Role of endothelial cells in bone marrow microenvironment-induced modulation of the gene expression of multiple myeloma cells’

Multiple myeloma (MM) is a plasma cell (PC) malignancy hallmarked by uncontrolled accumulation of monoclonal PCs within the bone marrow (BM). The BM microenvironment provides a sanctuary for the MM cells to survive, proliferate and evade drug-induced cell death due to intimate, reciprocal interactions between the MM cells and the surrounding cells. Based on our enhanced understanding of the pivotal role of this intimate reciprocal relationship in MM carcinogenesis, numerous new molecular targets were identified and novel therapies, including thalidomide, bortezomib and lenalidomide, were derived. Although the introduction of these drugs resulted in a significant improvement in the overall survival, patients inevitably relapse, underscoring the urgent need for new potential targets. BM endothelial cells (BMEC) are one of the surrounding cell types actively involved in MM disease progression. In short, BMEC are involved in the homing of the MM cells, angiogenesis, osteoclastogenesis and induce survival and drug resistance of the tumor cells. In this work we investigated the BMEC induced modulation of the gene expression of the MM cells in an attempt to find new molecular targets. We found that BMEC are actively involved in MM progression by regulating expression of the tetraspanins CD9 and CD53 and the pro-apoptotic molecule Bim in MM cells and this either through direct cell contact and/or the secretion of soluble factors. These data provide new molecular targets and furthermore support the rational for using therapeutic agents in MM that directly target BMEC in combination with both conventional and novel therapies.