Growth factor receptor inhibitor

About: Growth factor receptor inhibitor is a research topic. Over the lifetime, 4730 publications have been published within this topic receiving 297500 citations.

Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations

Abstract: Lung cancer with epidermal growth factor receptor (EGFR)-activating mutations responds favorably to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. However, 25% to 30% of patients with EGFR-activating mutations show intrinsic resistance, and the responders invariably acquire resistance to gefitinib. Here, we showed that hepatocyte growth factor (HGF), a ligand of MET oncoprotein, induces gefitinib resistance of lung adenocarcinoma cells with EGFR-activating mutations by restoring the phosphatidylinositol 3-kinase/Akt signaling pathway via phosphorylation of MET, but not EGFR or ErbB3. Strong immunoreactivity for HGF in cancer cells was detected in lung adenocarcinoma patients harboring EGFR-activating mutations, but no T790M mutation or MET amplification, who showed intrinsic or acquired resistance to gefitinib. The findings indicate that HGF-mediated MET activation is a novel mechanism of gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations. Therefore, inhibition of HGF-MET signaling may be a considerable strategy for more successful treatment with gefitinib.

A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor

Abstract: A heparin-binding mitogen was isolated from conditioned medium of human embryonic lung fibroblasts. It exhibited broad target-cell specificity whose pattern was distinct from that of any known growth factor. It rapidly stimulated tyrosine phosphorylation of a 145-kDa protein in responsive cells, suggesting that its signaling pathways involved activation of a tyrosine kinase. Purification identified a major polypeptide with an apparent molecular mass of 87 kDa under reducing conditions. Partial amino acid sequence analysis and cDNA cloning revealed that it was a variant of hepatocyte growth factor, a mitogen thought to be specific for hepatic cells and structurally related to plasminogen. Recombinant expression of the cDNA in COS-1 cells established that it encoded the purified growth factor. Its site of synthesis and spectrum of targets imply that this growth factor may play an important role as a paracrine mediator of the proliferation of melanocytes and endothelial cells, as well as cells of epithelial origin.

Cellular activation of latent transforming growth factor beta requires binding to the cation-independent mannose 6-phosphate/insulin-like growth factor type II receptor.

Abstract: The activation of latent transforming growth factor beta (LTGF-beta) normally seen in cocultures of bovine aortic endothelial and bovine smooth muscle cells can be inhibited by coculturing the cells with either mannose 6-phosphate (Man-6-P) or antibodies directed against the cation-independent Man-6-P/insulin-like growth factor type II receptor (anti-Man-6-PR). This result was established by measuring the ability of coculture conditioned medium (formed with or without Man-6-P or anti-Man-6-PR) to suppress bovine aortic endothelial cell migration and protease production, activities previously shown to be related to transforming growth factor beta activity. The inhibition by Man-6-P is dose dependent, with maximal inhibition seen at 100 microM and is specific because mannose 1-phosphate and glucose 6-phosphate do not interfere with activation of LTGF-beta. The inhibitory effect of anti-Man-6-PR is also specific and dose dependent; maximal inhibition of activation occurs at 400 micrograms/ml. Control experiments indicate that Man-6-P and anti-Man-6-PR do not interfere with the basal level of migration of bovine aortic endothelial cells, the migration observed when exogenous transforming growth factor beta is added, the activation of transforming growth factor beta by plasmin or transient acidification, and the release of LTGF-beta. Thus, binding to the cation-independent Man-6-P/insulin-like growth factor type II receptor appears to be a requirement for activation of LTGF-beta.

Regulation of neurogenesis by growth factors and neurotransmitters.

Abstract: The generation of neurons and glia in the developing nervous system is likely to be regulated by extrinsic factors, including growth factors and neurotransmitters. Evidence from in vivo and/or in vitro systems indicates that basic fibroblast growth factor, transforming growth factor (TGF)-alpha, insulin-like growth factor-1, and the monoamine neurotransmitters act to increase proliferation of neural precursors. Conversely, glutamate, gamma-aminobutyric acid, and opioid peptides are likely to play a role in down-regulating proliferation in the developing nervous system. Several other factors, including the neuropeptides vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide, as well as the growth factors platelet-derived growth factor, ciliary neurotrophic factor, and members of the TGF-beta family, have different effects on proliferation and differentiation depending on the system examined. Expression of many of these factors and their receptors in germinal regions of the central nervous system suggests that they can act directly on precursor populations to control their proliferation. Together, the findings discussed here indicate that proliferation and cell fate determination in the developing brain are regulated extrinsically by complex interactions between a relatively large number of growth factors and neurotransmitters.

Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro.

Abstract: Stimulation of epidermal growth factor receptor (EGFR) by ligand(s) leads to activation of signaling molecules including Stat1 and Stat3, two members of the signal transducers and activators of transcription (STAT) protein family. Activation of Stat1 and Stat3 was constitutive in transformed squamous epithelial cells, which produce elevated levels of TGF-alpha, and was enhanced by the addition of exogenous TGF-alpha. Targeting of Stat3 using antisense oligonucleotides directed against the translation initiation site, resulted in significant growth inhibition. In addition, cells stably transfected with dominant negative mutant Stat3 constructs failed to proliferate in vitro. In contrast, targeting of Stat1 using either antisense or dominant-negative strategies had no effect on cell growth. Thus, TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat3 but not Stat1.