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  • Final Report Summary - CANCERDEGRADOME (Extracellular Proteases and the Cances Degradome: Innovative Diagnostic Markers, Therapeutic Targets and Tumour Imaging Agents)
FP6

CANCERDEGRADOME Streszczenie raportu

Project ID: 503297
Źródło dofinansowania: FP6-LIFESCIHEALTH
Kraj: United Kingdom

Final Report Summary - CANCERDEGRADOME (Extracellular Proteases and the Cances Degradome: Innovative Diagnostic Markers, Therapeutic Targets and Tumour Imaging Agents)

The project focused on genes that encode enzymes known as proteases, whose job is to cut or destroy other proteins. There has long been a connection between proteases and cancer biology, since these enzymes can endow tumour cells with the ability to invade and metastasise (spread through the body). However, we now know that proteases are involved in a host of subtle regulatory mechanisms that determine the extracellular environment, and how cells respond to their environments, and in so doing, they can control cancer cell growth and death, the formation of new blood vessels (angiogenesis) that supply the growing tumour with nutrients, and also the ability of the immune system to detect cancers. It is this set of protease genes, together with their natural inhibitors, and the proteins with which they interact, that is referred to as the degradome.

The critical defining feature of a malignant tumour is the presence of cells that have broken through tissue boundaries and penetrated into surrounding normal tissues. It has long been recognised that cellular invasion of basement membranes and connective tissue stroma involves the actions of diverse extracellular proteases from multiple enzymatic classes, including the metalloproteinases (MPs) and the serine, thiol and aspartate proteases, which can be produced either by cancer cells themselves or by neighbouring host cells. These cellular proteases also participate in the formation of new blood vessels that support the burgeoning energy demands of a rapidly growing tumour, and in the ability of cancer cells to metastasise to distant organs.

The project aimed to define new molecular targets for drug design, and to develop novel specific interventions that are based on thorough knowledge of the pathophysiological roles of target proteases and related molecules, and to understand how and when to use such therapies. The goals in molecular diagnostics were to develop molecular profiling technologies and biomarkers of disease status. The identification of new molecular diagnostic and prognostic indicators of patient risk, together with new ways to enhance visualisation of tumours in the clinic, will improve health-care delivery based on an individualised, patient-oriented approach to cancer therapy.

A major legacy of the CANCERDEGRADOME project is that we now know the full cast of proteases in humans and many other organisms. This knowledge is essential for a systems biology approach to understanding normal developmental processes, tissue repair and disease pathogenesis. The full repertoire of proteases is now set at 572 genes in humans, and one of the surprises was just how much more complex the degradomes are from mouse and rat, with 653 and 642 genes, respectively.

Looking at where the differences lie can give some interesting insights. Some genes are 100 % conserved across several species, which could suggest that their functions are indispensable. In other cases, families of genes have undergone rapid expansion via duplication and mutation. It appears that these sorts of genes encode proteins that play roles in reproduction and immunity, suggesting that they may be important in the ways that species have evolved and adapted to habitats and ecological stresses. Thus one of the new directions for degradome studies is the interface with evolutionary biology.

Bioinformatic studies also revealed the full complexity of the families of protease inhibitors and protease receptors and extracellular substrates. The interplay of these genes will continue to be unravelled in the coming years. But one major area of interest is the linkage between the degradome and genetic diseases. Genome-wide sequencing and disease-association studies have identified numerous disorders whose roots lie in defective degradome genes. More and more of these connections are being unmasked as degradome gene knockout mice are studied, and the project highlights a few examples that have emerged from the work of the CANCERDEGRADOME consortium.

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Reported by

University of East Anglia
University Plain
NR4 7TJ Norwich
United Kingdom
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