Human myeloma cells adhere to fibronectin in response to hepatocyte growth factor.
OBJECTIVE
Multiple myeloma is characterized by an accumulation of malignant plasma cells in the bone marrow. Inside the bone marrow, adhesion of myeloma cells to extracellular matrix proteins such as fibronectin may promote cell survival and induce drug resistance. In this work we examined the effect of hepatocyte growth factor (HGF) on the adhesion of myeloma cells and the signaling pathways involved.


METHODS
Cell adhesion experiments were performed with the human myeloma cell line INA-6 and primary myeloma cells. The HGF signaling pathway was studied in INA-6 cells with the use of antibodies against VLA-4 integrin, and with inhibitors of various intracellular signaling molecules.


RESULTS
We found that HGF stimulated adhesion of myeloma cells to fibronectin. This event was dependent on the alpha4 and beta1 integrin subunits (VLA-4), but HGF did not increase the expression of integrins on the cell surface. Our findings suggest that HGF promotes myeloma cells to adhere via activation of the phosphatidylinositol 3-kinase (PI3K) pathway independently of AKT, but possibly through the involvement of nuclear factor kappa B (NF-kappaB). INA-6 cells adhered to fibronectin after stimulation by insulin-like growth factor or stromal cell-derived factor 1alpha, but this adhesion was less dependent on PI3K than HGF-mediated adhesion.


CONCLUSIONS
his work points to HGF as a pro-adhesive factor in cell adherence to the bone marrow matrix protein fibronectin, an event known to promote cancer cell survival and drug resistance. Inhibiting HGF, its receptor c-Met or the VLA-4 integrin may be beneficial to the myeloma patient.
Holt
Randi Utne
RU
Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, MTFS, N-7489 Trondheim, Norway. randi.u.holt@medisin.ntnu.no
Baykov
Vadim
V
Rø
Torstein Baade
TB
Brabrand
Sigmund
S
Waage
Anders
A
Sundan
Anders
A
Børset
Magne
M
D000730:Androstadienes / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D005353:Fibronectins / Q000502:physiology*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D039441:Integrin alpha4 / Q000502:physiology; D019012:Integrin beta1 / Q000502:physiology; D009101:Multiple Myeloma / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D000077191:Wortmannin
D000730:Androstadienes; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D005353:Fibronectins; D006575:Heterocyclic Compounds, 3-Ring; D019012:Integrin beta1; C456319:PS1145; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D039441:Integrin alpha4; D017228:Hepatocyte Growth Factor; D011493:Protein Kinase C; D000077191:Wortmannin