The insulin-like growth factor system in normal and malignant hematopoietic cells.

PROLIFERATION OF hematopoietic cells is controlled by a coordinated hierarchy of growth factors and their inhibitors. These growth factors form complex signaling networks either by stimulating or inhibiting cell proliferation and differentiation. They govern all growth stages of blood cells that emerge from a small common pool of ancestral stem cells. In addition, biologic effects are altered by the interaction of different growth factors, which adds another magnitude of complexity. Insulinlike growth factors (IGFs) are part of a number of growth factors and cytokines responsible of burst-like growth of early erythroid progenitor cells in vitro and may play a role in the ontogeny of marrow development. IGFs may not be considered as classical hematopoietic growth factors, but nonetheless their involvement in abberant hematopoietic growth regulation is intriguing. The complexity of the IGF system should be a challenge for conducting more research on this topic rather than a hurdle. This review aims to unravel the biological significance of IGFs in normal and malignant hematopoiesis as well as to stimulate further research in this rapidly expanding field. IGFs constitute a family of peptides capable of stimulating various cellular responses, including cell proliferation and differentiation.1 Both IGF-I and -II are mitogenic factors that are secreted by malignant cells as well.2 A steadily increasing number of IGF-binding proteins (IGFBP-1 to -6) and IGFBPrelated proteins (IGFBP-rP1 to 4) are part of the IGF system. These IGFBPs either enhance or inhibit the IGF-mediated effects. The IGFBP-related proteins (IGFBP-rPs) are newly described factors that appear to be implicated in tumorigenesis.3 The type I (IGF-I-R) and type II (IGF-II-R) IGF receptor bind IGFs and mediate their effects (Figs 1, 2, and 3). IGF-I-R is of particular interest because of its antiapoptotic role,4 and novel anticancer therapies may be designed aiming at this receptor.5 IGFs are also of importance for blood formation.6 They stimulate both myeloid and lymphoid cells in culture.7,8 Since epidemiologic studies have indicated that high birthweight is associated with an increased risk of infant leukemia,9 it has been postulated that IGF-I may both produce a larger baby and contribute toward leukemogenesis.10