Platelet Derived Growth Factor


The Expression of Platelet-Derived Growth Factor Transcripts in Medulloblastomas and Ependymomas
We used Northern blot analysis to measure the expression of mRNA for platelet-derived growth factor subunit A (PDGF-A), PDGF-B and the PDGF-alpha receptor (PDGFR-alpha) and PDGF-beta receptor (PDGFR-beta) in ependymomas and medulloblastomas. We analyzed tissue from 5 patients for each tumor type, looking specifically for components of an autocrine or paracrine system in these tumors. PDGF-A was expressed in all tumors, PDGFR-alpha, which binds all 3 PDGF isoforms, was only found in ependymomas. Thus only ependymomas appeared to have a potential for using PDGFR-alpha autocrine loops. PDGF-B was expressed only in ependymomas, although the PDGFR-beta was expressed in both medulloblastomas and ependymomas. Again, therefore, only ependymomas appear to have a potential autocrine loop with PDGFR-beta. These data suggest that ependymomas have the biochemical prerequisites for autocrine and/or paracrine loops using PDGFR-alpha or PDGFR-beta systems. In this they resemble other glial tumors such as anaplastic astrocytomas and glioblastomas. Medulloblastomas do not appear to have the ligand and/or receptor for either the PDGFR-alpha or PDGFR-beta autocrine loop.

Black PM, Carroll R, Glowacka D.  The Expression of Platelet-Derived Growth Factor Transcripts in Medulloblastomas and Ependymomas .  Pediatr Neurosurg., 24(2): 74-78, 1996.



Platelet-derived Growth Factor Expression and Stimulation in Human Meningiomas
The platelet-derived growth factor (PDGF) family consists of subunits A and B and receptors alpha and beta. This paper evaluates the potential role of the homodimer PDGF-BB as a growth factor in meningiomas. It analyzes the expression of messenger RNA in members of the PDGF family in these tumors, measures the growth response of meningiomas to exogenous PDGF-BB in culture, and examines the induction of the c-fos proto-oncogene by PDGF-BB. Northern blot analysis was carried out on tissue from 20 meningiomas to measure the expression of PDGF-A, PDGF-B, PDGF-alpha receptor (PDGF-alpha-R) and PDGF-beta receptor (PDGF-beta-R). All tumors expressed PDGF-A and PDGF-B subunits. Nineteen of the 20 tumors expressed PDGF-beta-R and none expressed PDGF-alpha-R as measured by this technique. Because the beta receptor is selectively sensitive to stimulation by the PDGF-B subunit, these data suggest that meningiomas might be susceptible to stimulation by PDGF-BB. To test this hypothesis, the effect of exogenous PDGF-BB on meningioma growth was evaluated by incubating cells from 10 human meningiomas. Tritiated thymidine incorporation was used to evaluate stimulation of growth over a 48-hour period using PDGF-BB concentrations of 1, 3, or 6 ng/ml. Linear regression analysis and multiple-factor analysis of variance were used to measure PDGF-BB effects. Three of the 10 tumor specimens responded significantly to PDGF-BB, with a three- to sixfold increase in thymidine incorporation over 72 hours of exposure, and there was a significant overall growth-stimulating effect of PDGF-BB in the 10 tumor specimens tested. In the last set of experiments, the functionality of the PDGF-beta-R was determined by examining the induction of the proto-oncogene c-fos by PDGF-BB in meningioma cell cultures. A significant increase in c-fos protein was observed 3 hours after PDGF-BB addition. These findings demonstrate that PDGF-A, PDGF-B, and PDGF-beta-R are expressed in meningiomas and suggest that the beta receptor is functional: when it is activated, c-fos levels are increased, and an increase in meningioma cell division is observed after the addition of PDGF-BB. These studies support the hypothesis that PDGF acts as a growth factor in meningiomas.

Black PM, Carroll R, Glowacka D, Riley K, Dashner K.  Platelet-derived Growth Factor Expression and Stimulation in Human Meningiomas . J Neurosurg, 81(3): 388-393, 1994.



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 PM, Carroll R, Zhang J. The Molecular Biology of Hormone and Growth Factor Receptors on Meningiomas . Acta Neurochir Suppl, 65: 50-53, 1996.



Platelet-derived growth factor in human brain tumors
This paper initially reviews ligand and receptor systems for the PDGF family and the signalling systems they use as well as their role in neural developments. It then describes the putative role of this family in astrocytoma, meningioma, and pituitary adenoma pathogenesis. Potential therapies with receptor antagonists or dominant negative mutants are discussed in the final sections.

Kirsch M, Wilson JC, Black P.  Platelet-derived growth factor in human brain tumors .  J NeuroOncol, 35(3): 289-302, 1997.



Messenger Ribonucleic Acid Expression of Platelet-Derived Growth Factor Subunits and Receptors in Pituitary Adenomas
Little is known about the expression of growth factors and their receptors in pituitary tumors or the relationship of growth factors to pituitary neoplasia. Platelet-derived growth factor (PDGF) is a potent mitogen that has been postulated to stimulate tumor growth through autocrine and/or paracrine loops in a number of human tumors. In the present study we demonstrate messenger ribonucleic acid expression of the PDGF subunits and receptors in a variety of human pituitary adenomas and in a normal human anterior pituitary gland. Northern blot analysis performed on 34 pituitary adenomas showed that all tumors expressed the PDGF-A and PDGF-B subunits, the majority (94%) expressed the PDGF-beta receptor, and a subset (44%) expressed the PDGF-alpha receptor. The normal anterior pituitary studied expressed all of the PDGF subunits and receptor subunits. Clinically, there was no correlation between expression of the PDGF subunits or receptors and tumor size or with invasion into adjacent structures (cavernous sinus, sphenoid sinus, or clivus). A higher proportion of the endocrinologically active adenomas expressed the PDGF-alpha receptor (5 of 8) compared to the endocrine inactive tumors (10 of 26). The function of PDGF in the pituitary is currently not known. The finding that PDGF subunit and receptor messenger ribonucleic acids are coexpressed in pituitary adenomas and normal anterior pituitary suggests that autocrine and/or paracrine loops involving PDGF may exist in pituitary adenomas and normal anterior pituitary.

Leon SP, Carroll RS, Dashner K, Glowacka D, Black PM.  Messenger Ribonucleic Acid Expression of Platelet-Derived Growth Factor Subunits and Receptors in Pituitary Adenomas .  J Clin Endocrinal Metab, 79(1): 51-55, 1994.



Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products
The present studies investigated the expression of the platelet-derived growth factor (PDGF) and PDGF-receptor genes in human meningiomas. Northern blot analysis demonstrated that all meningiomas examined expressed both the c-sis/PDGF-2 proto-oncogene and the PDGF-receptor gene. In situ hybridization localized the c-sis mRNA and the PDGF-receptor mRNA in the tumor cells of the meningioma tissues. Control pachymeninges derived from adult individuals, without meningiomas, expressed only PDGF-receptor mRNA but not the c-sis mRNA. Immunocytochemistry studies detected both the c-sis and the PDGF-receptor protein products in meningioma tissues but only the PDGF-receptor protein products in control pachymeninges. These findings indicate the presence of an autocrine mechanism in human meningiomas based on the co-expression of the c-sis/PDGF-2 proto-oncogene and PDGF-receptor gene and their protein products. This co-expression of a potent mitogen and its receptor may contribute to the growth and maintenance of human meningiomas.

Maxwell M, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN.  Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products .  Int J Cancer 46(1):16-21, 1990.



Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance
The present studies investigated the expression of the two PDGF genes (c-sis/PDGF-2 and PDGF-1) and the PDGF-receptor b gene (PDGF-R) in 34 primary human astrocytomas. Northern blot analysis demonstrated the coexpression of the c-sis/PDGF-2 protooncogene and the PDGF-R gene in all astrocytomas examined. The majority of the tumors also expressed the PDGF-1 gene. There was no correlation between the expression of the two PDGF genes. Nonmalignant human brain tissue expressed the PDGF-R and PDGF-1 genes but not the c-sis/PDGF-2 protooncogene. In situ hybridization of astrocytoma tissue localized the expression of the c-sis and PDGF-R mRNA's in tumor cells. Capillary endothelial cells also expressed c-sis mRNA. In contrast, nonmalignant human brain tissue expressed only PDGF-R mRNA but not c-sis/PDGF-2 mRNA. The coexpression of a potent mitogenic growth factor protooncogene (c-sis) and its receptor gene in astrocytoma tumor cells suggests the presence of an autocrine mechanism that may contribute to the development and maintenance of astrocytomas. The expression of c-sis mRNA in tumor cells but not in nonmalignant brain cells may serve as an additional diagnostic criterion for the detection of astrocytomas in small tissue specimen using in situ hybridization for the detection of c-sis mRNA and/or immunostaining for the recognition of its protein product.

Maxwell M, Naber SP, Wolfe HJ, Galanopoulos T, Hedley-Whyte ET, Black PM, Antoniades HN. Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance . J Clin Invest, 86(1):131-40, 1990.



Detection of Activated Platelet-derived Growth Factor Receptors in Human Meningioma
The beta receptor subunit of platelet-derived growth factor (PDGF) and its corresponding ligand (PDGF-BB) are coordinately expressed in fresh surgical isolates of human meningioma. These observations imply that PDGF autocrine loops are engaged in human meningioma and suggest that activated PDGF-beta receptors might contribute to the pathology of this common brain neoplasm. The study of PDGF autocrine loops and human meningioma has been slowed by the scarcity of meningioma cell culture model systems. Furthermore, in meningioma tumor tissue, the activation state of PDGF receptors is difficult to assess with conventional reagents, because the tumor is intermixed with normal stroma. In fact, there is no evidence that PDGF receptors within the tumor are activated by ligand. We used a synthetic tyrosine phosphopeptide to raise an antibody that reports the phosphorylation state of tyrosine 751 in the human PDGF-beta receptor. Phosphorylated tyrosine 751 is a recognition site for phosphatidylinositol 3'-kinase, a cytoplasmic effector of PDGF-induced mitogenesis, chemotaxis, and membrane ruffling. Immunoblotting and immunostaining analyses with this antibody show that the PDGF-beta receptor is constitutively phosphorylated at tyrosine 751 within multiple fresh surgical isolates of human meningioma. These findings are consistent with a role for activated PDGF receptors in the proliferation of human meningiomas.

Shamah SM, Alberta JA, Giannobile WV , Guha A, Kwon YK , Carroll RS, Black PM, Stiles CD.  Detection of Activated Platelet-derived Growth Factor Receptors in Human Meningioma .  Cancer Research, 57(18): 4141-4147, 1997.