Mn2+ regulates myeloma cell adhesion differently than the proadhesive cytokines HGF, IGF-1, and SDF-1alpha.
Adhesion of multiple myeloma (MM) cells in the bone marrow (BM) is important for the growth and survival of the myeloma cells. Very late antigen-4 (VLA-4) is one of the main adhesion receptors that mediate MM cell binding to fibronectin (FN). In this study we have examined the effect of divalent cations on adhesion of MM cells to FN, and compared this type of adhesion with the adhesion induced by the cytokines HGF, IGF-1 and SDF-1alpha. Mn(2+) induced adhesion in all cell lines tested. Cytokine- and Mn(2+)-induced VLA-4-mediated adhesion were different in many respects, including binding specificity, adhesion kinetics and the activation state of VLA-4. To study a potential role of divalent cations in vivo, we measured the concentrations of divalent cations in BM plasma from 14 MM patients. We also found that Mn(2+)-mediated adhesion to FN activated the MAPK pathway, indicating that the interaction of MM-cells with FN mediated by Mn(2+) could play a critical role for growth and proliferation. In conclusion, this study shows a potential important role of divalent cations in MM cell biology and supports earlier studies pointing to activated VLA-4 as a key for homing of MM cells to the BM.
Slørdahl
Tobias S
TS
Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology NTNU, Trondheim, Norway. tobiassc@stud.ntnu.no
Hov
Håkon
H
Holt
Randi U
RU
Baykov
Vadim
V
Syversen
Tore
T
Sundan
Anders
A
Waage
Anders
A
Børset
Magne
M
D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D002413:Cations, Divalent / Q000378:metabolism / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism / Q000494:pharmacology*; D005353:Fibronectins / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D039041:Integrin alpha4beta1 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008345:Manganese / Q000378:metabolism / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis
C515255:CXCL12 protein, human; D002413:Cations, Divalent; D054377:Chemokine CXCL12; D005353:Fibronectins; C066855:HGF protein, human; D039041:Integrin alpha4beta1; D009363:Neoplasm Proteins; D008345:Manganese; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I