The haematopoietic effects of growth hormone and insulin-like growth factor-I

The process of haemopoiesis, occurring primarily within the bone marrow, involves the proliferation and differentiation of pluripotent haemopoietic stem cells into committed, or pathway-restricted progenitors /1/. The latter further proliferate and undergo a process of maturation into circulating blood cells of myeloid and erythroid lineages /2/. Haemopoietic cell growth and differentiation is primarily regulated by the local production of various cytokines within the bone marrow micro-environment /3/, as well as by the circulating hormone, erythropoietin (EPO). The formation as well as functional activation of mature blood cells, are also modulated by a variety of hormones and growth peptides, including growth hormone (GH) and insulin-like growth factor-I (IGF-I) /4,5/. Early evidence for the role of GH in modulating haemopoiesis was provided in classical studies in rodents, which showed that removal of the pituitary gland affects blood cell formation and function /6/ and that impairment of the latter can be restored by GH administration /7/. GH exerts its effects on target cells by binding to its own receptor, which belongs to the class I cytokine receptor superfamily /8/. In humans, GB can also bind to and activate the prolactin receptor /9/. Based on the somatomedin hypothesis of Salmon and Daughaday /10/, it is now generally accepted that, in addition to the above, GH exerts many of its effects via autocrine or paracrine IGF-I, as well as via endocrine IGF-I produced in the liver. IGF-I, a small single-chain polypeptide, is one of two highly homologous peptides (IGF-I and IGF-TI), that stimulate the proliferation and differentiation of a wide variety of cell types, including bone marrow cells /5,11/. Both ICF-I and IGF-II play an important role in prenatal growth and IGF-T is also essential for postnatal growth and development /12/. Two types of IGF receptors have been described. The type I IGF receptor, a tyrosine kinase receptor highly homologous to the insulin receptor, binds IGF-I and IGF-II with a high affinity. The type II/mannose 6-phosphate receptor which lacks intrinsic kinase activity, binds IGF-II with a high affinity and IGF-I with a low affinity /13,14/. Haemopoietic progenitors and mature blood cells have been shown to produce GH and IGF-I and to express receptors for these peptides. GH and IGF-I may act independently on these cells or, as more commonly observed, in a synergistic manner with primary haemopoietic cytokines. GH and IGF-I receptors are also present on freshly explanted leukemic cells and leukemic cell lines. Thus, their possible contribution to the development of leukemia should also be considered. This review summarizes our current understanding of the role of GH and IGF-I in normal and malignant haemopoiesis.