Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis

Xie, Weimin; Li, Tianjia; Yang, Jing; Shang, Mengmeng; Xiao, Ying; Li, Qian; Yang, Jiaxin

doi:10.18632/oncotarget.20388

Cited by 12 publications

(10 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The use of MET in diabetic patients is associated with significantly lower risks of cancer incidence and mortality [9][10][11][12]. More germane to this study, EC patients with diabetes using MET exhibited improved overall and progression-free survival [11,13,14]. Whereas the therapeutic benefits of MET in many cancer types are known to be mediated by the inhibition of the PI3K/AKT/mTORsignaling pathways [7,15], the anti-cancer effects and signaling mechanisms of MET in non-diabetic vs. diabetic women with EC have not been fully characterized.…”

Section: Introductionmentioning

confidence: 64%

“…The in vivo (proof-of-concept) study involved a short-term MET treatment (pre-surgical; between diagnosis and hysterectomy) of non-diabetic obese women with EC, while the in vitro experiments analyzed the direct effects of MET on proliferation, apoptosis, and gene expression in the human endometrial carcinoma cell line Ishikawa. While the in vivo results were limited by the small patient sample size due in part to the prevalence of type 2 diabetes in obese women with EC [3], the non-diabetic obese control and treatment groups did not differ in BMI and age, thus precluding the confounding issues of insulin resistance, adiposity, and/or menopausal status found in other studies that had previously evaluated the effects of MET in EC [14,[30][31][32][33][34]. Importantly, the congruence of changes elicited by MET in vivo (protein) and in vitro (mRNA) on the expression of PGR, PTEN, KLF9, and ERα provides mechanistic underpinnings to the direct effects of MET on EC.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

et al. 2020

View full text Add to dashboard Cite

Metformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67-and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.

show abstract

Section: Introductionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

et al. 2020

View full text Add to dashboard Cite

show abstract

“…136 duplicate articles were initially excluded, and an additional 35 articles were screened by title. Another 102 articles were excluded after assessing the abstract, and 46 articles were finally excluded after full-text screening and finally, 16 eligible meta-analyses reporting various kinds of cancer mortality or survival in 11 cancers were finally selected for re-analysis ( Figure 1) [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. Overall, all-cause mortality was reported as outcomes in 11 cancer types, cancer-specific mortality in 8 cancer types, recurrence-free survival in 5 cancer types, progression-free survival in 4 cancer types and disease-free survival in one cancer type (Tables 1-4).…”

Section: Search Strategy For the Literature And Included Studies For mentioning

confidence: 99%

Statin and Cancer Mortality and Survival: An Umbrella Systematic Review and Meta-Analysis

Jeong

Lee

Kim

et al. 2020

JCM

View full text Add to dashboard Cite

The aim of this study is to provide an overview and understand the strength of evidence and the extent of potential biases and the validity of claimed associations between the use of statins and cancer mortality or survival. We performed a comprehensive umbrella review of meta-analyses and systematically appraised the relevant meta-analyses of observational studies on the associations between statin use and cancer mortality or survival in various kinds of cancer. We searched the PubMed database and screened the reference list of relevant articles. We obtained the summary effect, 95% confidence interval, heterogeneity, and also examined small study effects and 95% prediction intervals for effect sizes, and the level of evidence was determined from the criteria. Regarding cancer mortality, statin use showed convincing evidence for an association with a reduced cancer-specific mortality rate for colorectal cancer. Four associations with reduced all-cause mortality (for breast cancer, colorectal cancer, endocrine-related gynecological cancer, and ovarian cancer) had a suggestive evidence. Moreover, analyses in nine cancers showed a weak level of evidence, while the remaining 15 did not indicate significant changes in either direction. Although there was a preventive effect of statin on cancer mortality in some cancer types, the evidence supporting the use of statins to reduce cancer mortality or survival was low.

show abstract

“…Metformin represents a universal, but very weak, anticancer drug. Meta-analyses of multiple studies support its antitumor effect, affecting, for example, cancers of lung 6 , prostate 7 , and endometrium 8 . However, in some studies no improvement was observed, e.g., with non-small cell lung cancer (NSCLC) 9 .…”

Section: Introductionmentioning

confidence: 97%

Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification

et al. 2018

View full text Add to dashboard Cite

Use of the diabetes type II drug Metformin is associated with a moderately lowered risk of cancer incidence in numerous tumor entities. Studying the molecular changes associated with the tumor-suppressive action of Metformin we found that the oncogene SOX4, which is upregulated in solid tumors and associated with poor prognosis, was induced by Wnt/β-catenin signaling and blocked by Metformin. Wnt signaling inhibition by Metformin was surprisingly specific for cancer cells. Unraveling the underlying specificity, we identified Metformin and other Mitochondrial Complex I (MCI) inhibitors as inducers of intracellular acidification in cancer cells. We demonstrated that acidification triggers the unfolded protein response to induce the global transcriptional repressor DDIT3, known to block Wnt signaling. Moreover, our results suggest that intracellular acidification universally inhibits Wnt signaling. Based on these findings, we combined MCI inhibitors with H+ ionophores, to escalate cancer cells into intracellular hyper-acidification and ATP depletion. This treatment lowered intracellular pH both in vitro and in a mouse xenograft tumor model, depleted cellular ATP, blocked Wnt signaling, downregulated SOX4, and strongly decreased stemness and viability of cancer cells. Importantly, the inhibition of Wnt signaling occurred downstream of β-catenin, encouraging applications in treatment of cancers caused by APC and β-catenin mutations.

show abstract

Metformin use and survival outcomes in endometrial cancer: a systematic review and meta-analysis

Cited by 12 publications

References 44 publications

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

Statin and Cancer Mortality and Survival: An Umbrella Systematic Review and Meta-Analysis

Cancer cell specific inhibition of Wnt/β-catenin signaling by forced intracellular acidification

Contact Info

Product

Resources

About