DIFFERENCES BETWEEN PHOSPHOTYROSINE ACCUMULATION AND NEU ERBB-2 RECEPTOR EXPRESSION IN ASTROCYTIC PROLIFERATIVE PROCESSES - IMPLICATIONS FOR GLIAL ONCOGENESIS/

BACKGROUND. Previous work has shown that enhanced growth potential of malignant astrocytomas correlates with increased expression of growth factor receptor tyrosine kinases. The functional implications of incre ased receptor expression were addressed by analyzing possible accumula tion of phosphotyrosyl proteins in neoplastic and nonneoplastic astroc ytic proliferative processes. The results were compared with the expre ssion of Neu receptor protein (also called ErbB-2 or HER-2). METHODS. Western immunoblots and immunocytochemistry were utilized to evaluate glioma and carcinoma cell lines, neonatal astrocytic cultures, and hum an brain biopsies of graded gliosis and astrocytomas. The effects of t hree tyrosine kinase inhibitors on H-3-thymidine uptake and cell proli feration and viability were examined in cultured glioma cells. RESULTS . Phosphotyrosine was conspicuously elevated in all three grades of as trocytoma, but remained at low levels in nonneoplastic astrocytic prol iferations. Dose-dependent decreases in DNA synthesis and proliferatio n of cultured glioma cells occurred after inhibition of tyrosine kinas e. Neu receptor protein showed increased expression in malignant astro cytomas (including glioblastomas) and severe reactive gliosis. CONCLUS IONS. Upregulation of tyrosyl protein phosphorylation enables differen tiation of neoplastic from nonneoplastic astrocytic proliferative stat es. Inhibition of this phosphorylation impairs growth of glioma cells. Increased Neu receptor protein expression can distinguish malignant f rom low grade astrocytomas. We speculate that genetic events leading t o stably increased phosphotyrosine may be critical for neoplastic tran sformation of astrocytes, whereas increased receptor tyrosine kinase e xpression could be a factor in the aggressive growth associated with m alignancy. (C) 1996 American Cancer Society.