Taking Cancer Up (and Down) a Notch

Abstract

The Notch signaling pathway is aberrantly activated in several forms of human cancer, an observation that has triggered interest in the development of Notch inhibitors as possible cancer therapies. A new study reveals that in a mouse model of colon cancer, Notch signaling contributes to cancer development by promoting tumor invasion and metastasis. Sonoshita et al. investigated the function of a gene called Aes, whose expression is greatly reduced in liver metastases versus primary tumors, and found that its protein product, a transcriptional regulator, represses Notch signaling. Aes-deficient, tumor-prone mice showed more evidence of local tumor invasion than control mice, and in vitro assays indicated that loss of this gene enhances the ability of tumor cells to migrate across the endothelial lining of blood vessels—a key step in metastasis. Consistent with these findings, administration of a compound that inhibits Notch signaling to mice bearing primary colon tumors suppressed the formation of liver metastases. As is true for all therapies that target signaling pathways with complex functional roles, translation to the clinic will require careful preclinical studies to assess side effects. Highlighting the need for caution is a recent independent study by Liu et al., who found that genetic inactivation of one copy of the Notch1 receptor gene resulted in the formation of benign vascular tumors, which in some cases caused fatal hemorrhaging.