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NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.

ABSTRACT: NOTCH signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that NOTCH is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of NOTCH 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 NOTCH 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 NOTCH prevents CCIC apoptosis through repression of cell cycle kinase inhibitor p27 and transcription factor ATOH1. NOTCH is also critical to intrinsic maintenance of CCIC self-renewal and the repression of secretory cell lineage differentiation genes such as MUC2. Our findings describe a novel human cell system to study NOTCH signaling in CRC tumor initiation and suggest that inhibition of NOTCH signaling may improve CRC chemoprevention and chemotherapy.

SUBMITTER: Sikandar SS

PROVIDER: S-EPMC4010106 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.

Sikandar Shaheen S SS Pate Kira T KT Anderson Scott S Dizon Diana D Edwards Robert A RA Waterman Marian L ML Lipkin Steven M SM

Cancer research 20100209 4

NOTCH signaling is critical for specifying the intestinal epithelial cell lineage and for initiating colorectal adenomas and colorectal cancers (CRC). Based on evidence that NOTCH is important for the maintenance and self-renewal of cancer-initiating cells in other malignancies, we studied the role of NOTCH 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 polar ...[more]

PMID: 20145124

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Project description:In the past few years, mammary cancer initiating cells (CICs) have been identified in mouse and human as a subpopulation of tumor cells that selectively posses tumor initiation and self-renewal capacity and the ability to give rise to bulk populations of non-tumorigenic cancer cells progeny through differentiation. They could also be responsible for tumor progression, metastasis, resistance to therapy and recurrence. Thus, the understanding of the pathways regulating CIC self-renewal, differentiation and tumorigenicity represents an important task in the development of effective anticancer therapies. To detect the set of genes associated to CIC in our mouse breast cancer model we analysed three prototypic situations: TUBO cells grown in DMEM under adherent conditions (called TDA in GSE26517 and epithelial bulk in GSE21451), TUBO cells grown in mammosphere medium under adherent conditions (called TMA in GSE26517), TUBO cells grown in mammosphere medium under low-attachment conditions (called mammospheres p1 in GSE21451), i.e. the conditions used to support the formation of mammospheres. This analysis led to the identification of growth factors and immune system-related genes, including toll-like receptor 2 (TLR2). The inhibition of TLR2 signaling pathway strongly impaired mammosphere generation, demonstrating the involvement of TLR2 in CSC self-renewal. We profiled on MouseWG?6 v2.0 Illumina beadchips two independent experiments: ADHERENT (GSE26517) made by the comparison between TDA and TMA and SOSPENSION (part of GSE21451) made by the comparison between epithelial bulk and mammospheres p1. Mammosphere medium contains epidermal growth factor (EGF), insulin and basic fibroblast growth factor (bFGF) that may influence transcript expression in a way not necessarily related to the assembly of mammospheres. Therefore, following normalization and removal of those transcripts not expressed and not changing, we used the Integrative Correlation coefficient (IC, Parmigiani et al. Clin Cancer Res 2004, 10:2922–2927) as filter to remove genes only associate to growth factors present in the mammosphere medium under adherent growth conditions, i.e IC > 0.1. Differential gene expression was then assessed by regularized t?test (Smyth GK. Stat Appl Genet Mol Biol 2004, 3:Article3) comparing mammospheres p1 with respect to epithelial bulk, using an uncorrected p-value ? 0.05, together with an absolute log2 fold change threshold ?1.

Dataset Information

NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.

Publications

NOTCH signaling is required for formation and self-renewal of tumor-initiating cells and for repression of secretory cell differentiation in colon cancer.

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