Autocrine growth stimulation of human meningioma cells by platelet-derived growth factor

Abstract

The authors have previously shown that meningioma-derived conditioned medium profoundly stimulates the in vitro proliferation of meningioma cells. In this paper, self mitogenic agents found in the conditioned medium-autocrine growth-stimulatory factors actually secreted by human meningioma cells-are characterized as proteins related to the B chain of platelet-derived growth factor (PDGF) and possibly to the A chain of PDGF as well. The addition to conditioned medium of a neutralizing antibody against PDGF-BB caused a significant inhibition of the conditioned medium-stimulated DNA synthesis in all three meningioma cultures studied. A similar neutralizing effect was observed with an anti-PDGF-AA antibody in one meningioma culture studied. Gel filtration chromatography of concentrated conditioned medium from two different meningiomas using a Sephadex G-100 column revealed similar profiles from both conditioned media with a major peak of mitogenic activity against meningioma cells at a molecular weight (M(r)) of approximately 32 to 36 kD, accompanied by a minor peak at approximately 22 kD. The major peak mitogenic activity was significantly reduced by addition of an anti-PDGF-BB antibody. Western blot analysis of protein extracts from five meningioma specimens was performed using a monoclonal antibody against the B chain of PGDF, and a major band of PDGF-B immunoreactivity was detected at an M(r) of approximately 19 kD in all five meningiomas under both reducing and nonreducing conditions. Exogenous human and porcine PDGFs both exhibited a significant dose-dependent stimulation of DNA synthesis in two of three and three of five meningioma cultures examined, respectively. Although not all meningiomas investigated proved to share the biological activity associated with PDGF and these results may be preliminary, it seems that the autocrine growth-stimulatory loop established by PDGF-B-related molecules plays an important functional role in meningioma cell proliferation.

Phase II study of imatinib mesylate for recurrent meningiomas (North American Brain Tumor Consortium study 01-08)

“…PDGF ligands AA and BB and PDGF receptor-b (PDGFR-b) are present in the majority of meningiomas 19-30 regardless of grade, 23,28 which suggests the existence of an autocrine loop. 25,28 Administration of PDGF-BB to meningioma cells in culture stimulates growth and activates mitogen-activated protein kinases 22 and c-fos, 23 while anti-PDGF-BB antibodies inhibit tumor cell growth. 28 These data suggest that PDGFR inhibition may have therapeutic value in patients with recurrent meningiomas.…”

Reduced expression of neurofibromin in human meningiomas

“…More data indirectly suggest p21 ras importance. The strong inappropriate expression (compared with normal leptomeningeal cells) of polypeptide growth factors and their receptors on the same population of meningioma cells suggests the important possibility of autocrine or paracrine functions for these factors (Todo et al, 1996). Because extracellular growth factors found in meningiomas act through protein tyrosine kinase receptors and activate p21 ras, the reduced expression of neurofibromin and the consequent decrease in both the negative regulation of p21 ras and/or its effector activity might be of importance in the tumorigenesis of meningiomas.…”

Chromosomal alterations, prognostic factors, and targeted molecular therapies for malignant meningiomas

“…61 Such tumor proliferation can be inhibited by anti-PDGF-BB antibodies in vitro. 62 However, treatment with imatinib mesylate, a potent inhibitor of PDGF-a and b receptors, Bcr-Abl, and c-Kit tyrosine kinases, demonstrated minimal activity and no radiographic responses. 63 In a recent in vitro study, the combination of imatinib mesylate with a protease inhibitor and nelfinavir, a pro-apoptotic agent, demonstrated synergistic effects.…”