The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma.
The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma 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. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.
Derksen
P W B
PW
Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
de Gorter
D J J
DJ
Meijer
H P
HP
Bende
R J
RJ
van Dijk
M
M
Lokhorst
H M
HM
Bloem
A C
AC
Spaargaren
M
M
Pals
S T
ST
D000368:Aged; D017209:Apoptosis / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D005260:Female; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D006801:Humans; D048369:MAP Kinase Kinase 1; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology; D018631:ras Proteins / Q000502:physiology
D017228:Hepatocyte Growth Factor; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D019859:Proto-Oncogene Proteins c-met; D018631:ras Proteins; C482125:MAP2K1 protein, human