Hypoxia and hyperglycaemia determine why some endometrial tumours fail to respond to metformin

Vanitha N Sivalingam,Rhona Mcvey,Sarah Kitson,Emma J Crosbie,Ian J Stratford,Katherine G Finegan,Kay Marshall,Federica Sotgia,Ayşe Latif,Michael P Lisanti

doi:10.1038/s41416-019-0627-y

Abstract

BackgroundHigh expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Pre-surgical metformin reduces tumour Ki-67 expression in some women with endometrial cancer. Metformin’s anti-cancer activity may relate to effects on cellular energy metabolism. Since tumour hypoxia and glucose availability are major cellular redox determinants, we evaluated their role in endometrial cancer response to metformin.MethodsEndometrial cancer biopsies from women treated with pre-surgical metformin were tested for the hypoxia markers, HIF-1α and CA-9. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed.ResultsIn women treated with metformin (n = 28), Ki-67 response was lower in hypoxic tumours. Metformin showed minimal cytostatic effects towards Ishikawa and HEC1A cells in conventional medium (25 mM glucose). In low glucose (5.5 mM), a dose-dependent cytostatic effect was observed in normoxia but attenuated in hypoxia. Tumours treated with metformin showed increased mitochondrial mass (n = 25), while in cultured cells metformin decreased mitochondrial function. Metformin targets mitochondrial respiration, however, in hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response.ConclusionsUnderstanding the metabolic adaptations of endometrial tumours may identify patients likely to derive clinical benefit from metformin.

Highlights

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival
Tumour hypoxia affects metformin response in vitro and in vivo Pre- and post-intervention tumour biopsies were obtained in the context of a pre-surgical window study of metformin in women with endometrial cancer.[8]
We previously showed that short-term oral metformin reduces cellular proliferation in some patients with endometrioid endometrial cancer, as measured by a reduction in postintervention Ki-67 expression

Summary

Introduction

High expression of Ki67, a proliferation marker, is associated with reduced endometrial cancer-specific survival. Endometrial cancer cell lines were treated with metformin in variable glucose concentrations in normoxia or hypoxia and cell viability, mitochondrial biogenesis, function and energy metabolism were assessed. In hypoxic, high glucose conditions, there was a switch to glycolytic metabolism and decreased metformin response. Surgical treatment of early stage endometrial cancer is usually curative, but is accompanied by increased peri-operative morbidity in obese women.[4] Current non-surgical alternatives offer lower rates of cure and are associated with a high risk of relapse.[5,6] there is a need to explore new, efficacious, non-surgical approaches for those unsuitable for surgery, those who wish to avoid a hysterectomy for fertility reasons, as well as for women with advanced, recurrent endometrial cancer

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