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Other version: http://onlinelibrary.wiley.com/store/10.1002/emmm.201000098/asset/440_ftp.pdf?v=1&t=h1qifni2&s=5f1bc3246a1c77afe7711d...
Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas
|Published in||EMBO Molecular Medicine. 2010, vol. 2, no. 11, p. 440-457|
|Abstract||Previous studies demonstrate the initiation of colon cancers through deregulation of WNT-TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain WNT-TCF-dependent, prompting the search for WNT-TCF inhibitors. CCs and their stem cells also require Hedgehog (HH)-GLI1 activity, but how these pathways interact is unclear. Here we define coincident high-to-low WNT-TCF and low-to-high HH-GLI transitions in patient CCs, most strikingly in their CD133(+) stem cells, that mark the development of metastases. We find that enhanced HH-GLI mimics this transition, driving also an embryonic stem (ES)-like stemness signature and that GLI1 can be regulated by multiple CC oncogenes. The data support a model in which the metastatic transition involves the acquisition or enhancement of a more primitive ES-like phenotype, and the downregulation of the early WNT-TCF programme, driven by oncogene-regulated high GLI1 activity. Consistently, TCF blockade does not generally inhibit tumour growth; instead, it, like enhanced HH-GLI, promotes metastatic growth in vivo. Treatments for metastatic disease should therefore block HH-GLI1 but not WNT-TCF activities.|
|Keywords||Antigens, CD/analysis — Carcinoma/pathology/*physiopathology — Colonic Neoplasms/pathology/*physiopathology — Gene Expression Profiling — Glycoproteins/analysis — Hedgehog Proteins/*metabolism — Humans — Neoplasm Metastasis/pathology/*physiopathology — Peptides/analysis — Stem Cells — TCF Transcription Factors/*metabolism — Transcription Factors/*metabolism — Wnt Proteins/*metabolism|
|VARNAT, Frédéric et al. Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. In: EMBO Molecular Medicine, 2010, vol. 2, n° 11, p. 440-457. https://archive-ouverte.unige.ch/unige:21368|