Cell production in all tissues of multicellular organisms is under the control of a network of tissue-specific protein regulators called growth factors. They are usually produced in the tissue in which they function. Growth factors have been identified in
the epithelia, neural, lymphoid, muscle, blood vessels, the lymphatic system, myeloid, erythroid, and hepatic systems; inmany cases, several growth factors and cytokines are produced in each tissue
As well as controlling the normal production of mature cells, growth factors are important for regulating inflammatory, wound-healing, and antiviral responses. Growth factors and cytokines regulate the self-renewal of stem cells, the location of cells within a tissue, and the proliferation, differentiation, movement and survival of cells within a tissue.
Many diseases appear to be associated with inappropriate growth factor production or responses to growth factors. An overproduction of growth factors can lead to an accumulation of inappropriate cellular deposits within a tissue and the infiltration of tissues by inflammatory cells. Although cancers arise as the result of numerous genetic lesions, many metastatic cancers appear to be driven in part by a hypersensitivity to growth factors or cytokines, or the autocrine action of growth factors on mutated tissue stem cells. In some cancers the growth factor receptors are mutated to produce hyper-responsive or even constitutively active forms of the receptor. New therapeutic approaches to cancer involve the use of tissue growth factor antagonists or inhibitors, and in some cases hematopoietic growth factors, to improve the recovery of white blood cells lost as a result of anti-cancer treatments such as cytotoxic drugs or radiation therapy. The growth factor antagonists and growth factor receptor inhibitors suppress the proliferation and metastasis of the tumor cells and make the cancer cells more susceptible to killing by cytotoxic agents. An understanding of the mechanisms of action of growth factors/cytokine and the tissues acted on by these proteins is also important for developing more effective therapies for autoimmunediseases, such as rheumatoid arthritis, multiple sclerosis, skin diseases, and diabetes.
IGF-1 was discovered as the plasma protein that was responsible for nonsuppressible insulin-like activity. IGF-1, which for some time was known as somatomedin, also mediates the action of growth hormone, while IGF-II was the first growth factor to be associated with an aberrant growth of tumor cells in the laboratory. When the members of this growth factor family circulate in the serum, their availability is controlled by specific binding proteins (BPs). The cell-surface receptors for insulin and IGF-1 are composed of four chains (α2, β2); the β-chains are transmembrane, ligand-dependent tyrosine kinases, while the α-chains bind the ligand. The IGF-II receptor is a large (2000 amino acids) single-chain structure with no obvious intracellular catalytic domain, and also functions as the receptor for mannose-6- phosphate, which targets acid hydrolases to liposomes. It has been suggested that these two binding specificities might regulate complementary processes during tissue remodeling.
NGF, a humoral substance produced by some tumors, is responsible for the innervation of these tumors. Several other neurotrophins, such as brain-derived neurotrophic factor (BDNF), CTNF, NT-3, and NT-4/5 have been discovered. BDNF stimulates peripheral sensory ganglia as well as cholinergic and dopaminergic neurons. More recently, there have been reports of a glial growth factor that is a differentially spliced form of a ligand for the erbB3 or erbB4 receptors.
Detailed structure-Cfunction studies have identified many of the residues required for the binding of NGF and BDNF to the low-affinity (1-C5 nM) neurotrophin receptor p75. The other class of neurotophin receptors, trk A, trk B, and trk C, are ligand-activated tyrosine kinases. Trk A binds NGF, trk B binds BDNF or NT-4, and trk C recognizes NT-3.
EGF stimulates lung maturation and formation of the gastrointestinal mucosa, and inhibits the secretion of acid from the gastric mucosa. EGF binds to and stimulates a single-chain tyrosine kinase receptor. Several growth factors are closely related to EGF, including TGF-α, amphiregulin, cripto, heparinbinding epidermal growth factor (HBEGF), several heregulins, epigen, epiregulin, and β-cellulin. TGF-α was discovered as an autocrine growth factor induced in mammalian cells by some tumor viruses, while EGF and TGF-α are initially expressed as large precursor molecules. The TGF-α precursor is expressed on the surface of cells, and the mature protein is released by specific proteolysis. Amphiregulin and the neuregulins bind to distinct receptors within the EGF receptor family. There are four closely related tyrosine kinase receptors in the EGFR family, namely EGFR, HER2, HER3, and HER4. The sequence homology in the ligand binding domain is between 40% and 50%, and in the kinase domain there is up to 80% similarity between the family members. However, it is clear that the ligand-binding specificity for each receptor is distinct, with the EGFR having a preference for EGF and TGF-α, whereas HER3 and HER4 bind to neuregulins. There is now considerable evidence that heterodimers form on the cell surface between the EGFR and HER2, HER3, and HER4. The heterodimers bind appropriate ligands with high affinity and activate distinct signaling pathways.
TGF-β is released after a tumor virus infects the fibroblasts, and may also synergize with TGF-α to induce normal rat kidney (NRK) cells to form large colonies. Interestingly, TGF-β was also isolated independently through its ability to inhibit the proliferation of epithelial cells. TGF-β inhibits the proliferation of many mesenchymal cells, including both myeloid and lymphoid cells, and also induces the differentiation of bronchial epithelial cells and pre-chondrocytes, but inhibits the differentiation of adipocytes and myocytes. Inhibin, the Müllerian inhibitory substances (MISs), bone morphogenetic proteins (BMPs), and activin are all related to TGF-β. Three types of TGF-β receptor have been identified: types I, II, and III. Types I and II bind TGF-β with high affinity (KD 5-C25 pM), while the type III TGF-β receptor is a large transmembrane proteoglycan with no obvious cytoplasmic signaling motif. The TGF-β type II receptor has ligand-dependent Ser/Thr kinase activity, which appears to signal growth inhibition. The type II receptor requires the type I receptor for ligand binding.
Different cell types are known to secrete either PDGF-AA or PDGF-BB homodimers, both of which act as growth factors for fibroblasts, smooth muscle cells, and glial cells. There appear to be two forms of the PDGF receptor monomer (α and β), and these can combine to produce several, functional receptor dimers: αα, αβ, and ββ. Whereas, the αα receptor responds to all forms of PDGF (i.e., AA, AB, and BB), the ββ receptor responds only to PDGF-BB. The PDGF receptors are typical ligand-dependent tyrosine kinases, but the cytoplasmic domain contains an insert that modulates the intracellular signaling processes. PDGF increases the rate of wound-healing in rodents, and initial reports have indicated that it might be a valuable agent for treating cutaneous ulcers in diabetic patients.
VEGF stimulates the production of endothelial cells from both small and large blood vessels. As well as promoting angiogenesis, VEGF stimulates monocyte chemotaxis, and is produced by many neoplastic cells. Interestingly, antibodies against VEGF can inhibit the production of blood vessels in vivo and, as a consequence, inhibit the growth of human tumor cell lines. Similarly, negative dominant VEGF receptors can inhibit the vascularization of experimental tumors. There are in fact four closely related growth factors in the VEGF family: VEGF, VEGF-B, VEGF-C, and VEGF-D. The first two family members stimulate the formation
of blood vessels, whereas VEGF-C and VEGF-D stimulate the production of lymphatic vessels.
The acidic fibroblast growth factor (a-FGF) and basic fibroblast growth factor (b-FGF) forms are both single-chain proteins of approximately 140 amino acids, and 55% of their amino acid sequences are identical. Several other members of the FGF family have been identified, including hst/k53, FGF-5, FGF-6, FGF-7 (also known as keratinocyte growth factor; KGF), FGF-8, and FGF-9 (glial-activating factor), and there appears to be a distant homology (20–25%) with IL-1α and IL-1β. Both, a-FGF and b-FGF stimulate the proliferation of cells, including colonic and breast epithelia, endothelial cells, fibroblasts, and muscle cells.
Originally discovered as a factor that increases the motility and spreading of cells (called the scatter factor), hepatocyte growth factor (HGF) stimulates the proliferation of primary hepatocytes and increases the invasiveness of both endothelial and epithelial cells. HGF also appears to be involved in liver regeneration, tumor progression, and several embryological processes. HGF is a 92 kDa disulfide-linked heterodimer consisting of a light chain (33 kDa) and a heavy chain (62 kDa), which are produced from a single-chain precursor. The HGF receptor (c-met) is expressed in a number of epithelial tissues, including liver and colon. Interestingly, a fragment of HGF containing two Kringle domains binds to c-met and stimulates the motility response and the receptor tyrosine kinase activity, but does not stimulate a mitogenic response in primary rat hepatocytes. Mutations in c-met have been associated with a number of cancer types. Two other receptors related to c-met, namely c-ron and c-sea, have been reported.
At least 20 cytokines or growth factors have been identified by their action on the production or function of blood cells.The major classes of hematopoietic regulators are ILs, lymphokines, CSFs, epo, and SCF. As might be expected from such a large number of hematopoietic growth factors, several classes of cell-surface receptors have been identified, including tyrosine kinases (e.g., M-CSF, c-kit), multichain receptors (e.g., IL-2, IL-3, IL-6, and GM-CSF), and singlechain receptors (e.g., G-CSF). Several of the hematopoietic growth factor receptors share adaptor subunits (e.g., GM-CSF, IL-3, and IL-5 share a subunit), and these, along with the LIF oncostatin M, all appear to signal via complexes with the cell surface glycoprotein gp130.
Wnt proteins regulate cell location, movement, and proliferation processes in both the adult and embryo. There are many forms of Wnt with a myriad of biological activities. Specific Wnts are involved in stem cell self-renewal and homeostasis as well as wound-healing. Wnt signaling regulates the location and activity of β-catenin, and consequently this cytokine influences transcriptional programs as well as cell–cell adhesion processes during proliferation and differentiation. Colon stem cells with truncated Apc are hypersensitive to Wnt signaling, and crypt production increases in an uncontrolled manner. Many other cancers, including breast cancer, are also associated with excess Wnt signaling.
Wnt binds to and activates a multichain cell-surface receptor containing Fzd, lrp5/6, and lgr5. There appears to be competition between the Wnt:Fzd complex and the lgr5:R-spondin complex for binding lrp5/6. When the Wnt:Fzd:lrp5/6 complex forms, signaling occurs intracellularly which involves glycogen synthase kinase-3β (GSK-3β) and β-catenin. When lrp5/6 is sequestered by Lrg5:R-spondin in intestinal stem cells, a different signaling program favoring cell–cell adhesion is triggered. These interactions are perturbed in cancer cells. The critical functions of this cytokine in the maintenance of tissue production in so many organs means that a targeted delivery of antagonists to the cancer tissue may be necessary before Wnt antagonists are likely to be of any therapeutic benefit.
Notch is a cell-surface receptor that is important for generating cellular patterning in tissue systems. Notch receptors are activated by cell-surface-associated ligands (jagged and delta). In epithelial tissues, interactions between neighboring cells – which lead to proliferation and differentiation – are influenced by the activation and inhibition of notch signaling. The signaling patterns generated by notch lead to the formation of tissue boundaries and the separation of functional clusters of cells.
Eph receptors are single-pass transmembrane receptor tyrosine kinases. Ephs are regulated by cell-surface ligands (ephrins), and control cell location and differentiation during embryogenesis, tissue homeostasis, and oncogenic transformation. Although there are many types of Eph receptor, the two major classes – EphA and EphB – have distinct structural features and ligandbinding preferences. Similarly, there appear to be two classes of cell-surface-bound ligands, namely ephrin-A (GPI-linked) and ephrin-B (transmembrane).
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• Meyer M, et al. Fibroblast Growth Factors in Epithelial Homeostasis and Repair[M]//Fibroblast Growth Factors: Biology and Clinical Application: FGF Biology and Therapeutics. 2017: 187-209.