Netrin-1 controls colorectal tumorigenesis by regulating apoptosis

• Published in: Nature (London) Vol. 431; no. 7004; pp. 80 - 84
• Main Authors: Mazelin, Laetitia, Bernet, Agnès, Bonod-Bidaud, Christelle, Pays, Laurent, Arnaud, Ségolène, Gespach, Christian, Bredesen, Dale E, Scoazec, Jean-Yves, Mehlen, Patrick
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.09.2004; Nature Publishing; Nature Publishing Group
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenomatous Polyposis Coli - genetics; Adenomatous Polyposis Coli - metabolism; Adenomatous Polyposis Coli - pathology; Animals; Apoptosis; Biochemistry, Molecular Biology; Biological and medical sciences; Cancer; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Cells; Chickens; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Digestive system; Disease Progression; Female; Fundamental and applied biological sciences. Psychology; Gastrointestinal tract; Humanities and Social Sciences; Intestines - metabolism; Intestines - pathology; letter; Life Sciences; Male; Mice; Mice, Inbred C57BL; Molecular and cellular biology; multidisciplinary; Mutation - genetics; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Netrin-1; Proteins; RNA, Messenger - genetics; RNA, Messenger - metabolism; Rodents; Science; Science (multidisciplinary); Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - physiology; Tumors; Rectum; Digestive diseases; Intestinal disease; Tumor; Colon; Carcinogenesis; Apoptosis; Tumor suppressor gene; Biological receptor
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/nature02788

The expression of the protein DCC (deleted in colorectal cancer) is lost or markedly reduced in numerous cancers and in the majority of colorectal cancers due to loss of heterozygosity in chromosome 18q, and has therefore been proposed to be a tumour suppressor 1 . However, the rarity of mutations found in DCC, the lack of cancer predisposition of DCC mutant mice, and the presence of other tumour suppressor genes in 18q have raised doubts about the function of DCC as a tumour suppressor 2 . Unlike classical tumour suppressors, DCC has been shown to induce apoptosis conditionally: by functioning as a dependence receptor, DCC induces apoptosis unless DCC is engaged by its ligand, netrin-1 (ref. 3 ). Here we show that inhibition of cell death by enforced expression of netrin-1 in mouse gastrointestinal tract leads to the spontaneous formation of hyperplastic and neoplastic lesions. Moreover, in the adenomatous polyposis coli mutant background associated with adenoma formation, enforced expression of netrin-1 engenders aggressive adenocarcinomatous malignancies. These data demonstrate that netrin-1 can promote intestinal tumour development, probably by regulating cell survival. Thus, a netrin-1 receptor or receptors function as conditional tumour suppressors.