Sonic Hedgehog Promotes Tumor Cell Survival by Inhibiting CDON Pro-Apoptotic Activity

Abstract

CDON is a novel Sonic Hedgehog (SHH) dependence receptor and targeting the SHH-CDON interaction could represent an alternative therapeutic strategy for patients suffering from tumors that express high SHH levels.

Dependence Receptors and Cancer: Addiction to Trophic Ligands

“…According to the DR paradigm, a tumor, to grow independently of DR ligand presence, must silence DR-induced cell death, and the simplest way to achieve this would be to inactivate the receptor. Interestingly, not only DCC, but also more recently other DRs such as UNC5H, TrkC, and CDON, have been shown to be negatively regulated in various cancer types (6,12,13); moreover, the inactivation of DCC, UNC5H, or CDON in mice is associated with tumor progression (6,10,12). The decreased expression of DRs in various tumor types occurs either through loss-of-heterozygosity (LOH), transcriptional or epigenetic regulation (12)(13)(14)(15)(16).…”

“…Because of the current clinical failure of the Smo antagonists in solid cancers with hedgehog expression-as opposed to the clear beneficial effect in pathologies with mutations in the canonical pathway-and because of the description of a novel SHH receptor CDON as a DR (6), we have hypothesized that the effects of SHH overexpression in tumors is not simply to activate the canonical SHH pathway, but also to inhibit CDON-induced cell death. We have shown in different in vitro and in vivo models that silencing of SHH or systemic delivery of a recombinant protein interfering with SHH-CDON interaction (TRAP-SHH) is associated with tumor cell death in vitro and tumor growth inhibition in vivo through a mechanism dependent on CDON-induced apoptosis (6). Future clinical trials should compare whether a drug blocking SHH-CDON interaction-and thus triggering CDON-induced cell death-may be more efficient than Smo antagonists.…”

Dependence receptors and colorectal cancer

“…Even though CRCs will probably not be the most obvious indication as the loss of netrin-1 receptors appears to be the main selective advantage here, targeting netrin-1/receptors interaction may be of great interest in inflammatory-associated CRC 41 43. More generally, several studies have now demonstrated that in cancers overexpressing ligands of dependence receptors, that is, SHH in lung cancers, NT-3 in neuroblastoma, titration of the ligand is associated with tumour cell death in vitro and tumour growth inhibition in vivo 50 85 86. Whether these strategies may be useful in a fraction of CRC is of major interest.…”

“…It was indeed shown that the expression of CDON is silenced in a large fraction of CRC and its expression is significantly inversely correlated with tumour grade. Moreover, CDON invalidation was shown to promote CRC tumour progression in mice because of a deficit of apoptosis in the intestinal epithelium 50. Thus, CDON behaves like a colorectal tumour suppressor.…”

“…Recently, it was shown that CDON, which resembles in many aspects to DCC, is also a dependence receptor50 (table 1). CDON, similarly to DCC and Ptc, is cleaved by caspase in its intracellular domain, a cleavage that allows further caspase-9 interaction and activation 50…”