MET overexpression turns human primary osteoblasts into osteosarcomas.
The MET oncogene was causally involved in the pathogenesis of a rare tumor, i.e., the papillary renal cell carcinoma, in which activating mutations, either germline or somatic, were identified. MET activating mutations are rarely found in other human tumors, whereas at higher frequencies, MET is amplified and/or overexpressed in sporadic tumors of specific histotypes, including osteosarcoma. In this work, we provide experimental evidence that overexpression of the MET oncogene causes and sustains the full-blown transformation of osteoblasts. Overexpression of MET, obtained by lentiviral vector-mediated gene transfer, resulted in the conversion of primary human osteoblasts into osteosarcoma cells, displaying the transformed phenotype in vitro and the distinguishing features of human osteosarcomas in vivo. These included atypical nuclei, aberrant mitoses, production of alkaline phosphatase, secretion of osteoid extracellular matrix, and striking neovascularization. Although with a lower tumorigenicity, this phenotype was superimposable to that observed after transfer of the MET gene activated by mutation. Both transformation and tumorigenesis were fully abrogated when MET expression was quenched by short-hairpin RNA or when signaling was impaired by a dominant-negative MET receptor. These data show that MET overexpression is oncogenic and that it is essential for the maintenance of the cancer phenotype.
Patanè
Salvatore
S
Laboratory of Cancer Genetics, University of Turin School of Medicine, Candiolo (Turin), Italy.
Avnet
Sofia
S
Coltella
Nadia
N
Costa
Barbara
B
Sponza
Simone
S
Olivero
Martina
M
Vigna
Elisa
E
Naldini
Luigi
L
Baldini
Nicola
N
Ferracini
Riccardo
R
Corso
Simona
S
Giordano
Silvia
S
Comoglio
Paolo M
PM
Di Renzo
Maria Flavia
MF
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009857:Oncogenes; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000096:biosynthesis* / Q000235:genetics
D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met