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Growth is a complex process that is intimately linked to the developmental program to form adults with proper size and proportions. Genetics is an important determinant of growth, as exemplified by the role of local diffusible molecules setting up organ proportions. In addition, organisms use adaptive responses allowing modulating the size of individuals according to environmental cues, for example, nutrition. Here, we describe some of the physiological principles participating in the determination of final individual size., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

Insulin-like growth factors were discovered more than 50 years ago as mediators of growth hormone that effect growth and differentiation of bone and skeletal muscle. Interest of the role of insulin-like growth factors in cancer reached a peak in the 1990s, and then waned until the availability in the past 5 years of monoclonal antibodies and small molecules that block the insulin-like growth factor 1 receptor. In this article, we review the history of insulin-like growth factors and their role in growth, development, organism survival, and in cancer, both epithelial cancers and sarcomas. Recent developments regarding phase I to II clinical trials of such agents are discussed, as well as potential studies to consider in the future, given the lack of efficacy of one such monoclonal antibody in combination with cytotoxic chemotherapy in a first-line study in metastatic non-small-cell lung adenocarcinoma. Greater success with these agents clinically is expected when combining the agents with inhibitors of other cell signaling pathways in which cross-resistance has been observed.

Growth, the main characteristic of childhood and adolescence, has a similar pattern in the majority of the individuals. Genetic background and GH-IGF axis are the factors that directly influence this process. Pituitary GH acts on growth mainly through the regulation of IGF system. The IGFs (IGF-1 and IGF-2) are growth factors produced in the majority of the organs and body tissues. They have autocrine, paracrine and endocrine actions on metabolism and cell proliferation, growth and differentiation. The IGFs bind with high specificity and affinity to a family of 6 binding proteins, called IGFBPs (1 to 6) that modulate their bioactivity. Most of the known IGF actions are mediated via IGF type 1 receptor (IGF1R). In this article we are going to review the composition and regulation of the GH-IGF axis and the role of each component in the regulation of the growth process.

Introduction: Growth is regulated by the interaction of environmental signals with endogenous neuroendocrine responses to the genetic programs that determine the body plan. The insulin-like growth factors (IGFs) are integral components of multiple systems controlling both growth and metabolism., The Igf System: The IGF system is thouht to be more complex than other endocrine systems, as genes for six IGF-binding proteins (IGFBPs) have been identified so far. The IGFs play a critical role in both cell cycle control and apoptosis, two functions involved in regulation of tumorigenesis. Insulin-like growth factor-I (IGF-I) is essential for normal growth. Confirmation of the significance of IGF-I in human physiology was obtained by the discovery of a patient with intrauterine growth retardation and postnatal growth failure associated with a mutation in the IGF-I gene., Stages of Evolution of the Somatomedin Hypothesis: The original somatomedin hypothesis postulated that somatic growth was regulated by growth hormone's (GH's) stimulation of hepatic IGF-I production, with IGF-I acting in an endocrine fashion to promote growth. The dual effector theory proposed an alternative view, involving direct effects by GH on peripheral tissues not mediated by IGF-I and GH-stimulated local IGF-I production for autocrine/paracrine action. It is now clear that GH stimulates the formation of ternary IGF binding complex, which stabilizes IGF-I in the serum.

Pituitary growth hormone (GH) is present in early pregnancy in the fetal circulation. The concentrations are higher than ever found during life, due to an unrestrained, basal secretion. GH receptors develop around midpregnancy, when they are present in low concentrations, and there is a rapid increase during the first months of life. The function of fetal GH - characterized by a nearly complete GH resistance - is largely unclear: there is only a small effect on longitudinal growth, and the regulation of growth factors is independent of GH. Possibly, metabolic effects of GH on fat and glucose metabolism and body composition are of greater importance. During the first months of life, the rapid fetal (GH-independent, nutrition-dependent) growth decelerates, a process that is partly compensated by the onset of GH-dependent longitudinal growth., (Copyright 2000 S. Karger AG, Basel)

The IGFs are essential stimulators of fetal and postnatal growth. Their signals are mediated predominantly by the type I IGF receptor, but another as yet unidentified receptor seems to mediate some actions, especially some of those for IGF-II. During organogenesis, the actions of IGF-I seem to be local (autocrine/paracrine), because it, as well as IGFBPs and IGF receptors, are expressed coordinately in a highly tissue and developmentally specific fashion. IGF-I, however, most likely assumes endocrine functions during postnatal life and provides signals for GH and nutritional status. On the other hand, IGF-II may have only local growth-promoting functions, and its most essential actions may be restricted to in utero life. Both IGFs may be involved in regenerative organ growth, and their uncontrolled expression, especially that of IGF-II, may be involved in the formation of some tumors. The previous conclusions are drawn mainly from in vitro and animal experiments. Although they are generally consistent with data in humans, it is most likely incorrect to extrapolate to man all of the conclusions drawn from the experiments in mice. Differences in placentation are so marked between mice and humans that an exclusive role for IGF-II in human placental growth seems unlikely. On the other hand, it is reasonable to conclude that both IGFs are important stimulants of normal human fetal growth, that IGF-I is a more potent stimulator of human postnatal growth, and that the type I IGF receptor mediates most IGF actions in humans. The fact that no human growth disorders have been linked convincingly to lack of function mutations in IGF or IGF receptor genes suggests that such defects are lethal.

Growth hormone is the major regulator of postnatal growth. Although intrauterine growth seems to be largely growth hormone independent, gene knockout studies have established the pivotal role of the IGF system in both prenatal and postnatal growth. The original "somatomedin hypothesis" postulated that all of the growth-promoting actions of growth hormone were mediated by IGFs. Several in vitro and in vivo studies have suggested, however, that growth hormone may have specific growth-related actions in addition to stimulating IGF production, including promoting differentiation of prechondrocytes at the growth plate and stimulation of synthesis of proteins involved in IGF transport and clearance. An integrated model of interrelated role(s) of growth hormone and IGF in skeletal growth is proposed.

The skeletal growth-promoting action of growth hormone appear to be mediated by circulating somatomedins or insulin-like growth factor(s) (IGF), which act directly to promote the proliferation of growing cartilage. The actions of IGF(s) include also insulin-like activity in extraskeletal tissues and mitogenic activity. Serum concentrations of IGF(s) were found to be dependent on hormonal levels and nutritional status and are reduced by malnutrition or dietary restrictions. The actions of somatomedins may be modulated at the tissue level by somatomedins inhibitor, factor that may act to limit growth in conditions of hormonal and/or nutrition deficiency. Plasma concentration of somatomedins are a good marker of acute directional change in nitrogen balance and dietary energy and protein appears to be particularly important for both generation of somatomedins, and their action on growing cartilage. Measurement of somatomedin concentration shows promise as a means for monitoring the response of malnourished children and rats to nutrition repletion.

In the present review it is not possible to discuss the effects of the numerous endogenous mediators of growth. What we have attempted to do is to indicate the areas of controversy and the need for further research. In our view, four main questions arise. First, what are the relative contributions of the direct and indirect effects of GH? Indeed, if GH can produce all its effects by local production of IGF, is the original somatomedin hypothesis still tenable? Second, how is the biological activity of the IGF modified by the presence of binding proteins? Because of the role of binding proteins in modulating IGF bioactivity, care must be taken when interpreting results from immunoassays for IGF because this will only represent the concentration of IGF not the level of biological activity, a situation which is analogous to that which pertains with certain polypeptide hormones (for review, see Robertson et al. 1987). Third, how are the activities of the osteoblast and osteoclast coupled so that in the mature adult, bone formation and bone resorption are roughly equivalent? Understanding of this process will undoubtedly involve the elucidation of the roles and interactions between a number of locally acting growth factors and systemic hormones and will lead to the understanding of certain metabolic bone diseases such as osteoporosis. Last, how is the response to local stimuli such as mechanical stress transduced? This is again probably dependent on the activity of local growth factors but may also involve changes in the interactions between bone cells and their underlying matrix components (Skerry et al. 1988).

A line of transgenic mice expressing insulin-like growth factor-I (IGF-I) under the control of the mouse metallothionien-1 promoter was crossed to a line of dwarf transgenic mice lacking GH expressing cells that were genetically ablated by diphtheria toxin expression. Mice generated from this cross that carry both transgenes express IGF-I in the absence of GH. These mice grew larger than their GH-deficient transgenic littermates and exhibited weight and linear growth indistinguishable from that of their nontransgenic siblings. These results confirm the suspected role of IGF-I in mediating GH's stimulation of somatic growth, including that of long bones, and illustrates the essential role of GH and IGF-I in the modulation of postnatal growth. Analysis of differences in organ growth among these mice, however, suggests that GH and IGF-I also have growth promoting actions that are independent of one another; GH appears to be necessary for the attainment of normal liver size, while IGF-I can stimulate brain growth.

Serum somatomedins, or insulin-like growth factor(s) (IGF), originally characterized as primarily GH-dependent peptides, were found to also be dependent on insulin levels and nutritional status. Four properties characterize somatomedin peptides: their concentrations in serum are growth hormone dependent; they possess insulin actions in extraskeletal tissues; they promote the incorporation of sulfate into proteoglycans of cartilage; and they stimulate DNA synthesis and cell multiplication in certain types of cultured cells. Reduced somatomedin C levels are found in children with severe protein-energy malnutrition. Plasma concentration of growth hormone and cortisol are both elevated and there are low levels of insulin and somatomedin C. There is evidence that the ability of somatomedin C to stimulate cartilage is modulated by somatomedin inhibitor, factor that may act to limit growth in conditions of hormonal and/or nutritional deficiency. Dietary energy and protein appears to be particularly important for both generation of somatomedins and their action on growing cartilage. Measurement of somatomedins C concentration shows promise as a means for monitoring the response of malnourished patients and rats to nutrition repletion.

Plasma transferrin is significantly positively correlated to the growth velocity in normal children and children with various growth disorders. In hypopituitary dwarfs, both plasma transferrin and somatomedin are significantly lower than in controls. Acute variations of the plasma transferrin levels could be involved in the regulation of the GH secretion by a feedback mechanism. Yet, transferrin is neither a somatomedin or a somatomedin-binding protein, and the mechanisms relating growth to transferrin remain unknown.

Many endocrinological factors control cellular growth of different tissues (cell multiplication and cell volume) and skeletal growth. The role of neuro-transmitters and of hypothalamic releasing and inhibiting factors of growth hormone secretion will be reviewed. The importance of the somatomedins on cartilage growth will be stressed. Thyroid hormones, androgens, and oestrogens have important stimulating actions on skeletal growth and maturation. Conversely, glucocorticoids have an important inhibitory effect on growth. The precise roles of these hormone factors in the regulation of growth hormone secretion, somatomedin production and tissue growth, particularly the cartilage, remain to be completely elucidated.

The insulin-like growth factors (IGF) or somatomedins (Sm) are a family of low molecular weight circulating growth factors which have a major, but not absolute, dependence on GH, and have been shown to stimulate body growth and skeletal metabolism in vivo. They are thus considered to mediate the effects of GH on skeletal growth. In humans, the family consists of two well-characterized forms--IGF-I or SmC (a basic peptide) and IGF-II (a "neutral" peptide)--as well as perhaps two less well characterized forms--SmA (a neutral peptide) and an acidic insulin-like activity (ILA pI 4.8). Similar IGF/Sm species have been found and well-characterized in rat serum. Some higher mol wt forms also exist in tissues and body fluids and may represent possible precursor forms. On the basis of in vitro, clinical and in vivo evidence it has been postulated that IGF-I is the primary growth factor in the adult, whilst IGF-II is probably a major foetal growth factor. In vitro the IGF/Sms have a variety of effects including (1) acute insulin-like metabolic actions, which are observed primarily in insulin target tissues and are initiated largely at insulin receptors, and (2) longer term effects, associated with cell growth and skeletal tissue metabolism, and which occur in traditionally non-insulin target tissues, primarily via IGF/Sm receptors. These observations, together with the circumstantial clinical evidence favouring a close association between IGF levels and growth status, clearly indicate a role for IGF/Sms in growth regulation. This concept is now fully supported by the demonstration that IGF-I infused into hypophysectomized (GH-deficient) rats results in increased growth and skeletal metabolism. The physiological regulation of the expression of net IGF activity in vivo is complex and is controlled by the following three determinants: the levels of IGFs, the levels of the specific carrier-proteins and the levels of IGF inhibitors. Both IGFs and their carrier-proteins are influenced by the GH status of the animal as well as by other hormones, nutritional status and chronic illness. Little is known yet about the control of the various IGF inhibitors that have been described. Of importance, however, is the general concept that normal growth is dependent on an adequate balance between all three determinants and that some regard must be had for the contribution of each in determining the overall potential for growth under given circumstances.

The in-vivo biological activity of recombinant methionyl insulin-like growth factor I (met-IGF-I) was demonstrated in hypophysectomized rats by following blood glucose after an i.v. bolus injection of met-IGF-I; a dose-dependent decrease in blood sugar was seen. Membrane transport was studied using the non-metabolizable amino acid alpha-aminoisobutyric acid; stimulation was obtained with the highest dose used (90 micrograms/rat). To test the original somatomedin hypothesis, growth studies were performed in hypophysectomized rats. Two or three doses of met-IGF-I were given with three different administration regimes (i.v. or s.c. infusion, or s.c. injections twice daily) for 6 or 8 days. Little growth-promoting activity was observed, with a significant effect on body weight gain obtained only when met-IGF-I was given continuously at the highest dose used (180 micrograms/day). No effect was seen on the in-vivo uptake of radioactive sulphate into cartilage. Epiphyseal cartilage width increased slightly at the highest dose of met-IGF-I, but only when the hormone was given by infusion. When 180 micrograms met-IGF-I/day were given by injections, a significant effect on longitudinal bone growth was obtained (90 micron above control). The levels of IGF in the serum were not measurably increased after s.c. administration of met-IGF-I, whereas after i.v. infusion, significantly raised levels were obtained at the higher dose rates (3.0 +/- 0.3 and 2.8 +/- 0.1 units/ml). Growth hormone was much more effective than met-IGF-I even at 50-fold lower doses. Priming the animals with 10 mu. bovine GH/day followed by combined infusions of GH and met-IGF-I did not reveal any potentiating effects of met-IGF-I in the presence of GH. We conclude that met-IGF-I is a relatively poor growth-promoting agent when given systemically, and that somatomedins are more likely to act as local growth factors rather than as circulating mediators of the growth-promoting effects of GH.