy parenchyma. Collectively, our data shed light on an unexpected anti-tumor action of HCD imposed before tumor onset and identify FKBP10 as a putative therapeutic target to selectively hinder lung cancer. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Cell Metabolism
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    • "The euthanized mice did not show evidence of tumor burden. Sample size sufficient to detect a 20% change in tumor number was estimated a priori, using a power analysis based on group means and standard deviations previously reported [35]. Dietary intervention was delayed until 4 weeks after treatment with the carcinogen, to distinguish tumor initiation by the carcinogen from promotion of lesion growth by the diets. "
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    ABSTRACT: Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.
    Full-text · Article · Oct 2014 · Journal of Hepatology
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