Molecular and Cellular Pathobiology Notch Signaling in CD66þ Cells Drives the Progression of Human Cervical Cancers

Human epithelial tumor progression and metastasis involve cellular invasion, dissemination in the vasculature, and regrowth at metastatic sites. Notch signaling has been implicated in metastatic progression but its roles have yet to be fully understood. Here we report the important role of Notch signaling in maintaining cells expressing the carcinoembryonic antigen cell adhesion molecule CEACAM (CD66), a known mediator of metastasis. CD66 and Notch1 were studied in clinical specimens and explants of human cervical cancer, including specimens grown in a pathophysiologically relevant murine model. Gene expression profiling of CD66þ cells from primary tumors showed enhanced features of Notch signaling, metastasis, and stemness. Significant differences were also seen in invasion, colony formation, and tumor forming efficiency between CD66þ and CD66 cancer cells. Notably, CD66þ cells showed a marked sensitivity to a Notch small molecule inhibitor. In support of studies in established cell lines, we documented the emergence of a tumorigenic CD66þ cell subset within a metastatic lesion-derived cervical-cancer cell line. Similar to primary cancers, CD66 expression in the cell line was blocked by chemical and genetic inhibitors of ligand-dependent nuclear Notch signaling. Collectively, our work on the oncogenic properties of CD66þ cells in epithelial cancers provides insights into the nature of tumor progression and offers a mechanistic rationale to inhibit the Notch signaling pathway as a generalized therapeutic strategy to treat metastatic cancers. Cancer Res; 71(14); 1–10. 2011 AACR.