Abstract
In multiple myeloma (MM), the malignant plasma cells usually localize to the bone marrow where they develop drug resistance due to adhesion to stromal cells and various environmental signals. Hence, modulation of this interaction is expected to influence drug sensitivity of MM cells. Toll-like receptor (TLR) ligands have displayed heterogeneous effects on B-cell malignancies and also on MM cells in a few recent studies, but effects on adhesion and drug sensitivity of myeloma cells in the context of bone marrow stromal cells (BMSCs) have never been investigated. In the present study, we explored the modulatory effects of TLR1/2 ligand (Pam3CSK4) on adhesion of human myeloma cells to BMSCs. It is shown that TLR1/2 triggering has opposite effects in different HMCLs on their adhesion to BMSCs. Fravel, L363, UM-6, UM-9 and U266 showed increased adhesion to BMSC in parallel with an increased surface expression of integrin molecules α4 and αVβ3. OPM-1, OPM-2 and NCI-H929 showed a dose-dependent decrease in adhesion upon TLR activation following a downregulation of β7 integrin expression. Importantly, TLR1/2 triggering increased cytotoxic and apoptotic effects of bortezomib in myeloma cells independent of the effect on stromal cell adhesion. Moreover, the apoptosis-enhancing effect of Pam3CSK4 paralleled induction of cleaved caspase-3 protein in FACS analysis suggesting a caspase-dependent mechanism. Our findings uncover a novel role of TLR activation in MM cells in the context of bone marrow microenvironment. Stimulation of TLR1/2 bypasses the protective shield of BMSCs and may be an interesting strategy to enhance drug sensitivity of multiple myeloma cells.
Highlights
Adhesion of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs), mediated mostly by the integrin family of adhesion molecules, renders the tumor cells resistant against drugs and apoptotic stimuli, and contributes to other complications of the disease including osteolytic lesions and angiogenesis[1,2,3]
We found that TLR1/2 triggering results in a heterogeneous functional response of human myeloma cell lines (HMCLs) in terms of integrin surface expression and adhesion to BMSCs
OPM-1, OPM-2 and NCI-H929 myeloma cell lines showed a decrease in adhesion to BMSCs after Toll-like receptor (TLR)-1/2 activation, which was accompanied with a down-regulation in surface expression of b7 integrin
Summary
Adhesion of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs), mediated mostly by the integrin family of adhesion molecules, renders the tumor cells resistant against drugs and apoptotic stimuli, and contributes to other complications of the disease including osteolytic lesions and angiogenesis[1,2,3]. Possible contribution of TLRs to inflammation-related malignancy is indicated mostly by induction of pro-inflammatory cytokines in tumor environment [23], upregulation of cell adhesion molecules on cancer cells and their adhesion or migration following TLR triggering [12,24,25,26]. Regarding the fact that TLRs of MM cells may be activated in the inflammatory environment of bone marrow, possibly by microbial/endogenous ligands, we hypothesized that TLR triggering on MM cells might modulate their adhesion to BMSCs and subsequently modulate MM cells survival and drug resistance. We demonstrated that TLR1/2 activation either increased or decreased adhesion of human myeloma cells to fibronectin and modulated cytotoxicity of bortezomib in HMCLs [27]. Pam3CSK4 treatment of HMCLs increased their apoptotic response to bortezomib in the context of BMSCs, which suggests that TLR1/2 triggering may be of therapeutic use to decrease cellular resistance to the cytotoxic action of chemotherapeutic agents
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
