8Th Colloque Médecine et Recherche of La Fondation Ipsen in the Series Endocrinology: "IGFs: Local Repair and Survival Factors Throughout the Lifespan"

Hormones related to insulin, the Insulin–like Growth Factors (IGFs) are best known for regulating growth and metabolism. In recent years, however, they and their related binding proteins have been found to have a large range of activities throughout life, from embryonic development to ageing and, perhaps most significantly, in cancer. In many of these "˜alternative´ actions, IGFs act locally rather than throughout the body. To ensure the specific targeting of a particular action to the correct tissues, a complex system of regulation has evolved to maintain a delicate balance between promoting healthy ageing and the run–away proliferation that characterises cancer. The latest findings on these sophisticated control mechanisms, in animals ranging from nematode worms and flies to humans, and their potential clinical applications, were discussed by twelve leading scientists at the eighth Colloque Médecine et Recherche of La Fondation Ipsen devoted to Endocrinology, that has been held in Paris on December 1, 2008. The meeting has been organised by David Clemmons (University of North Carolina, Chapel Hill, USA), Iain Robinson (National Institute for Medical Research, London, UK) and Yves Christen (La Fondation IPSEN, Paris, France).

The more recently discovered roles of IGF include, in adults, the regulation of cell proliferation and survival, tissue repair and remodelling and, in the embryo, maturation and growth (Robinson). The regulation required to keep this complex of functions in check includes a set of binding proteins, known as IGFBP 1–6, which transport IGF in the blood circulation as well as modulating its availability, presenting it to the IGF receptor and inactivating it, according to circumstance. In addition, the binding proteins have actions that are independent of IGF. To complicate matters further, IGF can also bind to the insulin receptor - a particular problem for the design of IGF receptor inhibitors for use as anti–tumour agents. Investigation of the intracellular and intercellular signalling pathways associated with these molecules is providing leads to new therapeutics for a range of clinical problems, including the possibility in future of finding ways of preventing tumours developing (Derek LeRoith, Mount Sinai School of Medicine, New York, USA).

In adults, IGF stimulates cell proliferation and migration after tissue damage but the outcome is not always beneficial. The arteries of diabetic patients are more prone to develop atherosclerotic plaques than non–diabetics as a result of hyperglycaemia stimulating a signalling pathway that leads to local release of IGF. A monoclonal antibody that blocks one step of this signalling pathway may lead to a new way of treating this problem (Clemmons). Similarly the atrophy of skeletal muscle through disease or lack of use seems to be initiated by IGF binding to its receptor, resulting in stimulation of the production of a molecule that destroys contractile proteins (David Glass, Novartis, Cambridge, USA).

During brain development, IGF acting on the IGF receptor is essential for the proliferation of neuron progenitors, and for increasing the survival and promoting the differentiation of neurons and oligodendrocytes, including support for synaptogenesis and myelination. In mice with reduced numbers of IGF receptors, overall brain development is substantially reduced but the hippocampus is particularly affected (Joseph D´Ercole, University of North Carolina, Chapel Hill, USA). IGF and its receptors also have a role in the health of the adult brain (Martin Holzenberger, Inserm UMR 893, Hôpital Saint Antoine, Paris, France). Haematopoietic stem cells, the precursors of red and most white blood cells, can be stimulated to multiply in culture by addition of IGF binding protein 2 to the growth medium - a possibly invaluable tool for producing sufficient stem cells for transplantation (Cheng Cheng Zhang, University of Texas Southwestern Medical Center, Dallas, USA).

Insulin production and sensitivity is known to decrease with age, sometimes resulting in type 2 diabetes or contributing to the development of Alzheimer´s disease. IGF has recently been shown to act in the hypothalamus to increase the sensitivity of liver cells to insulin, whereas the IGF binding protein 3 increases insulin resistance. Analogues of an intermediary molecule in the IGFBP–3 pathway may be an effective way of treating type 2 diabetes (Nir Barzilai, Albert Einstein College of Medicine, Bronx, USA). Insulin resistance and hyperglycaemia accelerate ageing and tumour growth and IGF signalling is elevated in various cancers, whereas extended lifespan seems to correlate with reduced IGF (LeRoith). In the nematode worm, Caenorhabditis elegans, an insulin–like secretion pathway is important for longer life, in part by switching the animal into a state of suspended animation, or diapause, when conditions get tough; many components of this pathway are being identified by gene screens (Gary Ruvkun, Massachusetts General Hospital, Boston, USA).

The multiplicity of actions of IGF and the IGFBPs poses a problem for attempts to increase lifespan by targeting these signalling pathways, because enhancing on function may well have deleterious, even disastrous side effects. This is where the tools of gene manipulation in animals such as fruit flies and mice can provide useful insights (Linda Partridge, University College London, London, UK; Clifford Rosen, The Jackson Laboratory, Bar Harbor, USA).

IGF and its signalling molecules are now known to be involved in the growth of tumours. In many cancers, a high level of the IGF binding protein 3 are found, which seems to promote rapid tumour growth by potentiating the stimulation of the epithelial growth factor receptor, also often present in abnormally high concentration. Although this action is independent of IGF, the IGFBP can also potentiate the activation of the IGF1 receptor in tumours. Some of the essential steps in this pathway are being identified and may provide targets for new therapeutic molecules for some cancers (Robert Baxter, University of Sydney, Sydney, Australia).

The message that seems to be emerging from these recent studies is that regulation of IGF is a complex phenomenon which justifies, from a therapeutic point of view, to modulate its signalling pathway, according to the physiological situation, in enhancing (in case of deficiency) or inhibiting (in case of excess) its function.

La Fondation Ipsen

Established in 1983 under the aegis of the Fondation de France, the mission of La Fondation Ipsen is to contribute to the development and dissemination of scientific knowledge. The long–standing action of La Fondation Ipsen is aimed at furthering the interaction between researchers and clinical practitioners, which is indispensable due to the extreme specialisation of these professions. The ambition of La Fondation Ipsen is not to offer definitive knowledge, but to initiate a reflection about the major scientific issues of the forthcoming years. It has developed an important international network of scientific experts who meet regularly at meetings known as Colloques Médecine et Recherche, dedicated to six main themes: Alzheimer´s disease, neurosciences, longevity, endocrinology, the vascular system and cancer science. In 2007, La Fondation Ipsen started three new series of meetings. The first is in partnership with the Salk Institute and Nature and is an annual meeting which focuses on aspects of Biological Complexity; the second is the "Emergence and Convergence" series with Nature, and the third is with Cell and the Massachusetts General Hospital entitled "Exciting Biologies". Since its beginning, La Fondation Ipsen has organised more than 100 international conferences, published 67 volumes with renowned publishers and more than 200 issues of a widely distributed newsletter Alzheimer Actualités. It has also awarded more than 100 prizes and grants.