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Médecine et santé

Cancer: on the track of the MET oncogene

 
 
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After 24 hours' incubation, the Hepatocyte Growth Factor (HGF) provokes a 'scattering' of the epithelial cells (right).

It is relatively easy to treat an isolated tumour, but the task becomes more complicated once metastases have formed. This proliferation process is linked to the presence of the MET gene, which plays a major role in encoding the growth factor receptors for cancer cells. A European network is combining biochemical, molecular and cellular approaches to develop molecules capable of misleading the receptor and thereby preventing the spread of the cancer.

     

Cancer remains a mysterious disease, because it strikes at the heart of life itself: the ability of cells to divide into two identical daughter cells. In a healthy organism, this cell division allows tissue growth and renewal. Sometimes, however, the process gets out of control and cells divide again and again to form a tumour. The tumour then attracts new blood vessels so that it can grow. Once the disease also gains control of movement of the cells and their adhesion to neighbouring cells, the tumours form metastases which spread the cancer throughout the organism. One of the greatest advances in cell biology over the last two years has been identification of some of the molecules controlling these various stages, particularly the growth factors (proteins) which link up with receptors on the cell surface to activate the cell programmes. Blocking activation of growth factor receptors is therefore a promising approach to prevent the deregulation of the cell mechanism which causes cancer. This strategy is being applied to a growth factor secreted by cells in the liver - HGF (Hepatocyte Growth Factor) - by a research network headed by Paolo Comoglio from the Institute for Cancer Research in Turin (Italy) and supported by the European Commission.

A new oncogene

'Our objective is to use genetic engineering to design small molecules which block the action of the growth factors on their receptor and then to produce them in large enough quantities to test their anti-cancer effect first on cell cultures and then on mice' explains Paolo Comoglio. Such a project requires a mix of skills which have been brought together in this network: from protein biochemistry (Ermanno Gherardi's team at Cambridge University) to the molecular biology of their genes (Walter Birchmeier at the Max Delbruck Centre for Molecular Medicine in Germany), not forgetting cell biology (Max Burger at the Friedrich Miescher Institute in Basel, Switzerland, in collaboration with Paolo Comoglio's team). Both the scale and the objectives of the project call for an industrial partner, in this case the Italian company Dompé SpA from L'Aquila, with which Paolo Comoglio's team is already collaborating on the development of a derivative of HGF to treat the secondary effects of therapy.

Why choose HGF? First, because of its multiple roles in cells. As Walter Birchmeier and Ermanno Gherardi explain: 'HGF was "discovered" several times independently because of its action on epithelial cell movements, as growth factor in the liver, as epithelial morphogene, as tumour growth inhibitor and, finally, as chemoattractant for motor neurons.' All these physiological actions entail linking with the MET receptor which is then activated and triggers an 'invasive growth' programme, typified by longer cell life and the appearance of cell mobility. The cells detach from the matrix to which they adhere and arrange themselves into tube form. The second reason for choosing HGF as the research topic is that earlier work had found that the MET gene is over-expressed or amplified in certain cancers of the stomach, intestine and thyroid. Mutation of this gene is involved in certain hereditary forms of renal cancer: MET is a member of the oncogene family, the genes which, on mutation, cause cancer.

Targeting on an intracellular loop

But how can we be sure that this MET dysfunction observed in human cancers is indeed the cause of the disease and not one of its more or less direct consequences? This is where the expertise of Paolo Comoglio's team comes in. In 1997 they demonstrated that mutation of the homologue of MET in mice made cancer cells non-metastatic. After further research they discovered that a small domain, designated SH2, on the intra-cellular side of the MET receptor was solely responsible for its metastatic properties. Then the network used the latest biosensor and crystallography technology to take a look at the interaction between the receptor and SH2. The next task is to design small molecules capable of bonding with SH2, a little like making a key to fit a lock. Once the efficacy of these medicines of the future has been established on cell cultures, different methods of administration will be tested on mice. In the longer term, gene therapy could deliver these molecules straight to the site of the tumour.

Four candidates for the same strategy

In the future, the network plans to extend its approach to other growth factors derived from different organs: blood vessels (Vascular Endothelial Growth Factor or VEGF), blood platelets (Platelet-Derived Growth Factor or PDGF) and epithelial tissues (Epithelial Growth Factor or EGF). Like HGF, they are all notorious for their roles in certain human cancers, albeit at different stages: VEGF, for example, plays a role in the growth of blood vessels which nourish tumours, while EGF is involved in predisposition to certain cancers of viral or chemical origin. By applying the same strategy to these four molecules, the network expects to discover a panoply of medicinal products which will act hand in hand against the various forms of deregulation observed in cancer cells.

 
Title
Control of metastatic growth by the c-MET oncogene

Reference
BMH4-CT983852

Programme
Biomed

Contact
Paolo Comoglio
Institute for Cancer Research
Turin University
E-mail: pcomoglio@ircc.unito.it

Partners
- Max Delbruck Centre for Molecular Medicine, Berlin, Germany
- University of Cambridge, Cambridge, United Kingdom
- Friedrich Miescher Institute, Basel, Switzerland
- Dompé SpA, L'Aquila, Italy

image
Once the efficacy of these medicines of the future has been established on cell cultures, different methods of administration will be tested on mice. In the longer term, gene therapy could deliver these molecules straight to the site of the tumour

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