Sci. STKE, 7 September 2004
ONCOGENESIS Dying to Get Out of the Crypt
Initially identified as a diffusible protein that guides axonal migration, netrin-1 has more recently been suggested to also function as a survival factor that inhibits the initiation of apoptotic pathways (see Fearon and Cho). Mazelin et al. investigated the possibility that, by acting as a dependence receptor, the netrin-1 receptor DCC (deleted in colorectal cancer) functions as a tumor suppressor. The authors used in situ hybridization and immunohistochemistry to show that, in the mouse colon and small intestine, netrin-1 mRNA and protein were localized to the bases of epithelial crypts (a site of cell proliferation) rather than villus tips (where cells die and are shed). DCC, however, was located throughout the epithelium. In transgenic mice that overexpressed gastrointestinal (GI) netrin-1, in which it was found throughout the epithelium, there was a 50% reduction in the number of apoptotic GI epithelial cells compared to that in wild-type mice, whereas cell proliferation and differentiation appeared unchanged. In contrast, mice lacking netrin-1 showed increased cell death. Moreover, 17% of the netrin-1-overexpressing mice (and none of the wild-type mice) developed GI adenomas. When netrin-1 overexpression was combined with a mutation in adenomatous polyposis coli (APC, which itself triggers the development of low-grade adenomas), 40% of the mice developed high-grade adenomas and half of those developed adenocarcinomas. Thus, the authors propose that a gradient of netrin-1 within intestinal crypts may normally lead to the death of cells at the villus tip and loss of DCC may promote colorectal cancer by eliminating the dependence of cell survival on the presence of netrin-1.
L. Mazelin, A. Bernet, C. Bonod-Bidaud, L. Pays, S. Arnaud, C. Gespach, D. E. Bredesen, J. Y. Scoazec, P. Mehlen, Netrin-1 controls colorectal tumorigenesis by regulating apoptosis. Nature 431, 80-84 (2004). [Online Journal]
E. R. Fearon, K. R. Cho, Cell survival guide. Nature 431, 35-36 (2004). [Online Journal]
Citation: Dying to Get Out of the Crypt. Sci. STKE 2004, tw315 (2004).
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