Abstract
Multiple myeloma (MM) accounts for about 10% of hematologic malignancies, and it is the second most frequent hematologic neoplasm after lymphomas. The exact etiology of MM is still unknown and, despite the introduction of more effective and safe drugs in recent years, MM remains an incurable disease. Intrinsic and acquired resistance of malignant B cells to pharmacological treatments still represents an obstacle for survival improvement. Activation of the hepatocyte growth factor/c-MET axis has been reported as involved in MM pathogenesis: hepatocyte growth factor (HGF) levels are in fact higher in sera from MM patients than in healthy controls, the HGF/c-MET pathway may be activated in an autocrine or paracrine manner, and it is interesting to note that a higher c-MET phosphorylation is associated with disease progression. Several studies have further demonstrated the over-activation of c-MET either in resistant cell lines or in primary malignant plasma cells purified from bone marrow of patients resistant to chemotherapy. For this reason, c-MET has been proposed as a potential marker of multidrug resistance in the disease. Here, we first summarize the potential role of HGF/c-MET interaction in disease evolution and then describe novel approaches targeting this axis which could be conceptually utilized, alone or in combination with standard therapies, to treat MM and possibly overcome drug resistance.
Highlights
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells within bone marrow (BM) and accounts for about 10% of hematological malignancies
Higher expression of phosphorylated c-MET (p-c-MET) was detected in relapsed and refractory patients. These findings suggest that the hepatocyte growth factor (HGF)/c-MET autocrine loop is operative in MM-endothelial cells (ECs), further confirming the critical role played by this signaling cascade in angiogenesis
Among several pathways involved in MM pathogenesis, HGF/c-MET may have a pivotal role. c-MET and its ligand HGF contribute to survival, proliferation, migration, angiogenesis, and bone disease in MM
Summary
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells within bone marrow (BM) and accounts for about 10% of hematological malignancies. The complex interplay between myeloma cells and neighbor cells of the microenvironment is critical in the pathogenesis of MM and drug resistance. Several cellular components of the tumor microenvironment provide support to differentiation and expansion of the malignant clone either directly, by cell-to-cell interaction, or indirectly, through the release of soluble mediators (cytokines, microvescicles, and exosomes). Many other growth factors, secreted within the microenvironment, have been described as favoring MM cells expansion (i.e., VEGF, MIP1α, BAFF, and IGF-1)[4]. The aim of this review is to summarize the key findings on the pathogenetic activity of HGF in multiple myeloma and further describe novel therapeutic approaches potentially helpful to overcome signals provided by the HGF/c-MET axis, putatively involved in drug resistance
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