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Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors

1
Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, St Mary’s Hospital, Manchester M13 9WL, UK
2
Division of Pharmacy & Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
3
Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M20 4GJ, UK
4
Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
*
Authors to whom correspondence should be addressed.
Contributed equally.
Cancers 2019, 11(5), 653; https://doi.org/10.3390/cancers11050653
Received: 26 February 2019 / Revised: 2 May 2019 / Accepted: 7 May 2019 / Published: 11 May 2019
(This article belongs to the Special Issue Cancer Stem Cells and Personalized Medicine for Gynecologic Cancers)
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Abstract

Advanced endometrial cancer continues to have a poor prognosis, due to limited treatment options, which may be further adversely impacted by obesity. Endometrial cancer stem cells have been reported to drive metastasis, chemotherapy resistance and disease relapse, but have yet to be fully characterised and no specific targeted therapies have been identified. Here, we describe the phenotype and genotype of aldehyde dehydrogenase high (ALDHhigh) and CD133+ve endometrial cancer stem cells and how adipocyte secreted mediators block the inhibitory effect of metformin on endometrial cancer stem cell activity. Ishikawa and Hec-1a cell lines were used to characterise ALDHhigh and CD133+ve endometrial cancer cells using flow cytometry, functional sphere assays and quantitative-Polymerase Chain Reaction. The comparative effect of metformin on endometrial cancer stem cell activity and bulk tumour cell proliferation was determined using an Aldefluor and cytotoxicity assay. The impact of adipocyte secreted mediators on metformin response was established using patient-derived conditioned media. ALDHhigh cells demonstrated greater endometrial cancer stem cell activity than CD133+ve cells and had increased expression of stem cell and epithelial-mesenchymal transition genes. Treatment with 0.5–1 mM metformin reduced the proportion and activity of both endometrial cancer stem cell populations (p ≤ 0.05), without affecting cell viability. This effect was, however, inhibited by exposure to patient-derived adipocyte conditioned media. These results indicate a selective and specific effect of metformin on endometrial cancer stem cell activity, which is blocked by adipocyte secreted mediators. Future studies of metformin as an adjuvant therapy in endometrial cancer should be adequately powered to investigate the influence of body mass on treatment response. View Full-Text
Keywords: Endometrial cancer; cancer stem cells; metformin; adipocytes; patient-derived Endometrial cancer; cancer stem cells; metformin; adipocytes; patient-derived
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Kitson, S.J.; Rosser, M.; Fischer, D.P.; Marshall, K.M.; Clarke, R.B.; Crosbie, E.J. Targeting Endometrial Cancer Stem Cell Activity with Metformin Is Inhibited by Patient-Derived Adipocyte-Secreted Factors. Cancers 2019, 11, 653.

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