Fibroblast growth factor-2 is an important factor that maintains cellular immaturity and contributes to aggressiveness of osteosarcoma.
Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal-regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma.
Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
Takatsune
T
Shimizu
Tomoki
T
Ishikawa
Sayaka
S
Iwai
Arisa
A
Ueki
Eiji
E
Sugihara
Nobuyuki
N
Onishi
Shinji
S
Kuninaka
Takeshi
T
Miyamoto
Yoshiaki
Y
Toyama
Hiroshi
H
Ijiri
Hajime
H
Mori
Yumi
Y
Matsuzaki
Tomonori
T
Yaguchi
Hiroshi
H
Nishio
Yutaka
Y
Kawakami
Yasuo
Y
Ikeda
Hideyuki
H
Saya
D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D016222:Fibroblast Growth Factor 2; D048049:Extracellular Signal-Regulated MAP Kinases