MET/HGF pathway in multiple myeloma: from diagnosis to targeted therapy?

Abstract

This is an author version of the contribution published on:Questa è la versione dell 'autore dell'opera: Expert Rev Mol Diagn. 2015;15(7): 881-93. doi: 10.1586/14737159.2015.1046436 The definitive version is available at: La versione definitiva è disponibile alla URL: http://www.tandfonline.com.offcampus.dam.unito.it/doi/full/10.1586/14737159.20 15.1046436 MET/HGF pathway in multiple myeloma: from diagnosis to target therapy? AbstractInteraction between neoplastic cells and the microenvironment is critical in several cancers and plays a central role in multiple myeloma. Microenvironmental stimuli support plasma cells proliferation, survival, motility and can determine drug resistance. The network between plasma cells and surrounding cells is also responsible for increasing angiogenesis, unbalancing bone formation and bony lesions. The MET/HGF pathway is a key player of this interaction and has been found to be abnormally active in both malignant plasma cells and surrounding cells. Patients with abnormal MET and/or HGF levels usually experience a poor outcome even when treated with novel drugs. This review addresses the role of MET/HGF in the pathogenesis of myeloma and describes the role of MET/HGF signaling as a prognostic factor. The different techniques to detect MET/HGF abnormalities will also be examined. A final discussion on compounds targeting MET/HGF will summarize the current opportunities to introduce targeted therapy in myeloma patients.

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

“…It is known that HGF/c‐met signaling promotes the adhesion and migration of myeloma cells by stimulating multiple downstream pathways including PI3K/AKT and Ras/ERK . To confirm that SL1‐mediated effects are a result of HGF/c‐met pathway inhibition, we investigated the effects of SL1 on the expression levels of p‐c‐met (Y1349), p‐ERK and p‐AKT after stimulating with HGF.…”

“…It is known that HGF/c-met signaling promotes the adhesion and migration of myeloma cells by stimulating multiple downstream pathways including PI3K/AKT and Ras/ERK. 25 To confirm that SL1-mediated effects are a result of HGF/c-met pathway inhibition, we investigated the effects of SL1 on the expression levels of p-c-met (Y1349), p-ERK and p-AKT after stimulating with HGF. The results show that HGF-stimulated phosphorylation of c-met, ERK and AKT was dramatically reduced in the presence of SL1, while their total protein levels remained unchanged (Figure 5C).…”

Blocking MET receptor signaling in multiple myeloma cells in vitro and in vivo

“…Together with other mitogenic factors, such as the SDF-1-CXCR4 axis, it is involved in the colonization of distant tissues by tumor cells, and stimulates their growth in microenvironments normally foreign to them. 4 In this study, we observed the expression of MET mRNA and MET protein in myeloma cell lines. Reports on the role of HGF/MET axis encourage research on the use of inhibitors of this axis in the treatment of various neoplastic diseases, including multiple myeloma.…”

“…One potential target for MM therapy is the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) axis. 4 HGF belongs to the plasminogen protein family. Under physiological conditions, HGF can be produced by fibroblasts, fat collecting liver cells, bone marrow stromal cells, endothelial, and epithelial cells.…”

“…5,6 In patients with MM who showed elevated levels of HGF, there is a direct correlation between serum HGF levels and aggressiveness of the disease. 4,7 The prognosis of patients with MM is usually worse in the presence of high levels of HGF. [8][9][10] Among the many factors activating myeloma cells, HGF is one of the main factors and the presence of the MET receptor is a common finding in myeloma cells, both at the mRNA and protein levels.…”