Abstract
BackgroundComponents of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. However, functional distinctions between BMSCs in MM patients and those in disease-free marrow are not completely understood. We and other investigators have recently reported that NF-κB activity in primary MM cells is largely resistant to the proteasome inhibitor bortezomib, and that further enhancement of NF-κB by BMSCs is similarly resistant to bortezomib and may mediate resistance to this therapy. The mediating factor(s) of this bortezomib-resistant NF-κB activity is induced by BMSCs is not currently understood.ResultsHere we report that BMSCs specifically derived from MM patients are capable of further activating bortezomib-resistant NF-κB activity in MM cells. This induced activity is mediated by soluble proteinaceous factors secreted by MM BMSCs. Among the multiple factors evaluated, interleukin-8 was secreted by BMSCs from MM patients at significantly higher levels compared to those from non-MM sources, and we found that IL-8 contributes to BMSC-induced NF-κB activity.ConclusionsBMSCs from MM patients uniquely enhance constitutive NF-κB activity in MM cells via a proteinaceous secreted factor in part in conjunction with IL-8. Since NF-κB is known to potentiate MM cell survival and confer resistance to drugs including bortezomib, further identification of the NF-κB activating factors produced specifically by MM-derived BMSCs may provide a novel biomarker and/or drug target for the treatment of this commonly fatal disease.
Highlights
Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib
BMSCs from MM patients are functionally distinct in their ability to activate NF-B in MM cells Because we have previously found that co-culture with MM BMSCs can activate NF-B in the RPMI8226 MM cell line and a few primary MM samples in a manner that is largely resistant to bortezomib [33], we wanted to know (i) how variable this response is among BMSCs derived from different MM patients, and (ii) whether BMSCs derived from normal marrow possess similar NF-B-inducing activities
Confirming previous reports, we found that CD54, known as inter-cellular adhesion molecule-1 (ICAM-1), was heterogeneously expressed on the surface of MM-BMSCs, but very little on non-MM BMSCs [20]
Summary
Components of the microenvironment such as bone marrow stromal cells (BMSCs) are well known to support multiple myeloma (MM) disease progression and resistance to chemotherapy including the proteasome inhibitor bortezomib. BMSC production of matrix proteins and factors such as fibronectin [6], insulin-like growth factor-1 (IGF-1) [7], stromal derived factor 1 alpha (SDF-1) [8], tumor necrosis factor alpha (TNF-a), B cell activating factor family (BAFF), and a proliferation inducing ligand (APRIL) [5] have all been shown to promote MM cell proliferation and resistance to conventional chemotherapeutic agents These discoveries have contributed to the development of several recently approved targeted therapeutics, such as the proteasome inhibitor bortezomib, and lenalidomide, that are believed to exert their antiMM effects at least in part by disrupting the interactions between MM cells and the other cells in tumor microenvironment [5,9]
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