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met oncogene activation qualifies spontaneous canine osteosarcoma as a suitable pre‐clinical model of human osteosarcoma
Author(s) -
De Maria Raffaella,
Miretti Silvia,
Iussich Selina,
Olivero Martina,
Morello Emanuela,
Bertotti Andrea,
Christensen James G,
Biolatti Bartolomeo,
Levine Roy A,
Buracco Paolo,
Di Renzo Maria Flavia
Publication year - 2009
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.2549
Subject(s) - osteosarcoma , cancer research , oncogene , receptor tyrosine kinase , immunohistochemistry , biology , sarcoma , phosphorylation , cell culture , cancer , pathology , medicine , immunology , microbiology and biotechnology , cell cycle , genetics
The Met receptor tyrosine kinase (RTK) is aberrantly expressed in human osteosarcoma and is an attractive molecular target for cancer therapy. We studied spontaneous canine osteosarcoma (OSA) as a potential pre‐clinical model for evaluation of Met‐targeted therapies. The canine MET oncogene exhibits 90% homology compared with human MET , indicating that cross‐species functional studies are a viable strategy. Expression and activation of the canine Met receptor were studied utilizing immunohistochemical techniques in 39 samples of canine osteosarcoma, including 35 primary tumours and four metastases. Although the Met RTK is barely detectable in primary culture of canine osteoblasts, high expression of Met protein was observed in 80% of canine osteosarcoma samples acquired from various breeds. Met protein overexpression was also concordant with its activation as indicated by phosphorylation of critical tyrosine residues. In addition, Met was expressed and constitutively activated in canine osteosarcoma cell lines. OSA cells expressing high levels of Met demonstrated activation of downstream transducers, elevated spontaneous motility, and invasiveness which were impaired by both a small molecule inhibitor of Met catalytic activity (PHA‐665752) and met ‐specific, stable RNA interference obtained by means of lentiviral vector. Similar to observations in human OSA, these data suggest that Met is commonly overexpressed and activated in canine OSA and that inhibition of Met impairs the invasive and motogenic properties of canine OSA cells. These data implicate Met as a potentially important factor for canine OSA progression and indicate that it represents a viable model to study Met‐targeted therapies. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.