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New tool developed to identify cancer-causing mutations
The molecular mechanisms causing 'normal' cells to turn into cancerous ones have long baffled the research community, and huge efforts have been made worldwide to solve the mystery.
When the first cancer-causing genes, or 'oncogenes', were discovered and observed to be mutated forms of normal cellular genes, it was widely believed that a single mutation was enough to cause cancer. However, subsequent scientific investigations have since shown that most cancers develop as a result of several complex mutations rather than just one.
To date, working out which of these mutation combinations lead to cancer has mostly been a trial and error exercise, but now a new tool developed by a research team from Spain and Austria could change all that. The tool, dubbed the 'Multi-Hit' mouse, can identify which mutations really do collaborate to cause cancer.
The Multi-Hit mouse is presented in a new study, published in the journal Nature Methods. The research was supported in part by a European Research Council (ERC) grant to one of the study authors, Josef Martin Penninger from the University of Veterinary Medicine, Vienna.
The team analysed the Cre-recombinase, a tyrosine recombinase enzyme derived from the P1 bacteriophage (a virus that infects bacteria). They generated random combinations of correctly and incorrectly oriented oncogenes and investigated which combinations led to the development of tumours and which didn't.
They then tested their system on the well-known Ras protein, which has been shown to be mutated in many different cancers.
Ras mutations were once thought to only cause cancer if the so-called Raf gene was also mutated, but more recently it has been suggested that changes in other genes may also combine with mutated Ras proteins to trigger the development of a tumour. Such genes are those encoding the RalGEF (Ral guanine nucleotide exchange factor), MAPK (mitogen-activated protein kinase) or PI3K (phosphatidylinositol-3-kinase) proteins.
The researchers' results show that mutations in Ras alone do not cause tumours to develop. Following random activation of the Cre recombinase genes, all mice used in the experiment developed cancer.
Examination of the tumours developed showed that in most of them, all three genes had been activated, although activation of the PI3K gene alone (and in very rare cases of one of the other two genes alone) could also result in cancer.
Therefore, for the types of tumour that developed the fastest (which are the most life-threatening), all three of the genes investigated were activated. This shows that all the genes contribute in some way to the development of cancer, which means that drugs targeting any or all of them could play a crucial part in treatment.
One of the study authors, Robert Eferl, based at the Medical University of Vienna, comments on the results: 'Our work on Ras has given important clues to possible therapeutic strategies. But this was really only a proof of principle. More importantly, the results show that our Multi-Hit mouse can indeed be used to study interactions between gene mutations. This should make it much easier for us to understand how cancer arises and what we can do to treat it.'
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Data Source Provider:University of Veterinary Medicine, Vienna
Document of reference:Musteanu, M. et al., 'A mouse model to identify cooperating signaling pathways in cancer', Nature Methods, 2012. doi:10.1038/nmeth.2130.
Subject index:Coordination, Cooperation,Life Sciences,Medicine, Health,Scientific Research
Programme Acronym: MS-A C , MS-E C
Record control number (RCN):34919