Diet-induced obesity and ethanol impair progression of hepatocellular carcinoma in a mouse mesenteric vein injection model.
BACKGROUND
Hepatocellular carcinoma (HCC) is a rapidly increasing cancer whose known risk factors are chronic ethanol abuse, viral hepatitis infection, and aflatoxin exposure. Obesity, an emerging HCC risk factor, is reaching epidemic proportions in developed nations. This study investigated the effects of diet-induced obesity (DIO) and chronic ethanol consumption on HCC progression in mice in vivo.


METHODS
In this study, C57BL/6 DIO mice and lean litter mates were maintained on a 60% (high-fat diet [HFD]) diet or a 10% (control diet [CD]) kcal% fat diet for 7 weeks before they were weaned to 10/20% ([v/v], alternating days) ethanol in drinking water (EtOH) or maintenance on drinking water (H(2)O) alone. Hepatic tumor formation was initiated by intrahepatic Hepa1-6 cell (6 × 10(6) cells) inoculation 6 weeks later via the mesenteric vein.


RESULTS
The animals receiving the HFD showed decreased tumor incidence and area of hepatic foci versus the CD animals maintained on H(2)O alone. The action of EtOH suppressed tumor incidence further in both the CD and the HFD mice. Serologic analysis showed no significant differences in liver enzymes among the groups. Protein analysis demonstrated increased P450 2E1 (CYP2E1) in the groups maintained on EtOH, an effect exacerbated by HFD. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated increased tumor necrosis factor-alpha (TNF-α) expression in HFD HCC mice (H(2)O and EtOH) concomitant with decreased transforming growth factor-beta (TGF-β) expression.


CONCLUSIONS
Although obesity and EtOH consumption are known risk factors for HCC initiation and development, the data in this study suggest that these factors impair progression of established tumors within the liver.
Hepatobiliary and Pancreatic Surgery, Department of General Surgery, Carolinas Medical Center, Charlotte, NC 28203, USA. kyle.thompson@carolinas.org
Kyle J
KJ
Thompson
Ryan Z
RZ
Swan
David A
DA
Iannitti
Iain H
IH
McKillop
David
D
Sindram
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D018450:Disease Progression; D000431:Ethanol / Q000494:pharmacology*; D007275:Injections, Intravenous; D008114:Liver Neoplasms, Experimental / Q000503:physiopathology*; D008297:Male; D008642:Mesenteric Veins; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009765:Obesity / Q000209:etiology*; D011897:Random Allocation; D014183:Transplantation, Heterologous; D047368:Tumor Burden
D002492:Central Nervous System Depressants; D016207:Cytokines; D000431:Ethanol