Wnt signalling is a bi-directional vulnerability of cancer cells.
Oncotarget
; 7(37): 60310-60331, 2016 Sep 13.
Article
em En
| MEDLINE
| ID: mdl-27531891
ABSTRACT
Wnt signalling is involved in the formation, metastasis and relapse of a wide array of cancers. However, there is ongoing debate as to whether activation or inhibition of the pathway holds the most promise as a therapeutic treatment for cancer, with conflicting evidence from a variety of tumour types. We show that Wnt/ß-catenin signalling is a bi-directional vulnerability of neuroblastoma, malignant melanoma and colorectal cancer, with hyper-activation or repression of the pathway both representing a promising therapeutic strategy, even within the same cancer type. Hyper-activation directs cancer cells to undergo apoptosis, even in cells oncogenically driven by ß-catenin. Wnt inhibition blocks proliferation of cancer cells and promotes neuroblastoma differentiation. Wnt and retinoic acid co-treatments synergise, representing a promising combination treatment for MYCN-amplified neuroblastoma. Additionally, we report novel cross-talks between MYCN and ß-catenin signalling, which repress normal ß-catenin mediated transcriptional regulation. A ß-catenin target gene signature could predict patient outcome, as could the expression level of its DNA binding partners, the TCF/LEFs. This ß-catenin signature provides a tool to identify neuroblastoma patients likely to benefit from Wnt-directed therapy. Taken together, we show that Wnt/ß-catenin signalling is a bi-directional vulnerability of a number of cancer entities, and potentially a more broadly conserved feature of malignant cells.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Beta Catenina
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Via de Sinalização Wnt
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Proteína Proto-Oncogênica N-Myc
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Neuroblastoma
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Irlanda