Growth factors can be involved in the proliferation of cells at steady state as well as after injury, when irreversibly damaged cells must be replaced. Uncontrolled
Hepatocytegrowthfactor(HGF)Fibroblasts,stromalcellsintheliver,Enhancesproliferationofhepatocytesandotherepithelialcells;(scatterfactor)endothelialcellsincreasescellmotility
Keratinocytegrowthfactor(KGF)FibroblastsStimulateskeratinocytemigration,proliferation,anddifferentiation(i.e.,FGF-7)
ECM,Extracellularmembrane.
http://ebooksmedicine.net proliferation can result when the growth factor activity is dysregulated, or when growth factor signaling pathways are altered to become constitutively active. Thus, many growth factor pathway genes are proto-oncogenes, and gain-of-function mutations in these genes can convert them into oncogenes capable of driving unfettered cell proliferation and tumor formation. The following discussion summarizes selected growth factors that are involved in the important proliferative processes of tissue repair and regeneration; by virtue of their proliferative effects they can also drive tumorigenesis. Although the growth factors described here all involve receptors with intrinsic kinase activity, other growth factors may signal through each of the various pathways shown in
Fig. 1.12
Epidermal growth factor and transforming growth factor-α. Both of these factors belong to the EGF family and bind to the same receptors, explaining their shared biologic activities. EGF and TGF-α are produced by macrophages and a variety of epithelial cells, and are mitogenic for hepatocytes, fibroblasts, and a host of epithelial cells. The “EGF receptor family” includes four membrane receptors with intrinsic tyrosine kinase activity; the best-characterized is EGFR1, also known as ERB-B1, or simply EGFR. EGFR1 mutations and/or amplification frequently occur in a number of cancers including those of the lung, head and neck, breast, and brain. The ERBB2 receptor (also known as HER2) is overexpressed in a subset of breast cancers. To treat malignancies, many of these receptors have been successfully targeted by antibodies and small molecule antagonists.
Hepatocyte growth factor. Hepatocyte growth factor (HGF; also known as scatter factor) has mitogenic effects on hepatocytes and most epithelial cells. HGF acts as a morphogen during embryonic development (i.e., it influences the pattern of tissue differentiation), promotes cell migration (hence its designation as scatter factor), and enhances hepatocyte survival. HGF is produced by fibroblasts and most mesenchymal cells, as well as endothelium and nonhepatocyte liver cells. It is synthesized as an inactive precursor (pro-HGF) that is proteolytically activated by serine proteases released at sites of injury. The receptor for HGF is MET, which has intrinsic tyrosine kinase activity. It is frequently overexpressed or mutated in tumors, particularly renal and thyroid papillary carcinomas. Consequently, MET inhibitors are being evaluated as cancer therapies.