Epidermal growth factor-related peptides and their receptors in human malignancies

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the alpha-receptor and the beta-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

https://www.physiology.org/doi/pdf/10.1152/physrev.1999.79.4.1283

Mechanism of Action and In Vivo Role of Platelet-Derived Growth Factor

Purpose To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. Patients and Methods Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m2 or 125 mg/m2 every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. Results Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI...

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Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma

Signaling pathways that mediate the normal functions of growth factors are commonly subverted in cancer. Oncogenes identified by a variety of approaches have been shown to function at critical steps in mitogenic signaling. Progression through the cell cycle requires the coordinated actions of members of two complementary classes of growth factors, and oncogenes appear to replace the actions of one set of these growth factors. Growth factors can also influence normal cell differentiation, and constitutive activation of growth-promoting pathways in cancer cells can modulate the cell phenotype as well. Paracrine actions of growth factors and cytokines may also influence the stepwise series of genetic events that lead to malignancy. New approaches for cancer therapy are being developed that intervene at various steps in growth factor signaling pathways.

https://science.sciencemag.org/content/sci/254/5035/1146.full.pdf

Growth factors and cancer

PURPOSE: To evaluate the role of T2*-weighted echo-planar perfusion imaging by using a first-pass gadopentetate dimeglumine technique to determine the association of magnetic resonance (MR) imaging–derived cerebral blood volume (CBV) maps with histopathologic grading of astrocytomas and to improve the accuracy of targeting of stereotactic biopsy. MATERIALS AND METHODS: MR imaging was performed in 29 patients by using a first-pass gadopentetate dimeglumine T2*-weighted echo-planar perfusion sequence followed by conventional imaging. The perfusion data were processed to obtain a color map of relative regional CBV. This information formed the basis for targeting the stereotactic biopsy. Relative CBV values were computed with a nondiffusible tracer model. The relative CBV of lesions was expressed as a percentage of the relative CBV of normal white matter. The maximum relative CBV of each lesion was correlated with the histopathologic grading of astrocytomas obtained from samples from stereotactic biopsy or vo...

Glial neoplasms: dynamic contrast-enhanced T2*-weighted MR imaging.

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.

/pdf/coexpression-of-platelet-derived-growth-factor-pdgf-and-pdgf-f1x4u01du6.pdf

Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance.

Astrocytomas are highly malignant brain tumors and are among the most neovascularized solid tumors. We have investigated the expression of the angiogenic growth factors acidic fibroblast growth factor and transforming growth factor-α, together with its receptor epidermal growth factor receptor, in 30 primary astrocytomas. Both acidic fibroblast growth factor and transforming growth factor-α, together with epidermal growth factor receptor, are found to be greatly overexpressed in these tumors when compared with normal brain. This overexpression of angiogenic growth factors may underlie the intense neovascularization characteristic of astrocytomas.

/pdf/expression-of-angiogenic-growth-factor-genes-in-primary-2948arvy7v.pdf

Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression.

Mitotic index > 6, proliferating cell nuclear antigen (PCNA) index > 5%, high tumour grade and absence of progesterone receptors (PR) are significant predictors for poor outcome in meningiomas. Since MIB-1 (Ki-67) is a more specific cell proliferation marker, and overexpression of TGF-alpha is also associated with tumour progression, we compared the prognostic significance of these factors with the other indices. Intracranial meningiomas from 21 men and 36 women (age 54.5 +/- 1.7, mean +/- SEM) were classified as 24 benign, 24 atypical and nine malignant. Twenty-one of the 57 tumours recurred (mean interval to recurrence was 57.3 +/- 13.1 months). The mean follow-up period for patients without tumour recurrence was 81.9 +/- 8.7 months. MIB-1 labelling index (LI) was expressed as percentage of labelled nuclei to total tumour nuclei counted in the most densely labelled areas. Analysis of variance revealed significant differences between tumour grades for MIB-1 labelling indices (0.75 +/- 0.21 for benign, 3.2 +/- 0.57 for atypical 6.04 +/- 1.48 for malignant; P 3%, TGF alpha score > 4 (scoring scale 0-5), mitotic index > 6, and negative PR status were significant factors for worse outcome. Higher MIB-1 LI, TGF alpha score and mitotic index as continuous variables were also significant negative predictors. With multivariate analysis, both MIB-1 LI and TGF alpha score remained significant factors when paired with all other variables: TGF alpha or MIB-1 LI, respectively, mitosis, PCNA, tumour grade, PR status, age, sex, postoperative radiation therapy. We conclude that MIB-1 LI and TGF alpha score are important independent prognostic indicators for patients with meningiomas.

MIB-1(Ki-67) index and transforming growth factor-alpha (TGFα) immunoreactivity are significant prognostic predictors for meningiomas

Meningiomas are primarily benign brain tumors thought to arise through multistep tumorigenesis, involving both the activation of oncogenes and the loss of tumor suppressor genes The recently isolated neurofibromatosis 2 (NF2) tumor suppressor gene has been found to be mutated in a large proportion of meningiomas Almost all cases of familial meningioma occur in association with NF2 Familial meningioma in isolation from NF2 (sporadic) is exceedingly rare, with only 14 reports since 1959 The authors report the existence of a family lacking any stigmata of NF2, in which two members had spinal meningiomas Tumor specimens were subjected to immunocytochemical analysis for the NF2 protein product Merlin, which has been implicated in the tumorigenesis of meningioma Merlin immunoreactivity was present in both tumor specimens, implying that the NF2 tumor suppressor gene was not deleted in these tumors This supports the hypothesis that a second tumor suppressor gene locus, other than NF2, acts in the formation of familial sporadic meningioma The results are discussed in the context of putative oncogenic mechanisms of familial meningiomas

Familial meningioma: analysis of expression of neurofibromatosis 2 protein Merlin: Report of two cases

Platelet-derived growth factor (PDGF) has been implicated in the processes regulating gliogenesis in the CNS. Conflicting in vivo data in rodents have variously implicated either glia or neurons as being the primary source of PDGF. We have used in situ hybridization and immunocytochemical analysis to study the in vivo expression and cellular localization of PDGF-A, sis/PDGF-B, together with the two PDGF receptors α and β, in developing human forebrain. In this study we demonstrate the strong expression of mRNA and protein of both PDGF chains, A and B, and their receptors, α and β, in human embryonic glial cells. The neurons, in contrast to glial cells, expressed lower levels of PDGF and PDGF-receptor mRNAs and protein. Identification of the cell types expressing the PDGF and PDGF-receptor mRNAs was achieved by counterstaining with antibodies specific for glial cells (GFAP) and neurons (NF). The predominant glial-specific expression of both PDGF-A and PDGF-B, together with the coexpression of their receptors α and β, suggests an important role for the PDGF isoforms in the development of human embryonic glial cells and neurons in vivo.

E T Hedley-Whyte

Papers

Coexpression of platelet-derived growth factor (PDGF) and PDGF-receptor genes by primary human astrocytomas may contribute to their development and maintenance.

Expression of angiogenic growth factor genes in primary human astrocytomas may contribute to their growth and progression.

MIB-1(Ki-67) index and transforming growth factor-alpha (TGFα) immunoreactivity are significant prognostic predictors for meningiomas

Familial meningioma: analysis of expression of neurofibromatosis 2 protein Merlin: Report of two cases

Cellular localization of PDGF mRNAs in developing human forebrain.