Hepatocyte growth factor (HGF)/c-met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM.
The aim of the present study was designed to determine the effects of rHuEpo on cancer-associated fibroblasts (CAFs) from monoclonal gammopathy of undetermined significance (MGUS) and MM patients by means of in vitro and in vivo assays. rHuEpo treatment reduces the expression of mRNA levels of fibroblast activation markers, namely alpha smooth actin (αSMA) and fibroblast activation protein (FAP) in MGUS and MM CAFs, and of pro-inflammatory and pro-angiogenic cytokines, including interleukin (IL)-6 and IL-8, vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) in MM CAFs.
The receptor tyrosine kinase c-Met, its ligand HGF, and components of the downstream signalling pathway, have all been implicated in the pathogenesis of myeloma, both as modulators of plasma cell proliferation and as agents driving osteoclast differentiation and osteoblast inhibition thus, all these contribute substantially to the bone destruction typically caused by myeloma.
MGUS and MM patients presenting with hyposialylated pc IgGs had significantly higher levels of HGF, IL-6, tumor necrosis factor-α, TGF-β1, IL-17, and IL-33 compared to patients with hyper-sialylated pc IgGs (<i>p</i> < 0.05).
In this study, we examined the association between bone marrow angiogenesis estimated as micro-vessel density (MVD) and gene expression of SDC1, HGF, VEGF and IL6 in whole bone marrow biopsies from healthy volunteers (n = 10), patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 35) and MM (n = 65).
Abnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM).
An autocrine HGF/cMET loop sustains multiple myeloma angiogenesis and represents an appealing new target to potentiate the antiangiogenic management of patients with multiple myeloma.
Their expression was enhanced by vascular endothelial growth factor, fibroblast growth factor 2, hepatocyte growth factor and MM plasma cell conditioned medium in step with enhancement of MMEC angiogenesis.
In vitro, addition of recombinant heparanase to myeloma cells or transfection of myeloma cell lines with the cDNA for heparanase significantly increased tumor cell expression and secretion of biologically active HGF.
Our findings suggest that genetic variants in SERPINE1 and HGF, and possibly CCR7, are associated with MM risk, and warrant further investigation in other studies.
The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = -0.45, P = .008), in sera from 34 patients with myeloma.
Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in patients with clinically active MM, suggesting that HGF might play a role in the pathogenesis of MM.
Although we have previously shown that HGF/MET signaling controls survival and proliferation of multiple myeloma (MM), its role in the pathogenesis of other B-cell malignancies has remained largely unexplored.
A potential key signal in the evolution of MM is hepatocyte growth factor (HGF), which acts as a potent paracrine and/or autocrine growth factor and survival factor for MM cells.
An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction.
These results identify syndecan-1 as a functional coreceptor for HGF that promotes HGF/Met signaling in MM cells, thus suggesting a novel function for syndecan-1 in MM tumorigenesis.