Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth factor and osteopontin.
OBJECTIVE
Similar to osteoclastogenesis, angiogenesis is enhanced in the bone marrow in myeloma in parallel with tumor progression. We showed previously that myeloma cells and osteoclasts are mutually stimulated to form a vicious cycle to lead to enhance both osteoclastogenesis and tumor growth. The present study was undertaken to clarify whether myeloma cell-osteoclast interaction enhances angiogenesis and whether there is any mutual stimulation between osteoclastogenesis and angiogenesis.


METHODS
Myeloma cells and monocyte-derived osteoclasts were cocultured, and angiogenic activity produced by the cocultures was assessed with in vitro vascular tubule formation assays and human umbilical vascular endothelial cell (HUVEC) migration and survival. Osteoclastogenic activity was determined with rabbit bone cell cultures on dentine slices.


RESULTS
Myeloma cells and osteoclasts constitutively secrete proangiogenic factors, vascular endothelial growth factor (VEGF) and osteopontin, respectively. A cell-to-cell interaction between myeloma cells and osteoclasts potently enhanced vascular tubule formation. Blockade of both VEGF and osteopontin actions almost completely abrogated such vascular tubule formation as well as migration and survival of HUVECs enhanced by conditioned medium from cocultures of myeloma cells and osteoclasts. Furthermore, these factors in combination triggered the production of osteoclastogenic activity by HUVEC.


CONCLUSIONS
Osteoclast-derived osteopontin and VEGF from myeloma cells cooperatively enhance angiogenesis and also induce osteoclastogenic activity by vascular endothelial cells. These observations suggest the presence of a close link between myeloma cells, osteoclasts, and vascular endothelial cells to form a vicious cycle between bone destruction, angiogenesis, and myeloma expansion.
Tanaka
Yoichi
Y
Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medical Sciences, and Division of Transfusion Medicine, Tokushima University Hospital, Japan.
Abe
Masahiro
M
Hiasa
Masahiro
M
Oda
Asuka
A
Amou
Hiroe
H
Nakano
Ayako
A
Takeuchi
Kyoko
K
Kitazoe
Kenichi
K
Kido
Shinsuke
S
Inoue
Daisuke
D
Moriyama
Keiji
K
Hashimoto
Toshihiro
T
Ozaki
Shuji
S
Matsumoto
Toshio
T
D001862:Bone Resorption; D002465:Cell Movement; D002470:Cell Survival; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D009000:Monocytes / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010010:Osteoclasts / Q000378:metabolism*; D053495:Osteopontin / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017077:Culture Media, Conditioned; D042461:Vascular Endothelial Growth Factor A; D053495:Osteopontin