Lung cancer cells induce senescence and apoptosis of pleural mesothelial cells via transforming growth factor-beta1.
Tumour Biol
; 36(4): 2657-65, 2015 Apr.
Article
en En
| MEDLINE
| ID: mdl-25433501
ABSTRACT
Pleural dissemination is commonly associated with metastatic advanced lung cancer. The injury of pleural mesothelial cells (PMCs) by soluble factors, such as transforming growth factor-beta1 (TGF-ß1), is a major driver of lung cancer pleural dissemination (LCPD). In this study, we examine the effects of TGF-ß1 on PMC injury and the ability of TGF-ß1 inhibition to alleviate this effect both in vitro and in vivo. PMCs were co-cultured with the high TGF-ß1-expressing lung cancer cell line A549 and with various TGF-ß1 signaling inhibitors. Expression of cleaved-caspase 3, cleaved-caspase 9, p21, and p16 were evaluated by Western blot and immunofluorescent confocal imaging. Apoptosis was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltrazoliumbromide assay and AnnexinV-propidium iodide (PI) staining. PMC senescence was assessed by staining for senescence-associated ß-galactosidase (SA-ß-Gal). The ability of lung cancer cells (LCCs) to adhere to injured PMCs was investigated using an LCC-PMC adhesion assay. In our mouse model, PMC injury status was monitored by hematoxylin-eosin (H&E) and Masson's trichrome staining. LCCs expressing high levels of TGF-ß1 induce apoptosis and senescence of PMCs in a co-culture system. Injured PMCs adhere to LCCs, which may further promote LCPD. Importantly, PMC monolayer injury could be reversed with TGF-ß1 inhibitors. This was consistent with our in vivo data showing that the TGF-ß1 inhibitor SB-431542 attenuated PMC barrier injury induced by A549 culture medium in our mouse model. Our study highlights the importance of TGF-ß1 signaling in LCPD and establishes this signaling pathway as a potential therapeutic target in the disease.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Pleura
/
Senescencia Celular
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Factor de Crecimiento Transformador beta1
/
Neoplasias Pulmonares
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Tumour Biol
Asunto de la revista:
NEOPLASIAS
Año:
2015
Tipo del documento:
Article
País de afiliación:
China