Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation

Chen, Tsung-Ming; Lin, Chih Kuang; Huang, Pi‐Teh; Wen, Chen-Fan

doi:10.1111/j.1440-1746.2011.06664.x

Cited by 99 publications

(107 citation statements)

References 39 publications

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“…26 In diabetic patients, treatment with sulfonylurea or exogenous insulin increases HCC risk and worsens tumor response to radioablation, whereas HCC patients taking the insulin-sensitizing drug metformin have more favorable outcomes. [27][28][29] This finding suggests a direct role for insulin in liver tumor promotion. Because insulin resistance in the absence of obesity or diabetes was sufficient to promote HCC in AB6F1 mice, we investigated potential mechanisms of metabolic hepatocarcinogenesis.…”

Section: Discussionmentioning

confidence: 72%

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Hines

Hartwell

Feng

et al. 2011

The American Journal of Pathology

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Insulin resistance is a defining feature of metabolic syndrome and type 2 diabetes mellitus but also may occur independently of these conditions. Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of these disorders, increases the risk of hepatocellular carcinoma (HCC). However, mechanisms linking hyperinsulinemia to NAFLD and HCC require clarification. We describe a novel model of primary insulin resistance and HCC with strong parent-of-origin effects. Male AB6F1 (A/JCr dam ؋ C57BL/6 sire) but not B6AF1 (B6 dam ؋ A/J sire) mice developed spontaneous insulin resistance, NAFLD, and HCC without obesity or diabetes. A survey of mitochondrial, imprinted, and sex-linked traits revealed modest associations with X-linked genes. However, a dietinduced obesity study, including B6.A chromosome substitution-strain (consomic) mice, showed no segregation by sex chromosome. Thus, parent-of-origin effects were specified within the autosomal genome. Next, we interrogated mechanisms of insulin-associated hepatocarcinogenesis. Steatotic hepatocytes exhibited adipogenic transition characterized by vacuolar metaplasia and up-regulation of vimentin, adipsin, fatty acid translocase (CD36), peroxisome proliferator-activated receptor-␥, and related products. This profile was largely recapitulated in insulin-supplemented primary mouse hepatocyte cultures. Importantly, pyruvate kinase M2, a fetal anabolic enzyme implicated in the Warburg effect, was activated by insulin in vivo and in vitro. Thus, our study reveals parent-of-origin effects in heritable insulin resistance, implicating adipogenic transition with acquired anabolic metabolism in the progression from NAFLD to HCC.

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Section: Discussionmentioning

confidence: 72%

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Hines

Hartwell

Feng

et al. 2011

The American Journal of Pathology

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“…Four studies scored five points (36,37,42,43). Most studies lost one point on representativeness of exposed cohort because the population was taken from referral centers that do not represent the general population.…”

Section: Resultsmentioning

confidence: 99%

“…We identified diabetesrelated variables (HbA1c or diabetes duration) as markers of diabetes severity and the presence of a cancer stage variable (stage, tumor size, node status) as the most important covariates. Accounting for diabetes severity helps to minimize indication bias whereas stage (27,30,38,42) and fourteen adjusted for cancer stage in multivariable analyses.…”

Section: Resultsmentioning

confidence: 99%

The Effect of Metformin on Mortality Following Cancer among Patients with Diabetes

Lega

Shah

Margel³

et al. 2014

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Diabetes may be a risk factor for cancer and is associated with worse cancer outcomes. Metformin may reduce cancer risk; however, its effect on mortality following cancer remains less clear. EMBASE and Medline were searched through February 10, 2014, for studies reporting an adjusted risk estimate for the effect of metformin therapy on mortality following cancer among diabetic patients. Random-effects models were used to obtain summary HR for the association between metformin and all-cause and cancer-specific mortality. Twenty-one observational studies were meta-analyzed in the primary analysis. Metformin was associated with a reduction in all-cause mortality [HR, 0.73; 95% confidence intervals (CI), 0.64-0.83] and cancer-specific mortality (HR, 0.74; 95% CI, 0.62-0.88). Subgroup analyses by cancer site showed a significant reduction in mortality for colon cancer (four studies, HR, 0.65; 95% CI, 0.56-0.76) but not for breast and prostate cancers. Observational studies indicate that metformin exposure at cancer diagnosis may be associated with a reduction in mortality. However, these findings need to be interpreted with caution as methodologic limitations of individual studies may have introduced biases in these findings. Our results emphasize the need for well-designed studies to further understand the relationship between metformin and survival following cancer. Cancer Epidemiol Biomarkers Prev; 23(10);

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“…[1][2][3][4][5][6][7][8][9][10][11] The negative relationship between metformin usage and cancer incidence and mortality among diabetics, however, does not necessarily imply a universal chemoprevention effect of metformin, especially…”

Section: Introductionmentioning

confidence: 99%

Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

Cufí¹,

Vázquez-Martín

Oliveras‐Ferraros³

et al. 2012

Cell Cycle

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Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation

Abstract: Metformin users among diabetic patients with HCC undergoing RFA had a favorable overall survival compared with patients without metformin treatment.

Cited by 99 publications

References 39 publications

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

Insulin Resistance and Metabolic Hepatocarcinogenesis with Parent-of-Origin Effects in A×B Mice

The Effect of Metformin on Mortality Following Cancer among Patients with Diabetes

Metformin lowers the threshold for stress-induced senescence: A role for the microRNA-200 family and miR-205

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