Hedgehog signaling promotes angiogenesis directly and indirectly in pancreatic cancer.
Angiogenesis
; 23(3): 479-492, 2020 08.
Article
en En
| MEDLINE
| ID: mdl-32444947
ABSTRACT
INTRODUCTION:
The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis.METHODS:
Mice bearing three different xenografted human PDAC (n = 5/group) were treated with neutralizing antibodies to SHH. After treatment for 7 days, tumors were evaluated and the expression of 38 pro- and antiangiogenic factors was assessed in the tumor cells and their stroma. The effect of SHH on the regulation of pro- and antiangiogenic factors in fibroblasts and its impact on endothelial cells was then further assessed in in vitro model systems.RESULTS:
Inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment of the three cancers. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF.CONCLUSION:
Inhibition of Hh signaling reduces tumor vascularity, suggesting that Hh plays a role in the maintenance or formation of the tumor vasculature. Whether the reduction in tumor growth and viability seen in the epithelium is a direct consequence of Hh pathway inhibition, or indirectly caused by its effect on the stroma and vasculature, remains to be evaluated.Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Transducción de Señal
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Carcinoma Ductal Pancreático
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Proteínas Hedgehog
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Proteínas de Neoplasias
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Neovascularización Patológica
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Angiogenesis
Asunto de la revista:
HEMATOLOGIA
Año:
2020
Tipo del documento:
Article