Editors' ChoiceCancer

Notching Up Tumor Progression

Sci. Signal.  06 May 2008:
Vol. 1, Issue 18, pp. ec163
DOI: 10.1126/stke.118ec163

Hypoxia is associated with tumor progression and may contribute to epithelial-mesenchymal transition (EMT), a process in which epithelial cells become motile and invasive. In tumors, EMT may represent the initial stages of metastasis. Sahlgren et al. found that hypoxia enhanced activation of a Notch reporter in tumor cell lines cocultured with cells expressing the Notch ligand Jagged1 and enhanced ligand-dependent expression of Notch target genes. Hypoxia increased Notch activation [abundance of the Notch 1 intracellular domain (N1ICD)] in SKOV-3 ovarian tumor cells and also increased expression of the mRNA and protein of the Notch ligand Delta-like 1. Hypoxic conditions stimulated morphologic changes and decreased E-cadherin mRNA and protein in SKOV-3 cells, phenotypic changes characteristic of EMT that were blocked by a γ-secretase inhibitor (GSI, to prevent release of N1ICD) or transfection with dominant-negative components of the Notch pathway. In contrast, exposure to Jagged-1 under normoxic conditions promoted morphologic changes similar to those seen in hypoxia, and introduction of N1ICD decreased E-cadherin abundance. Hypoxia stimulated recruitment of the N1ICD to the promoter of Snail-1, which encodes a transcription factor implicated in the EMT; moreover, introduction of N1ICD increased Snail-1 expression, whereas GSI inhibited an increase in Snail-1 mRNA in response to hypoxia. Further, Notch signaling enhanced the hypoxia-dependent recruitment of hypoxia-inducible factor-1α (HIF-1α) to the promoter of lysyl oxidase (LOX, which encodes a protein that increases Snail-1 stability) and the hypoxia-dependent stimulation of LOX expression. GSI inhibited the promotion of SKOV-3 cell migration by hypoxia in a wound-healing assay and inhibited their migration across a membrane in an assay of invasion. The authors thus propose that Notch signaling plays a critical role in initiating EMT in response to tumor cell hypoxia.

C. Sahlgren, M. V. Gustafsson, S. Jin, L. Poellinger, U. Lendahl, Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl. Acad. Sci. U.S.A. 105, 6392-6397 (2008). [Abstract] [Full Text]