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 increased receptor expression were addressed by analyzing possible accumulation of phosphotyrosyl proteins in neoplastic and nonneoplastic astrocytic proliferative processes. The results were compared with the expression 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 human brain biopsies of graded gliosis and astrocytomas. The effects of three tyrosine kinase inhibitors on 3H-thymidine uptake and cell proliferation and viability were examined in cultured glioma cells.


RESULTS
Phosphotyrosine was conspicuously elevated in all three grades of astrocytoma, but remained at low levels in nonneoplastic astrocytic proliferations. Dose-dependent decreases in DNA synthesis and proliferation of cultured glioma cells occurred after inhibition of tyrosine kinase. Neu receptor protein showed increased expression in malignant astrocytomas (including glioblastomas) and severe reactive gliosis.


CONCLUSIONS
Upregulation of tyrosyl protein phosphorylation enables differentiation of neoplastic from nonneoplastic astrocytic proliferative states. Inhibition of this phosphorylation impairs growth of cells. Increased Neu receptor protein expression can distinguish malignant from low grade astrocytomas. We speculate that genetic events leading to stably increased phosphotyrosine may be critical for neoplastic transformation of astrocytes, whereas increased receptor tyrosine kinase expression could be a factor in the aggressive growth associated with malignancy.
Kristt
D A
DA
Institute of Pathology, Rabin Medical Center, Petah Tikvah, Israel.
Yarden
Y
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology*; D001254:Astrocytoma / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology*; D002277:Carcinoma / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology; D005910:Glioma / Q000473:pathology*; D005911:Gliosis / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D019000:Phosphotyrosine / Q000032:analysis / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D014407:Tumor Cells, Cultured
D004247:DNA; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases