Insulin-like growth factor binding protein-5 (IGFBP-5) influences cell migration , ageing and death

These studies are part of the research programme of the Cell Biology Group

Although insulin-like growth factor-I (IGF-I) is an important survival factor implicated in the growth of tumours, it increases cell-cell adhesion and thus,  stimulates the growth of the primary tumour, but may restrict its ability to migrate (metastasise) to other tissues, where typically tumours become more aggressive. In contrast, IGFBP-5 can inhibit the effects of IGF-I and induce cell death (anti-tumour) but paradoxically it can induce de-adhesion of cells and enhance their ability to metastasise.

More recently this role of IGFBP-5 has been implicated in the wound-healing response. Epithelial cells serve a variety of functions, one of which is to act as a barrier to infection. Injury, including death of the epithelial cells, provokes a wound-healing response which results in migration of cells into the wound site in an attempt to seal the injured tissue. This process also activates the underlying cells (principally fibroblasts) to secrete collagen and fibronectin, proteins which help to plug the wound in a process known as fibrosis, a form of tissue scarring. We believe that this process is part of a primitive wound-healing mechanism which has in turn evolved out of a process of cell:cell communication which is essential for normal development of the foetus. If blood loss occurs then a more pronounced inflammatory response is initiated in which cells from the immune system are also activated. It is now apparent that chronic damage to a variety of epithelial cells leads to various fibrotic diseases but that this is the result of a relatively minor but repetitive injury which does not activate the immune system to any great extent. Instead it appears that a factor(s) produced by the injured epithelial cells stimulates the underlying collagen-producing cells, resulting in fibrosis, which progressively impairs the function of major organs such as the lungs, kidneys and liver. This repetitive stimulus to cell proliferation may also be a trigger for premature cell aging (senescence) which has recently been linked to fibrosis. This mechanism is consistent with the late-onset of fibrotic diseases, which typically occur from middle-age onwards.

Our focus centres on a protein, IGFBP-5. IGFBP-5 is highly expressed in the developing mouse embryo and plays a fundamental role in epithelial-mesenchymal interactions in the embryo (interactions which are important for correct body pattern formation).

We seek to investigate whether this role for IGFBP-5 persists in the adult as part of the wound-healing response, which, in addition to being evident in epithelial injury, may also provoke a variety of disease states including sclerosis, pulmonary fibrosis and metastasis. Evidence to support this proposal comes from the fact that IGFBP-5 is secreted by epithelial cells, and:
• induces cell death,
• induces fibrosis in the adult 
• is implicated in the process of cell aging.

We are analysing the response of cells to different forms of injury (physical, hypoxia and oxidative stress). We intend to examine the response to injury in epithelial tissues subjected to different degrees of exposure, skin (maximum exposure) and breast (minimum exposure) to determine if the responses are tissue/site-specific. We are also examining the effect of epithelial damage on the response of the underlying tissue, which contains the collagen-secreting fibroblasts. Responses include changes in cell proliferation, migration and aging, as well as expression of various genes and proteins implicated in these events. The use of confocal microscopy allows visualisation of these changes in living cells in complex reconstructions of the 3-dimensional nature of tissues. We are seeking evidence that IGFBP-5 is a pivotal initial response to epithelial injury and that, by understanding this response, we will be better prepared to deal with the consequences when this repair mechanism malfunctions in processes such as fibrosis and cell aging.