Tom[a]
Overexpression of c-kit oncogene in human brain tumors
Landonio Giuseppe, Riva Maurizio, Galli Carlo, Schiavo Roberta, Carminati Ornella, Secondino Simona, Gambacorta Marcello, Defanti Carlo Alberto, Siena Salvatore, Depts of Oncology, Neurology, and Pathology-Ospedale Niguarda Ca Granda, Milano, Italy.
Background and Objective: In a systematic search for potential targets of new molecular cancer therapies, we evaluated c-kit expression in human primary brain tumors. c-kit, a 145-kd transmembrane glycoprotein, has a close structural homology with the kinase domains of platelet-derived growth factor receptor (PDGFr), implicated in the pathogenesis of various primary brain tumors. An activation of tyrosine kinase receptor and the association with some identical second messenger system for c-kit activity and PDGFr were demonstrated. Experimental findings show that STI-571 selectively inhibits c-kit activity and downstream activation of target proteins, involved in cellular proliferation.
Methods: We evaluated c-kit expression by immunocytochemistry in paraffin embedded tumors of 15 adults with high-grade glioma (2 PNET patients, 13 supratentorial glioblastoma). Well-differentiated oligodendroglioma or astrocytoma component was also associated to high-grade glioma in 5/15. WHO classification, histologic grading, and MIB-1 growth fraction were also evaluated. Results: Intense, weak, and absent expression of c-kit was found 8 (2 PNET, 6 glioblastoma), 5 (4 glioblastoma mixed with well differentiated glioma),and 2 (1 glioblastoma, 1 glioblastoma mixed with grade II oligodendroglioma) cases, respectively. The pattern of c-kit positivity was perivascular around normal and new microvessels for glioblastoma and diffuse for PNET. Tumor growth fraction ranged from 10% to 60% (median 40%) among intense-positivity cases and from 5 to 50% (median 25%) among weak-positivity cases.
Conclusions: Correlation between the presence of c-kit expression and a more aggressive malignancy was present in our cases; a predominant perivascular distribution was also present in patients with glioblastoma. Present data further motivate the therapeutic evaluation of c-kit targeted therapies for brain high grade gliomas