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

Overview

MeSH

  • Animals
  • Biomarkers, Tumor
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • RNA, Small Interfering
  • Signal Transduction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

MeSH Major

  • Carcinoma
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms
  • Enteroendocrine Cells
  • Neoplastic Stem Cells
  • Receptor, Notch1

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.

publication date

  • February 15, 2010

has subject area

  • Animals
  • Biomarkers, Tumor
  • Carcinoma
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms
  • Enteroendocrine Cells
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplastic Stem Cells
  • RNA, Small Interfering
  • Receptor, Notch1
  • Signal Transduction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4010106

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-09-2557

PubMed ID

  • 20145124

Additional Document Info

start page

  • 1469

end page

  • 1478

volume

  • 70

number

  • 4