Bone marrow derived Mesenchymal Stem Cells (MSCs) are known to specifically migrate to and engraft at tumor sites. Understanding interactions between cancer cells and MSCs has become fundamental to determining whether MSC-tumour interactions should be harnessed for delivery of therapeutic agents or considered a target for intervention. Breast Cancer Cell lines (MDA-MB-231, T47D & SK-Br3) were cultured alone or on a monolayer of MSCs, and retrieved using epithelial specific magnetic beads.Alterations in expression of 90 genes associated with breast tumorgenicity were analyzed using low density array. Expression of markers of Epithelial-Mesenchymal transition and array results were validated using RQ-PCR. Co-cultured cells were analyzed for changes in protein expression, growth pattern, and morphology. Gene expression and proliferation assays were also performed on indirect co-cultures. Following direct co-culture with MSCs, breast cancer cells expressed elevated levels of oncogenes (NCOA4, FOS), protooncogenes (FYN, JUN), genes associated with invasion (MMP11), angiogenesis (VEGF)and anti-apoptosis (IGF1R, BCL2). However, universal downregulation of genes associated with proliferation was observed (Ki67, MYBL2), and reflected in reduced ATP production in response to MSC-secreted factors. Significant upregulation of Epithelial-Mesenchymal Transition specific markers (N-cadherin, Vimentin, Twist and Snail) was also observed following co-culture with MSCs, with a reciprocal downregulation in E-cadherin protein expression. These changes were predominantly cell contact mediated and appeared to be MSC specific. Breast cancer cell morphology and growth pattern also altered in response to MSCs. Mesenchymal Stem Cells may promote breast cancer metastasis through facilitation of Epithelial-Mesenchymal Transition.
Over 70% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Mesenchymal Stem Cells (MSCs) and their derivative osteoblasts are subpopulations of cells within the bone marrow environment, postulated as potential interacting targets for disseminating cancer cells because of their ability to secrete a range of chemokines. This study aimed to investigate chemokine secretion throughout MSC differentiation into osteoblasts and their effect on the breast cancer cells. Primary MSCs and osteoblast progenitors were cultured in appropriate conditions to induce differentiation into mature osteoblasts. Chemokines secreted throughout differentiation were detected using ChemiArray and ELISA. Migration of breast cancer cells in response to the bone-derived cells was quantified using Transwell inserts. Breast cancer cells were cocultured with MSCs, retrieved using magnetic beads, and changes in CCL2 expression were analyzed. MSCs secreted a range of factors including IL-6, TIMP-1 and CCL2, the range and level of which changed throughout differentiation. CCL2 secretion by MSCs increased significantly above control cells as they differentiated into mature osteoblasts (p < 0.05). The bone-derived cells stimulated migration of breast cancer cells, and this was inhibited (21-50%) in the presence of a CCL2 antibody. CCL2 gene expression in breast cancer cells was upregulated following direct coculture with MSCs. The varying levels of chemokines secreted throughout MSC differentiation may play an important role in supporting tumor cell homing and progression. These results further highlight the distinct effect MSCs have on breast cancer cells and their potential importance in supporting development of metastases.
Vertical groin incisions (VGIs) have been used to access femoral vessels, but reports allude to wound complications. Our aim was to compare VGI with transverse groin incision (TGI) for femoral artery exposure. Over a 5-year interval, 196 patients with 284 femoral artery exposures for supra- and infrainguinal procedures were studied. Primary endpoints were surgical skin site wound infection, seroma, haematoma formation, and major lower limb amputation. Secondary endpoints were graft patency, wound paresthesias, and length of hospital stay. There were 160 TGIs and 124 VGIs. The demographics and risk factor profile were not statistically different between groups. Seroma developed in 4.4% of TGIs and 13.7% of VGIs (p= .005). The complicated skin and soft tissue infection rate was five times greater with VGI (p= .001). The VGI group had a significantly higher rate of major amputation (p= .0005). Significantly higher graft failure rates were observed in the VGI group (p= .011). No paresthesia was reported in any TGI wound. The mean hospital stay was also significantly shorter in the TGI group (p= .006). The study data support and expound on the theory that an alternative incision to VGI offers lower short- and long-term morbidity. Our findings sustain the selection of the TGI in femoral artery surgery for both supra- and infrainguinal procedures without compromise of vessel exposure.
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