Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 283

Table 10.10 Overview of some of the effects of the IGFs
Promotes cell cycle progression in most cell types
Foetal development: promotes growth and differentiation of foetal cells and organogenesis
Promotes longitudinal body growth and increased body weight
Promotes enhanced functioning of the male and female reproductive tissue
Promotes growth and differentiation of neuronal tissue
levels of insulin and glucagon, increases tissue glucose uptake and inhibits hepatic glucose export.
IGFs display pluripotent activities, regulating the growth, activation, differentiation (and mainte-
nance of the differentiated state) of a wide variety of cell and tissue types (Table 10.10). The full
complexity and variety of their biological activities are only now beginning to be appreciated.
The liver represents the major site of synthesis of the IGFs, from where they enter the blood
stream, thereby acting in a classical endocrine fashion. A wide variety of body cells express IGF
receptors, of which there are two types. Furthermore, IGFs are also synthesized in smaller quanti-
ties at numerous sites in the body and function in an autocrine or paracrine manner at these specifi c
locations. IGF activity is also modulated by a family of IGFBPs, of which there are at least six.
10.3.2 Insulin-like growth factor biological effects
IGFs exhibit a wide range of gross physiological effects (Table 10.10), all of which are explained
primarily by the ability of these growth factors to stimulate cellular growth and differentiation.
Virtually all mammalian cell types display surface IGF receptors. IGFs play a major stimulatory
role in promoting the cell cycle (specifi cally, it is the sole mitogen required to promote the G1b
phase, i.e. the progression phase; various other phases of the cycle can be stimulated by additional
growth factors). IGF activity can also contribute to sustaining the uncontrolled cell growth char-
acteristic of cancer cells. Many transformed cells exhibit very high levels of IGF receptors, and
growth of these cells can be inhibited in vitro by the addition of antibodies capable of blocking
IGF-receptor binding.
Most of the growth-promoting effects of GH are actually mediated by IGF-I. Direct injection of
IGF-I into hypophysectionized animals (animals whose pituitary, i.e. source of GH, is surgically
removed) stimulates longitudinal bone growth, as well as growth of several organs/glands (e.g.
kidney, spleen, thymus).
Such effects render IGFs likely therapeutic candidates in treating the various forms of dwarfi sm
caused by a dysfunction in some element of the GH-IGF growth axis. Initial trials show that s.c.
administration of recombinant human IGF-I over a 12-month period signifi cantly increases the
growth rate of Laron-type dwarfs.
IGFs also play a core role in tissue renewal and repair (e.g. wound healing) during adulthood.
For example, these growth factors play a central role in bone remodelling (i.e. reabsorption and
rebuilding, which helps keep bones strong and contributes to whole-body calcium homeostasis).
Reabsorption of calcifi ed bone is undertaken by osteoclasts, cells of haemopoietic origin whose
formation is stimulated by IGFs. These mitogens may, therefore, infl uence the development of
osteoporosis, a prevalent condition (especially amongst the elderly), which is characterized by
brittle, uncalcifi ed bone.