Abstract
Simple SummaryThe SDF-1α/CXCR4 axis plays crucial roles in proliferation, survival, invasion, dissemination, and drug resistance in multiple myeloma. This review summarizes the pleiotropic role of the SDF-1α/CXCR4 axis in multiple myeloma and introduces the SDF-1α/CXCR4 axis-targeted therapies in multiple myeloma.The C-X-C chemokine receptor type 4 (CXCR4) is a pleiotropic chemokine receptor that is expressed in not only normal hematopoietic cells but also multiple myeloma cells. Its ligand, stromal cell-derived factor 1α (SDF-1α) is produced in the bone marrow microenvironment. The SDF-1α/CXCR4 axis plays a pivotal role in the major physiological processes associated with tumor proliferation, survival, invasion, dissemination, and drug resistance in myeloma cells. This review summarizes the pleiotropic role of the SDF-1α/CXCR4 axis in multiple myeloma and discusses the future perspective in the SDF-1α/CXCR4 axis-targeted therapies in multiple myeloma.
Highlights
Multiple myeloma (MM) is the second most common hematological malignancy
Martin et al reported that high levels of Stromal cell-derived factor-1α (SDF-1α) produced by MM plasma cells promoted osteolysis and bone marrow angiogenesis [16,35]. These findings suggest that tumor cell-generating SDF-1 plays critical roles in osteolysis and angiogenesis in MM, and that abnormal SDF-1 auto-secretion may contribute to circulating plasma cells (cPCs) extramedullary translocation from the BM
The Jagged inhibition was shown to cause a decrease in both myeloma-intrinsic and stromal cell-induced resistance to antimyeloma drugs including bortezomib, lenalidomide, and melphalan. These findings indicate that Notch may have a role in MM progression and in drug resistance through regulating the SDF-1α/CXCR4 axis and providing the proof of concept that targeting strategy for Jagged/Notch pathway in MM cells and BM stromal cells could restore drug resistance
Summary
Multiple myeloma (MM) is the second most common hematological malignancy. The availability of new drugs (e.g., proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors (HDACi)) has greatly advanced the treatment and improved the survival of patients with MM over the last two decades [1,2]. The SDF-1α/CXCR4 axis plays a critical role in proliferation, survival, invasion, dissemination, metastasis, and drug resistance in MM cells [29]. The Jagged inhibition was shown to cause a decrease in both myeloma-intrinsic and stromal cell-induced resistance to antimyeloma drugs including bortezomib, lenalidomide, and melphalan These findings indicate that Notch may have a role in MM progression and in drug resistance through regulating the SDF-1α/CXCR4 axis and providing the proof of concept that targeting strategy for Jagged/Notch pathway in MM cells and BM stromal cells could restore drug resistance. Ulocuplumab, a monoclonal anti-CXCR4 antibody, suppressed MM cell dissemination, suggesting the inhibition of EMT-like phenotype conversion of MM cells by targeting CXCR4 [100] These findings strongly suggest that SDF-1α and CXCR4 play a central role in MM disease progression and EMD development. This section introduces developing drugs targeting the SDF-1α/CXCR4 axis in MM (Table 1)
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