Effects of metformin on human bone-derived mesenchymal stromal cell—breast cancer cell line interactions

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.

The cellular composition of the tumor microenvironment is an important marker for predicting therapeutic efficacy in breast cancer

“…The good one is associated with apoptisis, and the bad one is related to treatment resistance ( 12 , 111 , 144 , 171 , 178 ). As vaccines, lentiviral vectors, non-anticancer drugs and biological extracts were found to have positive implications for cellular compositions changes in the TME, we see the benefits of combination administration targeted cellular compositions of the TME and other conventional treatments in BC ( 187 , 191 , 193 , 197 ). The cellular compositions of the TME and and therapeutic mechanisms deserves further study.…”

“…Metformin is used to treat patients with type 2 diabetes and has recently been found to reduce the incidence of cancer. Teufelsbauer et al reported that, when treated with metformin, MSCs preferentially differentiate into the osteogenic lineage, thus releasing factors that inhibit the migration of breast cancer cells (191). The exosomal CXCR4 + TRAIL is transduced from MSCs via a lentiviral vector.…”

Nano-Hydroxyapatite Composite Scaffolds Loaded with Bioactive Factors and Drugs for Bone Tissue Engineering

“…Metformin, an organic compound, is a first-line drug for treatment of type 2 diabetes. Metformin has been widely studied for its anticancer, anti-inflammatory and osteogenic effects [ 158 , 159 ]. Tan et al successfully developed the poly (L-lactic ac-id)/n-HAp/metformin (PLLA/n-HAp/MET) nanocomposite scaffold using SLS technology.…”