A microRNA-operated switch of asymmetric-to-symmetric cancer stem cell divisions

Abstract

Defective asymmetric cell divisions of stem and progenitor cells are associated with tumorigenesis by a largely unknown mechanism. A signalling axis involving Snail, microRNA-146a and Numb is now shown to regulate the switch between symmetric and asymmetric cell division in colorectal cancer stem cells.

Figure 1

Cell division modes used by cancer stem cells and their regulation in colorectal cancer. (a) Colorectal cancer stem cells (CRCSCs) undergo symmetric self-renewing divisions giving rise to two self-renewing daughter cells (red). The red curved arrows indicate self-renewal. (b) CRCSCs also undergo asymmetric self-sustaining divisions by localizing cell fate determinants with opposite functions (red and blue crescents) to opposite poles, thereby generating one self-renewing (red) and one differentiating (blue) daughter cell. (c) Symmetric differentiating divisions can also be induced in non-CSC colorectal cancer cells (blue); for example, by the presence of miR-34a (ref. 12). (d) Model of integrated regulation of cell division mode, tumour progression and metastasis. Left: miRNA-regulated Wnt and Notch signalling promotes symmetric self-renewing cell divisions of intestinal stem cells at the bottom of intestinal crypts. In non-neoplastic stem cells and CRCSCs from early tumour stages, Snail expression is low or absent, whereas Numb expression is high, leading to proteasomal degradation of β-catenin (β-cat) and attenuation of Wnt signalling. As a result, intestinal stem cells and early-stage CRCSCs divide asymmetrically. Right: Hwang et al. propose a positive feedback mechanism in late tumorigenesis, whereby the Snail-dependent action of nuclear β-catenin (β-catⁿ) and TCF4 induces miR-146a expression and the subsequent downregulation of Numb. This relieves the Numb-mediated degradation of β-catenin and enhances Wnt signalling, thereby increasing symmetric divisions and maintaining the self-renewing CRCSC phenotype. The Snail–β-cat–miR-146a axis promotes tumour growth and metastasis, in part independently of the epithelial-to-mesenchymal transition (EMT).