Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma
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Xianda Zhao1,2,*, Wei Fan1,*, Zhigao Xu3, Honglei Chen4, Yuyu He1,5, Gui Yang1, Gang Yang1, Hanning Hu1, Shihui Tang1, Ping Wang1, Zheng Zhang1, Peipei Xu1, Mingxia Yu1
1Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China
2Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota, 55455, USA
3Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China
4Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, 430071, China
5Biomedical Sciences Graduate Program, Temple University, Philadelphia, Pennsylvania, 19140, USA
*These authors contribute equally to this work
Mingxia Yu, email: [email protected]
Keywords: pancreatic adenocarcinoma, tumor microenvironment, tumor necrosis factor, desmoplasia, chemoresistance
Received: January 13, 2016 Accepted: November 01, 2016 Published: November 08, 2016
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.
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