Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma.

Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia

Zhao, Xianda; Fan, Wei; Xu, Zhigao; Chen, Honglei; He, Yuyu; Yang, Gui; Yang, Gang; Hu, Hanning; Tang, Shihui; Wang, Ping; Zhang, Zheng; Xu, Peipei; Yu, Mingxia.

Afiliación

Zhao X; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Fan W; Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
Xu Z; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Chen H; Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
He Y; Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, 430071, China.
Yang G; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Yang G; Biomedical Sciences Graduate Program, Temple University, Philadelphia, Pennsylvania, 19140, USA.
Hu H; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Tang S; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Wang P; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Zhang Z; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Xu P; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Yu M; Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.

Oncotarget ; 7(49): 81110-81122, 2016 Dec 06.

Article en En | MEDLINE | ID: mdl-27835602

RESUMEN

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-α) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-α, underlying mechanisms by which anti-TNF-α treatments inhibit PDAC, and potential synergistic effects of anti-TNF-α treatments with chemotherapy are still unclear. RESULTS AND METHODS: To identify the targeting values of TNF-α in PDAC, we measured TNF-α expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-α expression elevated in PDAC initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-α treatments in PDAC. Anti-TNF-α treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-α treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-α treatments with chemotherapy partly overcame chemoresistance of PDAC tumor cells and prolonged the survival of PDAC mouse model. CONCLUSIONS: In conclusion, our findings indicated that TNF-α in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-α synergized with chemotherapy in PDAC resulted in better pre-clinical responses via killing tumor cells as well as diminishing desmoplasia and inflammation in PDAC tumor stroma.

Asunto(s)

Antiinflamatorios/farmacología; Protocolos de Quimioterapia Combinada Antineoplásica/farmacología; Carcinoma Ductal Pancreático/tratamiento farmacológico; Resistencia a Antineoplásicos/efectos de los fármacos; Neoplasias Pancreáticas/tratamiento farmacológico; Células Estrelladas Pancreáticas/efectos de los fármacos; Células del Estroma/efectos de los fármacos; Factor de Necrosis Tumoral alfa/antagonistas & inhibidores; Animales; Citotoxicidad Celular Dependiente de Anticuerpos/efectos de los fármacos; Carcinoma Ductal Pancreático/metabolismo; Carcinoma Ductal Pancreático/mortalidad; Carcinoma Ductal Pancreático/patología; Línea Celular Tumoral; Supervivencia Celular/efectos de los fármacos; Activación de Complemento/efectos de los fármacos; Desoxicitidina/análogos & derivados; Desoxicitidina/farmacología; Sinergismo Farmacológico; Etanercept/farmacología; Femenino; Humanos; Infliximab/farmacología; Estimación de Kaplan-Meier; Masculino; Ratones Endogámicos BALB C; Ratones Desnudos; Persona de Mediana Edad; Paclitaxel/farmacología; Neoplasias Pancreáticas/metabolismo; Neoplasias Pancreáticas/mortalidad; Neoplasias Pancreáticas/patología; Células Estrelladas Pancreáticas/metabolismo; Células Estrelladas Pancreáticas/patología; Modelos de Riesgos Proporcionales; Células del Estroma/metabolismo; Células del Estroma/patología; Factores de Tiempo; Microambiente Tumoral; Factor de Necrosis Tumoral alfa/metabolismo; Ensayos Antitumor por Modelo de Xenoinjerto; Gemcitabina

Palabras clave

chemoresistance; desmoplasia; pancreatic adenocarcinoma; tumor microenvironment; tumor necrosis factor

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Protocolos de Quimioterapia Combinada Antineoplásica / Factor de Necrosis Tumoral alfa / Células del Estroma / Resistencia a Antineoplásicos / Carcinoma Ductal Pancreático / Células Estrelladas Pancreáticas / Antiinflamatorios Tipo de estudio: Prognostic_studies Idioma: En Revista: Oncotarget Año: 2016 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google