Data from <i>NOTCH</i> Signaling Is Required for Formation and Self-Renewal of Tumor-Initiating Cells and for Repression of Secretory Cell Differentiation in Colon Cancer

Abstract

<div>Abstract<p><i>NOTCH</i> signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that <i>NOTCH</i> is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of <i>NOTCH</i> signaling in colon cancer–initiating cells (CCIC). Tumors formed by CCICs maintain many properties of the primary CRCs from which they were derived, such as glandular organization, cell polarity, gap junctions, and expression of characteristic CRC molecular markers. Furthermore, CCICs have the property of self-renewal. In this study, we show that <i>NOTCH</i> signaling is 10- to 30-fold higher in CCIC compared with widely used colon cancer cell lines. Using small-molecule inhibition and short hairpin RNA knockdown, we show that <i>NOTCH</i> prevents CCIC apoptosis through repression of cell cycle kinase inhibitor <i>p27</i> and transcription factor <i>ATOH1. NOTCH</i> is also critical to intrinsic maintenance of CCIC self-renewal and the repression of secretory cell lineage differentiation genes such as <i>MUC2</i>. Our findings describe a novel human cell system to study <i>NOTCH</i> signaling in CRC tumor initiation and suggest that inhibition of <i>NOTCH</i> signaling may improve CRC chemoprevention and chemotherapy. Cancer Res; 70(4); 1469–78</p></div>