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

被引：65
作者：
Zhao, Xianda [1 ,2 ]
Fan, Wei [1 ]
Xu, Zhigao [3 ]
Chen, Honglei [4 ]
He, Yuyu [1 ,5 ]
Yang, Gui [1 ]
Yang, Gang [1 ]
Hu, Hanning [1 ]
Tang, Shihui [1 ]
Wang, Ping [1 ]
Zhang, Zheng [1 ]
Xu, Peipei [1 ]
Yu, Mingxia [1 ]
机构：
[1] Wuhan Univ, Zhongnan Hosp, Dept Clin Lab, Wuhan 430071, Hubei, Peoples R China
[2] Univ Minnesota, Microbiol Immunol & Canc Biol Grad Program, Minneapolis, MN 55455 USA
[3] Wuhan Univ, Zhongnan Hosp, Dept Pathol, Wuhan 430071, Hubei, Peoples R China
[4] Wuhan Univ, Sch Basic Med Sci, Dept Pathol, Wuhan 430071, Hubei, Peoples R China
[5] Temple Univ, Biomed Sci Grad Program, Philadelphia, PA 19140 USA
来源：
ONCOTARGET | 2016年 / 7卷 / 49期
基金：
中国国家自然科学基金;
关键词：
pancreatic adenocarcinoma; tumor microenvironment; tumor necrosis factor; desmoplasia; chemoresistance; TNF-ALPHA; NAB-PACLITAXEL; CANCER; FIBROBLASTS; PROGRESSION; MECHANISMS; THERAPY; BIOLOGY; CELLS; SERUM;
D O I：
10.18632/oncotarget.13212
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common cancer death reasons. Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies have shown promising effects in PDAC pre-clinical models. However, the prognostic values of TNF-alpha, underlying mechanisms by which anti-TNF-alpha treatments inhibit PDAC, and potential synergistic effects of anti-TNF-alpha treatments with chemotherapy are still unclear. Results and Methods: To identify the targeting values of TNF-alpha in PDAC, we measured TNF-alpha expression in different stages of PDAC initiation and evaluated its prognostic significance in a pancreatic cancer cohort. We found that TNF-alpha expression elevated in PDAC initiation process, and high expression of TNF-alpha was an independent prognostic marker of poor survival. We further evaluated anti-tumor effects of anti-TNF-alpha treatments in PDAC. Anti-TNF-alpha treatments resulted in decreased cell viability in both PDAC tumor cells and pancreatic satellite cells in similar dose in vitro. In vivo, anti-TNF-alpha treatments showed effects in reducing desmoplasia and the tumor promoting inflammatory microenvironment in PDAC. Combination of anti-TNF-alpha 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-alpha in PDAC can be a prognostic and therapeutic target. Inhibition of TNF-alpha 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.
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收藏
页码：81110 / 81122
页数：13
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