Abstract
Metformin is used to treat patients with type 2 diabetes mellitus and was found to lower the incidence of cancer. Bone metastasis is a common impairment associated with advanced breast cancer. The present study investigated the effects of metformin on human bone-derived mesenchymal stromal cells (BM-MSC)—breast cancer cell line interactions. BM-MSCs grown from box chisels were tested for growth-stimulating and migration-controlling activity on four breast cancer cell lines either untreated or after pretreatment with metformin. Growth stimulation was tested in MTT tests and migration in scratch assays. Furthermore, the expression of adipokines of BM-MSCs in response to metformin was assessed using Western blot arrays. Compared to breast cancer cell lines (3.6 ± 1.4% reduction of proliferation), 500 µM metformin significantly inhibited the proliferation of BM-MSC lines (mean 12.3 ± 2.2 reduction). Pretreatment of BM-MSCs with metformin showed variable effects of the resulting conditioned media (CM) on breast cancer cell lines depending on the specific BM-MSC—cancer line combination. Metformin significantly reduced the migration of breast cancer cell lines MDA-MB-231 and MDA-MB-436 in response to CM of drug-pretreated BM-MSCs. Assessment of metformin-induced alterations in the expression of adipokines by BM-MSC CM indicated increased osteogenic signaling and possibly impairment of metastasis. In conclusion, the anticancer activities of metformin are the result of a range of direct and indirect mechanisms that lower tumor proliferation and progression. A lower metformin-induced protumor activity of BM-MSCs in the bone microenvironment seem to contribute to the positive effects of the drug in selected breast cancer patients.
Highlights
Bone metastasis remains one of the most frequent challenges of patients suffering from advanced breast cancer [1]
The breast cancer cell lines MDA-MB-231, MDA-MB-436, T47D and HCC1937 were obtained from the ATCC (Rockville, MD, USA), cultured in RPMI-1640 medium and upon confluence, cells were detached with trypsin/EDTA (Sigma-Aldrich) and cells counted with a LUNA cell counter (Biozym, Vienna, Austria)
The adipose-derived stromal cells (ADSCs) line TRI revealed an inhibitory effect of metformin of 7.9 ± 3.1%
Summary
Medical Oncology (2022) 39:54 within the TME secreted by resident MSCs seem to trigger dormancy [5]. EVs, including exosomes and microvesicles, derived from MSCs exert similar effects as their parental cells [6]. MCF7 breast cancer cells treated with MSC-derived EVs exhibited reduced migration and proliferation as well as increased adhesion, supporting cancer cell residence in bone tissue. We reported recently that metformin showed minor direct inhibitory effects on breast cancer cell lines but exerted a significant impairment of the growth and adipocytic differentiation of adipose-derived stromal cells (ADSCs). Metastasis to bone is frequently observed in advanced breast cancer and, locally, malignant cells may be affected by BM-MSCs. In the present study, the potential effects of metformin on BM-MSCs and four breast cancer cell lines were tested employing proliferation and migration assays as well as Western blot adipokine arrays. Inhibitory activities of metformin on BM-MSCs may constitute another mechanism retarding metastasis and progress of breast cancer
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