VEGF and PDGF Receptors: Biologic Relevance and Clinical Approaches to Inhibition
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The dependence of tumor growth on the development of a neovasculature is well established. One of the best studied angiogenic factor is vascular endothelial growth factor (VEGF). VEGF belongs to a family of homodimeric glycoproteins that bind to three different VEGF receptor (VEGFR) tyrosine kinases in an overlapping pattern. VEGFRs share regulatory mechanisms with other well-characterized receptor tyrosine kinases, such as the platelet-derived growth factor receptor (PDGFR). These mechanisms include receptor dimerization and activation of tyrosine kinase, as well as creation of docking sites for signal transducers to direct cellular function including cell migration, survival, and proliferation. Tumor biology studies, drug development, and clinical studies have established VEGFR and PDGFR as validated drug targets. Well-interconnected preclinical and clinical efforts are necessary for the continued development of this exciting process. This chapter will review the biological role of VEGFR and PDGFR signal transduction and the interplay between the different receptors as it relates to kidney cancer.Keywords:
Platelet-derived growth factor
Receptor Protein-Tyrosine Kinases
Platelet-derived growth factor (PDGF) is a 30 kilodalton dimeric peptide comprising A and B chains. The two types of PDGF receptors (alpha and beta) that have been identified belong to the protein-tyrosine kinase family of growth factor receptors. PDGF is a potent mitogen for a variety of cell types, and in gene knock-out experiments has been shown to be required for the development of inter alia mesangial cells of renal glomeruli and smooth muscle cells of lung alveolar septa. PDGF is believed to fulfil important autocrine and paracrine growth-related functions, and its overproduction has been recognised in various malignant tumours and in non-neoplastic hyperproliferative disorders.
Platelet-derived growth factor
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Platelet-derived growth factor
Imatinib Mesylate
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Microprecipitates of calcium phosphate (CaPO4) can substitute for platelet-derived growth factor (PDGF) to stimulate the growth of cultured 3T3 cells. In two-part complementation assays, CaPO4 behaves as a PDGF-like "competence factor"--that is, the mitogenic response to CaPO4 is enhanced synergistically by "progression factors" contained in platelet-poor plasma. In studies described here, we show that early cytoplasmic and intranuclear events in the mitogenic response to CaPO4 are equivalent to those induced by PDGF. However, no net increase in tyrosine kinase activity of either the PDGF-alpha or PDGF-beta receptor is seen following exposure to CaPO4. Our data suggest that calcium acts within the cell, regulating events which normally proceed from activation of PDGF receptors. Alternatively, microprecipitates of CaPO4 could act externally by activating a growth factor receptor which escapes detection with available reagents.
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Platelet-derived growth factor(PDGF)and its receptors(PDGFR)play crucial role in devel- opment and progression of tumor,and are becoming hot targets for research of anti-cancer therapy.Blockade of PDGF/PDGFR signal transduction pathway can provide a potential and strategic approach to antitumor therapy. In this review,we give an overview about clinical development of pharmaceutical chemical compounds targeted PDGFR.
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Gliomas are primary tumor originated from the glial cells of the central nervous system, with the characteristics of unrestricted proliferation and widespread invasion to the surrounding normal brain tissue. The aberrant expression of the platelet-derived growth factor (PDGF) and its membrane receptor (PDGFR) activates the downstream signaling pathway, which affects the development of human glioma, but the molecular mechanisms remain unclear. PDGF and PDGFR play an important role in embryonic development and cell differentiation. PDGF-induced glioma animal model provides an important research method for the study of PDGF signaling pathway in the development of glioma. This article reviews the role of platelet-derived growth factor and its receptor in the development of glioma.
Key words:
Platelet-derived growth factor; Platelet-derived growth factor receptor; Glioma; Animal model
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Preincubation of Swiss 3T3 cells or human fibroblasts with purified platelet-derived growth factor (PDGF) at 4 degrees C or 37 degrees C rapidly inhibits subsequent binding of 125I-epidermal growth factor (125I-EGF). The effect does not result from competition by PDGF for binding to the EGF receptor since (a) very low concentrations of PDGF are effective, (b) cells with EGF receptors but no PDGF receptors are not affected, and (c) the inhibition persists even if the bound PDGF is eluted before incubating the cells with 125I-EGF. PDGF does not affect 125I-insulin binding nor does EGF affect 125I-PDGF binding under these conditions. Endothelial cell-derived growth factor also competes for binding to PDGF receptors and inhibits 125I-EGF binding. The inhibition demonstrated by PDGF seems to result from an increase in the Kd for 125I-EGF binding with no change in the number of EGF receptors.
Platelet-derived growth factor
Cell surface receptor
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Progress in cancer biology has led to an increasing discovery of oncogenic alterations of the platelet-derived growth factor receptors (PDGFRs) in cancers. In addition, their overexpression in numerous cancers invariably makes PDGFRs and platelet-derived growth factors (PDGFs) prognostic and treatment markers in some cancers. The oncologic alterations of the PDGFR/PDGF system affect the extracellular, transmembrane and tyrosine kinase domains as well as the juxtamembrane segment of the receptor. The receptor is also involved in fusions with intracellular proteins and receptor tyrosine kinase. These discoveries undoubtedly make the system an attractive oncologic therapeutic target. This review covers elementary biology of PDGFR/PDGF system and its role as a prognostic and treatment marker in cancers. In addition, the multifarious therapeutic targets of PDGFR/PDGF system are discussed. Great potential exists in the role of PDGFR/PDGF system as a prognostic and treatment marker and for further exploration of its multifarious therapeutic targets in safe and efficacious management of cancer treatments.
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The v-sis oncogene product p28v-sis and the platelet-derived growth factor (PDGF) B chain share 92% homology with each other and over 50% homology with the PDGF A chain. Exogenously added homodimers of PDGF A and PDGF B and of p28v-sis are potent mitogens but only PDGF B and p28v-sis induce transformation when endogenously expressed with a strong promoter. Because exogenous PDGF AA and PDGF BB both initiate a full mitogenic response, understanding the mechanisms underlying the difference in their transforming potential may clarify how growth factor genes act as oncogenes. In this work, we compared cells expressing high levels of PDGF A and v-sis. We observed that transformation by v-sis correlated directly with the rapid degradation (t1/2 approximately 20 min) of the alpha and beta PDGF receptors, with a failure of either the alpha or beta receptor to be fully processed and with the association of high levels of phosphatidylinositol (PI) 3-kinase with immunoprecipitates of the PDGF receptors. In contrast, in cells expressing essentially equal levels of PDGF A, transformation was not detected, alpha and beta PDGF receptor processing was normal, and association of PI 3-kinase with receptors in immunoprecipitates was not found above control values. The ability of v-sis to autoactivate PDGF receptors within processing compartments and to initiate activation of the PI 3-kinase signaling pathway coupled with the failure of PDGF A to activate its receptor intracellularly and to induce transformation when endogenously expressed at high levels suggests that the internal autoactivation of PDGF receptors may be essential for transformation by v-sis.
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Alpha (finance)
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Background: Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor of the PDGF family [1]. It regulates several cellular processes including cell proliferation, transformation, invasion, and angiogenesis through specifically binding to and activating its cognate receptor PDGFR-β. In experimental liver fibrotic models (BDL and carbon tetrachloride), we have shown that PDGF-D is upregulated comparable to that of PDGF-B [2, 3]. Moreover, adenoviral expression of PDGF-D induces hepatic stellate cell (HSC) proliferation and liver fibrosis [4]. We now seek to investigate the molecular mechanism of PDGF-D involvement in liver fibrogenesis.
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Hepatic stellate cell
Hepatic fibrosis
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