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Neuronal Guidance Protein Netrin-1 Induces Differentiation in Human Embryonal Carcinoma Cells

¹ Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, Bethesda, Maryland; ² CROM–Istituto Nazionale Tumori "Pascale" Napoli, Mercogliano (AV), Italy; and ³ Cell Biology and Preclinical Models Unit, Istituto Nazionale Tumori-Fondazione Pascale, Naples, Italy

Requests for reprints: Mario Mancino, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, 37 Convent Drive, Room 1112, Bethesda, MD 20892. Phone: 301-443-3133; Fax: 301-402-8652; E-mail: mario.mancino{at}cro-m.eu.

Key Words: Cripto-1 • embryonal carcinoma cells • Netrin-1

Pluripotent cells within embryonal carcinoma (EC) can differentiate in vivo or in vitro on treatment with specific agents. Differentiating EC cells express lower levels of stem cell–related genes, such as Cripto-1. We show that migration of human EC cells (NTERA/2 and NCCIT) can be reduced following treatment with the guidance molecule Netrin-1. Moreover, Netrin-1 treatment increased the levels of β-III tubulin, glial filament acidic protein, Nestin, and -aminobutyric acid and reduced the expressions of Cripto-1, Nanog, and Oct4 in EC cells. These Netrin-1–induced effects in the EC cells were mediated via binding of Netrin-1 to the Neogenin receptor and activation of SHP-2, resulting in increased levels of inactive phosphorylated c-src^(Y527). These results suggest that Netrin-1 can induce neuroectodermal-like differentiation of human EC cells by affecting c-src signaling via SHP-2 activation and regulation of Nanog, Oct4, and Cripto-1 expressions. [Cancer Res 2009;69(5):1717–21]