Inhibition of in vitro meningioma proliferation after growth factor stimulation by calcium channel antagonists: Part II--Additional growth factors, growth factor receptor immunohistochemistry, and intracellular calcium measurements.
We have previously reported that calcium channel antagonists can block both the growth of meningiomas in culture and the potent growth stimulation of meningioma cells by epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). This study further defines the nature of this growth inhibition. Primary meningioma cultures were established, and cells were characterized. Fibroblast growth factor or insulin-like growth factor-I growth stimulation in the presence of calcium channel antagonists was examined. In addition, the effects of ethylene glycol-bis-(aminoethylether) N,N,N',N"-tetraacetic acid and Bay K 8644, a calcium channel agonist, on the growth factors were analyzed. Growth factor receptor immunohistochemistry was performed on the original tumors and the in vitro meningioma cells. Twelve of 17 (71%) meningiomas in this study were positive for the EGF receptor, and 14 of 17 (82%) were positive for the PDGF receptor. Five of six (83%) of the culture cells were positive for the EGF receptor, and four of five (80%) were positive for the PDGF receptor. Intracellular calcium changes were quantified using the intracellular calcium-chelating, fluorescent dye, Fura-2. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I on meningioma cells in culture was decreased in a dose-dependent manner by calcium channel antagonists. The growth stimulation of fibroblast growth factor and insulin-like growth factor-I was not affected by a reduction of extracellular calcium, whereas the growth stimulation of EGF and PDGF was. Interestingly, intracellular calcium was not increased after exposure to growth factors but was increased after serum stimulation. This increase could be blocked by preincubation with verapamil. Calcium channel antagonists can inhibit proliferation of meningioma cells in culture after stimulation with a number of growth factors. These drugs might disrupt intracellular calcium homeostasis or interfere with key elements of the growth factor signal transduction pathways. These mechanisms as well as the potential clinical relevance of these findings are discussed.
Jensen
R L
RL
Department of Neurological Surgery, Loyola University, Maywood, Illinois, USA.
Lee
Y S
YS
Guijrati
M
M
Origitano
T C
TC
Wurster
R D
RD
Reichman
O H
OH
D000328:Adult; D000368:Aged; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007424:Intracellular Fluid / Q000187:drug effects / Q000502:physiology; D008297:Male; D008577:Meningeal Neoplasms / Q000473:pathology*; D008579:Meningioma / Q000473:pathology*; D008875:Middle Aged; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017978:Receptors, Growth Factor / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology
D002121:Calcium Channel Blockers; D006133:Growth Substances; D010982:Platelet-Derived Growth Factor; D017978:Receptors, Growth Factor; D005346:Fibroblast Growth Factors; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I; D002118:Calcium