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

Abstract

PurposeAdvanced 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 (ALDH high ) 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 ALDH high 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. ResultsALDH high 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.

Clinical and Prognostic Significance of CD117 in Non-Small Cell Lung Cancer: A Systemic Meta-Analysis

“…Cancer stem cells (CSCs) are a special subpopulation of cancer cells, which are responsible for the major capabilities of self-renewal and uncontrolled proliferation and dif-ferentiation, and increasing evidence suggests that CSCs contribute to cancer metastasis, a worse prognosis, and resistance to chemotherapy or radiation therapy [5][6][7]. Cluster of differentiation 117 (CD117), termed c-kit proto-oncogene, encoded by the c-kit gene, and located on human chromosome 4q11-12, belongs to a type-III transmembrane receptor tyrosine kinase [8,9].…”

LncRNA MONC suppresses the malignant phenotype of Endometrial Cancer Stem Cells and Endometrial Carcinoma Cells by regulating the MiR-636/GLCE axis

“…In recent years, there have been reports on ECSCs, but there are few related studies. Nevertheless, studies have found selective and specific effects of metformin on the activity of ECSCs [ 24 ]. In another study, SPIONs were found to be highly efficient nanocarriers for nucleic acids.…”

LncRNA MONC suppresses the malignant phenotype of Endometrial Cancer Stem Cells and Endometrial Carcinoma Cells by regulating the MiR-636/GLCE axis

“…In recent years, there have been reports of ECSCs, but there are few related studies. Studies have found selective and speci c effects of metformin on the activity of ECSCs [24] . In another study, SPIONs were found to be highly e cient nanocarriers for nucleic acids.…”