Growth Factors
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.
