title: DCC constrains tumour progression via its dependence receptor activity.
abstract: 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.
authors.affiliation: Apoptosis, Cancer and Development Laboratory - Equipe labellisée La Ligue, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Castets
authors.forename: Laura
authors.initials: L
authors.lastname: Broutier
authors.forename: Yann
authors.initials: Y
authors.lastname: Molin
authors.forename: Marie
authors.initials: M
authors.lastname: Brevet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Chazot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gadot
authors.forename: Armelle
authors.initials: A
authors.lastname: Paquet
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mazelin
authors.forename: Loraine
authors.initials: L
authors.lastname: Jarrosson-Wuilleme
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Agnès
authors.initials: A
authors.lastname: Bernet
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D000075389:DCC Receptor; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts; D020868:Gene Silencing; D017491:Genes, APC; D057809:HEK293 Cells; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009414:Nerve Growth Factors / Q000172:deficiency / Q000235:genetics; D000075388:Netrin-1; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; D050505:Mutant Proteins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1; D020169:Caspases