Stromal Hedgehog signalling is downregulated in colon cancer and its restoration restrains tumour growth.
Nat Commun
; 7: 12321, 2016 08 05.
Article
em En
| MEDLINE
| ID: mdl-27492255
ABSTRACT
A role for Hedgehog (Hh) signalling in the development of colorectal cancer (CRC) has been proposed. In CRC and other solid tumours, Hh ligands are upregulated; however, a specific Hh antagonist provided no benefit in a clinical trial. Here we use Hh reporter mice to show that downstream Hh activity is unexpectedly diminished in a mouse model of colitis-associated colon cancer, and that downstream Hh signalling is restricted to the stroma. Functionally, stroma-specific Hh activation in mice markedly reduces the tumour load and blocks progression of advanced neoplasms, partly via the modulation of BMP signalling and restriction of the colonic stem cell signature. By contrast, attenuated Hh signalling accelerates colonic tumourigenesis. In human CRC, downstream Hh activity is similarly reduced and canonical Hh signalling remains predominantly paracrine. Our results suggest that diminished downstream Hh signalling enhances CRC development, and that stromal Hh activation can act as a colonic tumour suppressor.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Regulação para Baixo
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Regulação Neoplásica da Expressão Gênica
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Neoplasias do Colo
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Proteínas Hedgehog
Limite:
Animals
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2016
Tipo de documento:
Article