Induction of matrix metalloproteinases MMP-1 and MMP-2 by co-culture of breast cancer cells and bone marrow fibroblasts

Two invasive breast cancer cell lines (MDA-MB-231 and BT-549) were found to be more adherent and have greater migratory capacity on bone marrow fibrob lasts than three non-invasive cell lines (MCF-7, T47D and BT-483). Antibodi es to the adhesion molecules CD44, E-cadherin, ICAM-1, and integrin chains alpha2, alpha3, alpha4, alpha5, alpha6, alphav, beta1, beta3 and beta7 fail ed to inhibit breast cancer cell migration through bone marrow fibroblasts. Inhibitors of matrix metalloproteases, 1, 10-phenanthroline, Ro-9790, TIMP -1 and TIMP-2 were able to attenuate the migration of MDA-MB-231 cells thro ugh bone marrow fibroblast monolayers suggesting a role for these enzymes i n the migration of breast cancer cells through bone marrow adherent layers. Co-culture of MDA-MB-231 cells and bone marrow fibroblasts resulted in aug mentation of the levels of the matrix metalloproteases MMP-1 and MMP-2 in c ulture supernatants. Soluble factors produced by bone marrow fibroblasts we re responsible for the increase in MMP-1 levels. However, maximal MMP-2 pro duction was dependent on direct contract between the breast cancer cells an d the bone marrow fibroblasts. Modulation of MMP production by cell-cell co ntact or soluble factors suggests a mechanism by which breast cancer cells can enhance their ability to invade the bone marrow microenvironment.