IGFBPs/ALS : more than just IGF carrier proteins

HORACIO M. DOMENÉ

Leipzig

Congreso; Symposium: IGF-I as an Oncogene; 2012

European Society for Paediatric Endocrinology

IGFBPs/ALS: More than just IGF carrier proteins Presentation aim: The role of IGFBPs/ALS on the regulation of IGF-I actions: Lessons from animal models and human diseases. Insulin-like binding proteins (IGFBPs) 1 to 6 by forming binary complex of high affinities with IGF-I and -II regulate endocrine, paracrine and autocrine actions on growth, differentiation and metabolism.  Acid labile subunit (ALS), with no affinity to IGFs, binds binary complexes formed by IGFs and IGFBP-3 or -5, to form heterotrimers of about 150 kDa. ALS plays a key role to maintain IGF-I reservoir because not only prevent the passage of IGF-I to the extravascular compartment, but also prevents degradation of both IGF-I and IGFBP-3 by proteases. In addition to functioning as simple carrier proteins, circulating and locally produced IGFBPs regulate the amount of IGF-I available to interact with IGF1 receptors. IGFBPs may also act as modulators of cell growth by IGF-independent mechanisms. Some antiproliferative actions of IGFBP-3 have been reported to be independent of IGFs. Recently, a new cell death receptor, IGFBP-3R, has been reported. This receptor mediates IGFBP-3-induced caspase-8-dependent apoptosis and cross-talk with NF-êB signaling in various cancer cells. Mice models of individual IGFBPs KO show modest phenotypes, probably related to overlapping function. Triple null mice for IGFBP-3, -4 and -5 have significantly reduction in IGF-I levels and reduced adult sizes. The ALS-KO mice presented a mild growth deficit despite a marked reduction in the circulating levels of IGF-I and IGFBP-3. Aged ALS-KO mice showed increased hepatic and gastric tract tumors. Knock-in mouse models of mutated IGF-I with reduced affinity for IGFBPs have reduced serum IGF-I and increased GH levels, presenting increased body weight, body and bone lengths and selective organomegaly. Only IGFALS gene defects have been characterized in human, because patients with a complete inactivation of the IGFBP-1 to -6 have still to be described. Human ALS deficiency is characterized by severe reduction of IGF-I and IGFBP-3 that remain low after GH treatment, associated to mild growth retardation. This relative mild growth retardation might be related to the preserved autocrine/paracrine of locally produced IGF-I.   In many animal models and epidemiologic studies high IGF-I and low IGFBP-3 levels have been positively associated to increased cancer risk. On the other hand, congenital IGF-I deficiency, as that observed in complete GH insensitivity (Laron’s Syndrome) and GH deficiency, seem to protect for cancer development. In ALS deficiency circulating IGF-I levels are similarly reduced, but local production is preserved. In addition, while GHI and GHD patients present increased insulin sensitivity, ALS deficient patients are frequently insulin resistant. Increased insulin and GH secretion and reduced IGFBP-3 may hypothetically result in a favorable milieu to tumor progression. Carefully follow up are required to evaluate long term consequences in these patients.