Publication Date:
2011-12-14
Description:
The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. 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. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Castets, Marie -- Broutier, Laura -- Molin, Yann -- Brevet, Marie -- Chazot, Guillaume -- Gadot, Nicolas -- Paquet, Armelle -- Mazelin, Laetitia -- Jarrosson-Wuilleme, Loraine -- Scoazec, Jean-Yves -- Bernet, Agnes -- Mehlen, Patrick -- England -- Nature. 2011 Dec 11;482(7386):534-7. doi: 10.1038/nature10708.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Apoptosis, Cancer and Development Laboratory - Equipe labellisee La Ligue, LabEx DEVweCAN, Centre de Cancerologie de Lyon, INSERM U1052-CNRS UMR5286, Universite de Lyon, Centre Leon Berard, 69008 Lyon, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158121" target="_blank"〉PubMed〈/a〉
Keywords:
Adenocarcinoma/genetics/pathology
;
Animals
;
Apoptosis/genetics
;
Caspases/metabolism
;
Cells, Cultured
;
Disease Models, Animal
;
*Disease Progression
;
Fibroblasts
;
Gene Silencing
;
Genes, APC
;
HEK293 Cells
;
Humans
;
Intestinal Neoplasms/*genetics/metabolism/*pathology
;
Mice
;
Mutant Proteins/genetics/metabolism
;
Mutation
;
Nerve Growth Factors/deficiency/genetics
;
Receptors, Cell Surface/deficiency/genetics/*metabolism
;
Tumor Suppressor Proteins/deficiency/genetics/*metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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