For an embryo to develop into an adult, its cells must increase in number by the process of division (mitosis) and grow in size (hyper-trophy). As they mature, cells develop specializations according to the tissue of which they are a part (differentiation). In tissue development, excess production of cells is the norm, so that the final shaping of organs depends on programmed death (apoptosis) of supernumerary cells. Some tissues, such as nerve and skeletal muscle, reach a stage of terminal differentiation in adulthood and undergo no further cell division. However, most cells in the adult retain the ability to divide, allowing tissues (e.g. blood vessels, bones) to remodel or repair themselves as required. Some cells face particularly high rates of attrition (e.g. enterocytes in the gut lining, skin cells, hair follicles) and are produced continuously throughout life. The processes of mitosis, cell growth and apoptosis are controlled by a large number of systemic and local peptide hormones, known as growth factors (Chapter 42). To varying extents, these factors stimulate mitosis (they are mitogens), promote growth (a trophic effect) and inhibit apoptosis (promote cell survival).
Growth factor families and their receptors Growth factors are classified into a number of families based on common amino acid sequences and the types of receptor that they activate. Neurotrophins, which include nerve growth factor (NGF), are important chemical signals in the development of the nervous system and are potent survival factors for neurones in adults. The epidermal growth factor (EGF) family includes EGF itself and transforming growth factor-α (TGFα), both of which are mitogens in a wide range of tissues, including the gut and skin. Fibroblast growth factors (FGF-1–24) are strongly mitogenic and induce the production of new blood vessels (angiogenesis). The transforming growth factor-β (TGFβ) superfamily includes a number of bone transforming proteins (Chapter 43) and is crucial in embryogenesis and the development and remodelling of structural tissues. The origins of platelet derived growth factor (PDGF) are self explanatory. It stimulates division, growth and survival in a number of cell types, and is important in tissue repair after injury. Insulin and insulin-like growth factors (IGF-1 and IGF-2) have similar structures but rather different actions: insulin promotes anabolic activity generally (Chapter 40), whereas the IGFs are mitogenic, trophic and act as survival factors for several cell types. Numerous other hormones have mitogenic properties, e.g. the stimulation of red blood cell production by erythropoi- etin (Chapter 8) and white cell production by cytokines (Chapter 10) means that these hormones are also described as growth factors.
Mitosis occurs during the cell cycle (Fig. 46a). Some mitogens, including PDGF, stimulate transition from the non-dividing state (G0) into the growth phase of the cycle (G1), whereas others, such as EGF and IGF-1, stimulate progress through G1. With the exception of
TGFα, erythropoietin and the cytokines, growth factors work by activating receptor tyrosine kinases (Chapter 43; Fig. 46b). Binding of the hormone leads to phosphorylation of the tyrosine residues of a number of important intracellular proteins, including phospholipase C, Grb2 and phosphatidylinositol-3 kinase, eventually leading to the production of more kinases: protein kinases C and B, calcium-calmodulin kinase (CAM kinase) and mitogen-activated protein kinase (MAP kinase) (Fig. 46b). These enzymes have many targets within the cell, but MAP kinase, in particular, enters the nucleus and activates immediate to early genes, such as c-fos and c-jun. The products of these genes are transcription factors, driving the expression of further genes, such as those that produce G1 cyclins, proteins that are required for cell division. The MAP kinase pathway appears to be the main intra-cellular signalling system for the stimulation of mitosis. The TGFβ family exerts its effects through receptor serine–threonine kinases that phosphorylate their target proteins at serine and threonine residues. The pathway activated by these receptors involves proteins called SMADs [the name is derived from genes that code for similar proteins in Drosophila melanogaster (fruit fly) and Caenorhabditis elegans, a nematode worm]. SMAD-2 and/or SMAD-3 is phosphorylated while it is attached to the receptor; it then dissociates to dimerize with SMAD-4, forming a complex that directly activates gene regulatory proteins (Fig. 46c). Growth hormone, erythropoietin and the cytokines activate receptors that signal through Janus kinases (JAKs; Chapter 47).
Growth factors and cancer
Cell division and growth are strictly controlled so that organs do not invade the space needed for other tissues. When this process is deranged, cancers are formed. Cancer cells do not recognize the normal constraints of organ growth or the limits to the number of divisions to which cells are normally subjected, and are unusually mobile. These features make cancer cells extremely dangerous, as they supplant healthy tissues and cause fatal damage to physiological systems. Cancerous growths start with mutations in particular genes (oncogenes) that impact on cell division and/or apoptosis. Ras genes, which produce the Ras GTPases that are key mediators in the MAP kinase pathway (Fig. 46b), are commonly found to be defective in human tumours. In view of the importance of this pathway in mitogenesis, it is not difficult to see how the abnormal activation of these genes could lead to excessive cellular proliferation. In this situation, the signals involved in normal tissue growth provide the driving force for tumour growth and survival. EGF, in particular, has been associated with the maintenance of colorectal and breast cancers, and anti-EGF drugs are showing some promise as tumour-controlling agents.