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bioRxiv · 10.1101/562744

Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors

Kitson, S. J.·Rosser, M.·Fischer, D. P.·Marshall, K. M.·Clarke, R. B.·Crosbie, E. J.
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Abstract

Translational relevanceEndometrial cancer stem cells are reported to drive metastasis and disease relapse and are resistant to commonly used chemotherapeutic drugs. Here, we characterise ALDHhigh and CD133+ve endometrial cancer stem cells with differing levels of cancer stem cell activity and stem cell and epithelial-mesenchymal transition (EMT) gene expression. Their proportions and activity are reduced following treatment with metformin at a lower concentration than that required to affect bulk tumour cell proliferation, establishing a selective and specific effect on endometrial cancer stem cells. We demonstrate that this effect is abrogated when endometrial cancer cells are pre-treated with adipocyte conditioned media, indicating adipokine-mediated resistance to metformin. These results support future studies of metformin as an adjuvant therapy to reduce the risk of disease recurrence but should also investigate the impact of obesity on treatment response. AbstractO_ST_ABSPurposeC_ST_ABSAdvanced 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. Experimental designIshikawa 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. ResultsALDHhigh 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 0.5-1mM 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. ConclusionsThese 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.

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Kitson, S. J., Rosser, M., Fischer, D. P., Marshall, K. M., Clarke, R. B., Crosbie, E. J.. 2019-02-28. Targeting endometrial cancer stem cell activity with metformin is inhibited by patient-derived adipocyte-secreted factors. https://doi.org/10.1101/562744

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