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.

EGFR transactivation in the regulation of SMC function.

Abstract: Vascular smooth muscle cells (SMCs) are the principal cellular component of the normal artery and intimal lesions that develop in response to arterial injury. Several growth factors and their receptors participate in SMC activation, including the tyrosine kinase receptors for platelet-derived growth factor (PDGF) and basic fibroblast growth factor as well as the G-protein-coupled receptors (GPCRs) for thrombin and angiotensin II. During the last couple of years, it has become evident that GPCRs transactivate receptor tyrosine kinases, particularly the epidermal growth factor receptor (EGFR). The EGFR is not well characterized in terms of its role in vascular biology, but recent findings indicate that GPCRs induce EGFR transactivation in cultured vascular SMCs, perhaps by intracellular and extracellular pathways. Studies from our laboratory as well as two other groups have demonstrated that EGFR transactivation by different GPCR agonists and in different cell types, including SMCs, is mediated by heparin-binding EGF-like growth factor (HB-EGF). HB-EGF-dependent EGFR activation is blocked by heparin, a growth inhibitor of SMCs in vitro and in vivo. These data suggest that the EGFR may be important in the regulation of SMC function. The complexity of the GPCR-EGFR crosstalk, involving several different cell surface molecules and an inside-out signaling step, may provide novel targets for the control of SMC growth and intimal hyperplasia in the arterial injury response.

Expression of growth factors and growth factor receptors in capillary hemangioblastoma.

Abstract: To elucidate the mechanisms underlying the regulation of growth and differentiation of capillary hemangioblastoma we studied the expression of selected growth factors and growth factor receptors by immunocytochemistry. As stromal cells of capillary hemangioblastoma express high levels of vascular endothelial growth factor (VEGF) and placental growth factor (P1GF) mRNA, we studied the distribution of the corresponding VEGF and P1GF proteins. We also studied the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptors (PDGFR) because their ligands have been reported to promote angiogenesis. The stromal cells expressed abundant EGFR and, in addition, some stromal cells expressed PDGFR-alpha but not PDGFR-beta. In contrast, the endothelial cells co-expressed PDGFR-alpha and PDGFR-beta. VEGF and P1GF were expressed by scattered stromal cells; however, more intense staining was observed in the endothelial cells of the intratumoral blood vessels, possibly indicating the secreted growth factors bound to their target receptors. We conclude that capillary hemangioblastomas express a variety of growth factor receptors and ligands, potentially involved in both autocrine and paracrine loops. The uniformly high EGFR expression is unique among brain tumors and may be associated with the typical morphology of capillary hemangioblastoma. The expression of highly angiogenic growth factors and their receptors may contribute to the rich vascularity of this enigmatic tumor.

Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1).

Abstract: The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG1 antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. Cancer 2010;116(4 suppl):1027–32. © 2010 American Cancer Society.

Functional Role of Insulin-Like Growth Factor Binding Proteins

Abstract: Insulin-like growth factors (IGF-I, IGF-II) are important regulators of cell division and differentiation. In their free form, IGFs form a complex with specific binding proteins (IGFBPs), six of which have now been characterized. These IGFBPs differ in their ability to bind IGF-I and/or IGF-II, and, depending on their location and metabolic circumstances, they inhibit or augment IGF action to varying extents. New findings have changed our understanding of IGFBPs, which are now considered to be major regulators of IGF action and IGF transport proteins between compartments. Recently, the IGF-inde-pendent action of IGFBPs was discovered. Levels of IGFBP-3, for instance, are important indicators of states of altered growth hormone secretion and action, as well as being important during treatment with growth hormone or IGF-I. IGFBP-1 and -2 levels reflect changes related to nutrition, insulin secretion, foetal development and malignant state. The unravelling of the intricate interactions of IGFs, IGFBPs and their targets is bound to influence our understanding of the physiology and development of biological systems. Likewise, the possibility of regulating the IGFBP system is likely to open up new fields in the treatment of diseases in the future.