Netrin-1 and its receptors have been proposed to have a profound impact on colorectal tumour progression by two complementary events. One event involves the loss of netrin-1 receptors that are frequently observed in human colorectal cancer. Netrin-1 receptors function as dependence receptors which can induce apoptosis in the absence of ligand binding, but elicit cell survival in the presence of ligand binding. Hence, loss of netrin-1 receptors on tumour cells represents the loss of the dependence receptors capable of mediating apoptosis, resulting in enhanced tumour cell survival (Castets et al., 2012). The second event involves overexpression of netrin-1, which acts as a cell survival factor. Consequently this overexpression confers a selective advantage for tumour cells to become metastatic cancer cells (Krimpenfort et al., 2012). Although a correlation between netrin‑1 and metastasis has been reported, issues concerning the effect of netrin-1 on fundamental tumour cell biology have not been properly assessed. In this study, we investigated the effect of netrin-1 in both murine and human colorectal cancer cells using various metastatic parameter assays including those for proliferation, adhesion, migration, invasion and colony formation assays. A high concentration of netrin-1 (200 ng/ml) inhibited murine CT26 cell migration but not proliferation. However, no significant effect of netrin-1 was observed in human HT29 cells with respect to both cell proliferation and migration, though netrin-1 enhanced cell adhesion in a dose-dependent manner. Furthermore, significant reduction in colony formation was observed in both cell types, particularly at a physiological dose of netrin-1, 50 ng/ml. Collectively, our in vitro studies suggest that netrin-1 does not appear to be positively linked to malignant morphological processes.
Castets M, Broutier L, Molin Y, Brevet M, et al. 2012. Nature advance online publication
Krimpenfort P, Song J-Y, Proost N, Zevenhoven J, Jonkers J, Berns A. 2012. Nature 482: 538-41