Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway.
J Clin Invest
; 128(1): 402-414, 2018 01 02.
Article
em En
| MEDLINE
| ID: mdl-29202476
ABSTRACT
Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11-mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Transdução de Sinais
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Transformação Celular Neoplásica
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Proteínas Serina-Treonina Quinases
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Interleucina-11
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Fator de Transcrição STAT3
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Janus Quinase 1
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Janus Quinase 2
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Neoplasias Intestinais
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Proteínas de Neoplasias
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article