Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma.
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
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.
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.|Microbiology, Immunology and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
Xianda
X
Zhao
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Wei
W
Fan
Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Zhigao
Z
Xu
Department of Pathology, School of Basic Medical Science, Wuhan University, Wuhan, Hubei, 430071, China.
Honglei
H
Chen
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.|Biomedical Sciences Graduate Program, Temple University, Philadelphia, Pennsylvania, 19140, USA.
Yuyu
Y
He
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Gui
G
Yang
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Gang
G
Yang
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Hanning
H
Hu
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Shihui
S
Tang
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Ping
P
Wang
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Zheng
Z
Zhang
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Peipei
P
Xu
Department of Clinical Laboratory & Center for gene diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China.
Mingxia
M
Yu
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000068800:Etanercept / Q000494:pharmacology; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016016:Proportional Hazards Models; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D059016:Tumor Microenvironment; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000893:Anti-Inflammatory Agents; D014409:Tumor Necrosis Factor-alpha; D003841:Deoxycytidine; D000069285:Infliximab; D000068800:Etanercept; D017239:Paclitaxel; D000093542:Gemcitabine
chemoresistance; desmoplasia; pancreatic adenocarcinoma; tumor microenvironment; tumor necrosis factor