EGF and PDGF receptor tyrosine kinases as therapeutic targets for chronic lung diseases
ABSTRACT Cell-surface receptor tyrosine kinases play pivotal roles in development, tissue repair, and normal cellular homeostasis. Aberrant expression or signaling patterns of these kinases has also been linked to the progression of a diversity of diseases, including cancer, atherosclerosis, asthma, and fibrosis. Two major families of receptor tyrosine kinases, the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) families, have received a great deal of attention as potential therapeutic targets for pulmonary diseases, as these receptors have been shown to play key roles in chronic tissue remodeling in asthma, bronchitis, and pulmonary fibrosis. The EGFR system on epithelial cells and underlying mesenchymal cells (fibroblasts, myofibroblasts, and smooth muscle cells) drives numerous phenotypic changes during the progression of these pulmonary diseases, including epithelial cell mucous cell metaplasia and mesenchymal cell hyperplasia, differentiation, and extracellular matrix production. The PDGFR system, located primarily on mesenchymal cells, transduces signals for cell survival, growth and chemotaxis. The variety of EGFR and PDGFR ligands produced by the airway epithelium or adjacent mesenchymal cells allows for intimate epithelial-mesenchymal cell communication. A full understanding of the complex mechanisms involving these receptors and ligands should lead to therapeutic strategies for the treatment of a wide range of fibroproliferative lung diseases.
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ABSTRACT: Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), the AA and BB isoforms of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) are involved in the pathogenesis of airway inflammation in asthma. In the present study, the associations between asthmatic phenotypes and the expression levels of these mediators in induced sputum and serum were investigated. A total of 62 asthmatic patients were divided into eosinophilic or neutrophilic phenotypes by cytological classification of the induced sputum. In addition, patients were classified according to lung function (FEV1/FVC >70% or FEV1/FVC <70%) and asthma severity (mild, moderate or severe). The concentrations of EGF, bFGF, PDGF-AA, PDGF-BB and VEGF in the serum and induced sputum were measured using sandwich enzyme immunoassays. VEGF levels in the serum and induced sputum were higher in patients with an eosinophilic phenotype compared with those with a neutrophilic phenotype. In addition, VEGF expression was higher in patients with an FEV1/FVC value of <70% as compared with patients with an FEV1/FVC value of >70%. Furthermore, the levels of VEGF were higher in patients with severe asthma compared with the patients with mild and moderate asthma. There were no statistically significant differences observed with regard to EGF, bFGF, PDGF-AA and PDGF-BB levels among the various phenotypes. Therefore, the observations of the present study indicated that increased VEGF expression in the serum and induced sputum of patients may be associated with eosinophilic airway inflammation, severe airflow limitation and the severity of asthma.Experimental and therapeutic medicine 08/2014; 8(2):573-578. DOI:10.3892/etm.2014.1759 · 0.94 Impact Factor
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ABSTRACT: Cell migration directed by spatial cues, or taxis, is a primary mechanism for orchestrating concerted and collective cell movements during development, wound repair, and immune responses. Compared with the classic example of amoeboid chemotaxis, in which fast-moving cells such as neutrophils are directed by gradients of soluble factors, directed migration of slow-moving mesenchymal cells such as fibroblasts is poorly understood. Mesenchymal cells possess a distinctive organization of the actin cytoskeleton and associated adhesion complexes as its primary mechanical system, generating the asymmetric forces required for locomotion without strong polarization. The emerging hypothesis is that the molecular underpinnings of mesenchymal taxis involve distinct signaling pathways and diverse requirements for regulation.Current Opinion in Cell Biology 07/2014; 30C:74-82. DOI:10.1016/j.ceb.2014.06.005 · 8.74 Impact Factor
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ABSTRACT: Background Platelet-derived growth factor-BB (PDGF-BB) has been implicated in the proliferation, migration and synthetic activities of smooth muscle cells that characterize physiologic and pathologic tissue remodeling in hollow organs. However, neither the molecular basis of PDGFR-regulated signaling webs, nor the extent to which specific components within these networks could be exploited for therapeutic benefit has been fully elucidated.ResultsExpression profiling and quantitative proteomics analysis of PDGF-treated primary human bladder smooth muscle cells identified 1,695 genes and 241 proteins as differentially expressed versus non-treated cells. Analysis of gene expression data revealed MYC, JUN, EGR1, MYB, RUNX1, as the transcription factors most significantly networked with up-regulated genes. Forty targets were significantly altered at both the mRNA and protein levels. Proliferation, migration and angiogenesis were the biological processes most significantly associated with this signature, and MYC was the most highly networked master regulator. Alterations in master regulators and gene targets were validated in PDGF-stimulated smooth muscle cells in vitro and in a model of bladder injury in vivo. Pharmacologic inhibition of MYC and JUN confirmed their role in SMC proliferation and migration. Network analysis identified the diaphanous-related formin 3 as a novel PDGF target regulated by MYC and JUN, which was necessary for PDGF-stimulated lamellipodium formation.Conclusions These findings provide the first systems-level analysis of the PDGF-regulated transcriptome and proteome in normal smooth muscle cells. The analyses revealed an extensive cohort of PDGF-dependent biological processes and connected key transcriptional effectors to their regulation, significantly expanding current knowledge of PDGF-stimulated signaling cascades. These observations also implicate MYC as a novel target for pharmacological intervention in fibroproliferative expansion of smooth muscle, and potentially in cancers in which PDGFR-dependent signaling or MYC activation promote tumor progression.Cell Communication and Signaling 08/2014; 12(1):44. DOI:10.1186/PREACCEPT-9184871921296322 · 4.67 Impact Factor