Academic Journal
Main Category: Colorectal Cancer
Also Included In: Cancer / Oncology; Genetics
Article Date: 15 Dec 2011 - 6:00 PST
email to a friend 
printer friendly 
opinions 
A research team in France has bred a lab mouse with a gene mutation that allows colorectal cancer tumors to grow because the protein coded by the gene is no longer able to trigger cell suicide ("apoptosis"). They hope their discovery will pave the way for developing a treatment that targets the gene so it reactivates apoptosis in cancer cells. They write about their findings in a letter published online on 11 December in the journal Nature.
The team has been working for some time in trying to understand more about cell death, and apoptosis in particular. Once activatived, the mechanism sets the cell onto a self-destruct path. The team's leader is Patrick Mehlen, Director of the DEVweCAN 'Laboratory of Excellence' at the Lyon Cancer Research Centre at the Université de Lyon, Centre Léon Bérard.
For the past 15 years, researchers in this field have been debating about the tumor-suppressing ability of a gene called DCC which in humans codes for a receptor protein known as Deleted in Colorectal Carcinoma. Receptor proteins sit on the surfaces of cells and are receptive to "ligands", special molecules that engage with them and change their behavior, such as activating or silencing signals that do things like control processes inside the cell.
We already know from previous research that DCC expression is either lost or significantly reduced in the majority of advanced colorectal cancers. We also know, that the DCC receptor triggers apoptosis, unless engaged to its ligand, netrin-1.
Mehlen and colleagues proposed that the receptors act like sentinels on the surface of the cells: these sentinels are constantly looking at what is happening in their environment, which is why they are also called "dependence receptors".
While the ligand is engaged, the DCC receptor protein sends out a signal that "all is well", and so does not activate cell death, and the cell survives. But when the ligand is not there, the receptor effectively interprets this as "all is not well", and releases the cell-death trigger.
When you apply this sentinel idea to cancer cells, then it would suggest that the absence of ligands causes the DCC receptors to signal "all is not well", and so set the cells on a path of self-destruction, thus causing the death of rogue cells that would otherwise grow into a tumor.
But, as Mehlen and colleagues point out in their Nature paper, until now, no animal tests have been able to support the idea that this side of DCC is a cause of aggressive cancer development.
So, to investigate the role that DCC-triggered apoptosis might play in the control of tumor development, they used mice already genetically predisposed to develop colon cancer (they have a particular variant of the APC gene), and further modified them so they carried a mutation of DCC whose apoptosis trigger is silent.
They found that the mice spontaneously developed colon cancer.
Mehlen and colleagues describe their findings in the Nature letter:
"Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas."
They conclude that these results show that DCC behaves as a tumor suppressor in that it has the ability to trigger apoptosis in cancer cells.
Mehlen told the press:
"The organism is naturally protected from the development of cancers thanks to the presence of this tumour-suppressing gene."
But, unfortunately, there are some cancer cells that manage to escape this control by blocking the dependence receptor mechanism of DCC.
"That is how we know that the DCC gene is extinguished in most human cancers,' he explained.
The researchers hope it won't be long before this work leads to new target treatments that reactivate cell death in cancer cells. This could apply to other cancers too, such as breast and lung cancer.
"Our group has developed several candidate drugs that reactivate the cell death induced by the DCC receptor in animal models, and we hope to be able to carry out human clinical testing of these candidate drugs in three years' time," said Mehlen.
Mehlen has just been awarded Liliane Bettencourt Schueller Life Sciences Prize, which will help to fund his work.
Written by Catharine Paddock PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today
Additional source: INSERM Please use one of the following formats to cite this article in your essay, paper or report:
MLA
15 Dec. 2011.
Please note: If no author information is provided, the source is cited instead.
Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.
If you write about specific medications or operations, please do not name health care professionals by name.
All opinions are moderated before being included (to stop spam)
Contact Our News Editors
For any corrections of factual information, or to contact the editors please use our feedback form.
Please send any medical news or health news press releases to:
Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.
