Epidermal Growth Factor Receptors


The Molecular Biology of Hormone and Growth Factor Receptors on Meningiomas
Expression of a number of steroid hormone and growth factor receptors is characteristic of meningiomas. This paper reviews the analysis of receptors for progesterone, estrogen, androgen and platelet derived growth factor (PDGF) in human meningioma tissue specimens. Progesterone receptor was assessed by Northern blot analysis and immunohistochemistry in meningioma tissue specimens. Progesterone receptor mRNA was expressed in 64% of the meningiomas examined. Immunohistochemical data correlated well with the Northern blot analysis. The staining was clearly nuclear. Expression was more common in meningioma tissue from women than from men. Analysis of receptor expression in tissue culture derived from meningioma specimens demonstrated the loss of progesterone receptor within one to two passages. It was shown that the progesterone receptor mRNA expression which is present in meningiomas is functional by transfection techniques. The estrogen receptor was undetectable by Northern blot analysis; a small amount could be detected in meningioma tissue specimens by polymerase chain reaction (PCR). The androgen receptor was found in 67% of the specimens examined. Like the progesterone receptor, it was more common in women than in men (69% vs. 31%). The immunohistochemical data correlated well with the Northern blot analysis, with the receptor predominantly found in the nucleus. Unlike progesterone receptor, androgen receptor expression was not lost in cell culture. The subunits for PDGF were expressed in various quantities in meningiomas. Only the PDGF beta-receptor (PDGFR-beta) not alpha-receptor, was found in meningioma tissue specimens. In contrast, the ligands PDGF A and PDGF B were expressed in all tumors. The functionality of the PDGF beta-R was determined by examining the induction of the protooncogene C-fos by PDGF BB in meningioma cell cultures. A significant increase in C-fos protein was observed with the addition of PDGF BB to meningioma cultures.

Black P, Carroll R, Zhang Z. The Molecular Biology of Hormone and Growth Factor Receptors on Meningiomas . Acta Neurochir, 1996, [Suppl], vol 65, pp 50-53.

Expression and activation of epidermal growth factor receptors in meningiomas
Previous studies have demonstrated expression of epidermal growth factor receptors (EGFRs) in human cerebral meningiomas. However, the activation status of the EGFRs and whether they activate cytoplasmic mitogenic signaling pathways are not known. In this study, using Northern blot analysis and the polymerase chain reaction, the authors report expression of epidermal growth factor, transforming growth factor-alpha, and EGFR messenger RNA in 27 meningioma specimens. Using Western blot and immunohistochemical analyses of the meningioma samples, the authors demonstrate that the EGFRs expressed by these meningiomas are activated. These activated EGFRs interact with and phosphorylate Shc, an SH2 domain-containing adapter protein that is important in transducing mitogenic signals from EGFRs to the nucleus via activation of the Ras signaling pathway. These results support the concept that activation of EGFRs in human meningiomas by autocrine/paracrine stimulation may contribute to their proliferation.

Carroll RS, Black PM, Zhang J, Kirsch M, Percec I, Lau N, Guha A.  Expression and activation of epidermal growth factor receptors in meningiomas .  J Neurosurg, 87(2): 315-323, 1997.



Correlation of Vascular Endothelial Growth Factor Messenger RNA Expression with Peritumoral Vasogenic Cerebral Edema in Meningiomas
Intracranial meningiomas are often complicated by peritumoral vasogenic cerebral edema, which appears to result from increased microvascular permeability and extravasation of proteinaceous and plasma fluid into the adjacent peritumoral space. The source of such edema has long been mysterious. The contents of this paper support the concept that vascular endothelial growth factor (VEGF) production plays a significant role in edema formation. Vascular endothelial growth factor messenger RNA expression has been found in a wide range of intracranial neoplasms, including malignant gliomas, metastatic melanomas, meningiomas, and other benign tumors. Several studies have confirmed the importance of VEGF in tumorigenesis, neovascularization, and edema production. This study tests the hypothesis that the presence of peritumoral edema in meningiomas is positively correlated with increased expression of VEGF mRNA. To investigate this hypothesis, 31 meningioma specimens were subjected to Northern blot analysis, hybridization with a complementary DNA VEGF probe, and laser densitometry to determine the relative levels of VEGF mRNA expression. Magnetic resonance imaging was then used in a double-blind fashion to correlate the neuropathological tissue samples with the presence of preoperative peritumoral edema. Of 31 patients studied, 14 exhibited no edema and 17 exhibited some level of peritumoral fluid accumulation. There was a marked increase in VEGF expression in patients with edema (p = 0.0004, Wilcoxon-Mann-Whitney rank-sum test). Meningiomas with peritumoral edema exhibited 3.4 times the level of VEGF mRNA as those without edema. These data demonstrate a strong link between VEGF mRNA expression and peritumoral edema and indicate that VEGF expression is an important factor in the etiology of edema around meningiomas.

Kalkanis SN, Carroll RS, Zhang JP, Zamani AA, Black PM.  Correlation of Vascular Endothelial Growth Factor Messenger RNA Expression with Peritumoral Vasogenic Cerebral Edema in Meningiomas . J Neurosurg 1996 85:1095-1101.



Brain Tumor Tropism of Transplanted Human Neural Stem Cells is Induced by Vascular Endothelial Growth Factor
The transplantation of neural stem cells (NSCs) offers a new potential therapeutic approach as a cell-based delivery system for gene therapy in brain tumors. This is based on the unique capacity of NSCs to migrate throughout the brain and to target invading tumor cells. However, the signals controlling the targeted migration of transplanted NSCs are poorly defined. We analyzed the in vitro and in vivo effects of angiogenic growth factors and protein extracts from surgical specimens of brain tumor patients on NSC migration. Here, we demonstrate that vascular endothelial growth factor (VEGF) is able to induce a long-range attraction of transplanted human NSCs from distant sites in the adult brain. Our results indicate that tumor-upregulated VEGF and angiogenic-activated microvasculature are relevant guidance signals for NSC tropism toward brain tumors.

Schmidt NO, Przylecki W, Yang W, Ziu M, Teng Y, Kim SU, Black PM, Aboody KS, Carroll RS. Brain Tumor Tropism of Transplanted Human Neural Stem Cells is Induced by Vascular Endothelial Growth Factor . Neoplasia, 7(6): 623-629, 2005.