Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling.
Caveolin-1 (Cav-1) is highly expressed in normal osteoblasts. This article reports that Cav-1 down-regulation is part of osteoblast transformation and osteosarcoma progression and validates its role as oncosuppressor in human osteosarcoma. A survey of 6-year follow-up indicates a better overall survival for osteosarcoma expressing a level of Cav-1 similar to osteoblasts. However, the majority of primary osteosarcoma shows significantly lower levels of Cav-1 than normal osteoblasts. Accordingly, Met-induced osteoblast transformation is associated with Cav-1 down-regulation. In vitro, osteosarcoma cell lines forced to overexpress Cav-1 show reduced malignancy with inhibited anchorage-independent growth, migration, and invasion. In vivo, Cav-1 overexpression abrogates the metastatic ability of osteosarcoma cells. c-Src and c-Met tyrosine kinases, which are activated in osteosarcoma, colocalize with Cav-1 and are inhibited on Cav-1 overexpression. Thus, Cav-1 behaves as an oncosuppressor in osteosarcoma. Altogether, data suggest that Cav-1 down-modulation might function as a permissive mechanism, which, by unleashing c-Src and Met signaling, enables osteosarcoma cells to invade neighboring tissues. These data strengthen the rationale to target c-Src family kinases and/or Met receptor to improve the extremely poor prognosis of metastatic osteosarcoma.
Cantiani
Lara
L
Laboratory of Oncology Research, Rizzoli Orthopaedic Institute, Italy.
Manara
Maria Cristina
MC
Zucchini
Cinzia
C
De Sanctis
Paola
P
Zuntini
Monia
M
Valvassori
Luisa
L
Serra
Massimo
M
Olivero
Martina
M
Di Renzo
Maria Flavia
MF
Colombo
Mario Paolo
MP
Picci
Piero
P
Scotlandi
Katia
K
D000818:Animals; D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D000081247:CSK Tyrosine-Protein Kinase; D051242:Caveolin 1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases
C495540:CAV1 protein, human; D051242:Caveolin 1; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C491743:MET protein, human; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human