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MET Overexpression Turns Human Primary Osteoblasts into Osteosarcomas

¹ Laboratory of Cancer Genetics, ² Laboratory of Gene Transfer and Therapy, and ³ Division of Molecular Oncology of the Institute for Cancer Research and Treatment, University of Turin School of Medicine, Candiolo (Turin); ⁴ Laboratory for Pathophysiology of Orthopaedic Implants, Istituti Ortopedici Rizzoli, Bologna; ⁵ HSR-TIGET, San Raffaele-Telethon Institute for Gene Therapy, Milan; and ⁶ Department of Orthopaedics, A.S.O. San Giovanni Battista, Turin, Italy

Requests for reprints: Maria Flavia Di Renzo, Laboratory of Cancer Genetics of the Institute for Cancer Research and Treatment, University of Turin Medical School, SP 142, KM 3.95, 10060 Candiolo (Turin), Italy. Phone: 39-011-993-3343; Fax: 39-011-993-3524; E-mail: mariaflavia.direnzo{at}ircc.it.

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. (Cancer Res 2006; 66(9): 4750-7)

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Researchers Find Genetic Link in Bone Cancer

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