Dependence of autocrine growth factor stimulation in platelet-derived growth factor-B-induced mouse brain tumor cells.
In human gliomas, platelet-derived growth factor (PDGF) ligand and receptor mRNA are often co-expressed, which suggests the presence of an autocrine loop. To further investigate the significance of PDGF stimulation in brain tumors, we used a previously developed mouse tumor model, in which malignant brain tumors of neuroepithelial origin were induced by injecting a murine retrovirus containing the human PDGF B-chain gene into the brains of neonatal mice. In the present investigation, we have characterized a cell line established from such an experimentally induced tumor in an INK4a-/- mouse. Cultured tumor cells expressed nestin and NG2 chondroitin sulfate proteoglycan and are thus most likely derived from an oligodendrocyte precursor cell. Tumor cells produced PDGF-B protein and displayed constitutively activated PDGF alpha receptors. Autocrine receptor activation could be blocked with the specific PDGF receptor tyrosine kinase inhibitor CGP 57148B, which led to almost complete inhibition of cell proliferation, which was much less affected by a PDGF B-chain aptamer that inhibits binding of PDGF-B to PDGF receptors and is unlikely to be able to pass through the plasma membrane. Our results imply an important role for PDGF autocrine stimulation in both initiation and progression of a subtype of gliomas.
Uhrbom
L
L
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala, Sweden.
Hesselager
G
G
Ostman
A
A
Nistér
M
M
Westermark
B
B
D000818:Animals; D019898:Autocrine Communication; D001549:Benzamides; D015152:Blotting, Northern; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000139:chemically induced / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009419:Nerve Tissue Proteins; D064231:Nestin; D010879:Piperazines / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020574:Proto-Oncogene Proteins c-sis / Q000008:administration & dosage; D011743:Pyrimidines / Q000494:pharmacology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001549:Benzamides; D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha