Abstract
BackgroundPancreatic 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 MethodsTo 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.ConclusionsIn 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.
Highlights
We found that TNF-α expression elevated in Pancreatic ductal adenocarcinoma (PDAC) initiation process, and high expression of TNF-α was an independent prognostic marker of poor survival
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
We found that high expression of TNF-α was mainly shown in pancreatic intraepithelial neoplasia (PanIN) and PDAC lesions, but not in normal pancreas (Figure 1A)
Summary
Pancreatic adenocarcinoma (PDAC) is a lethal disease, evidenced by the around five months’ average survival time. [1, 2] The burden of PDAC was steadily increasing in past decades and is projected to be the second lethal cancer in 2030 in the United States.[3, 4] Due to the high aggressiveness of PDAC, only a small proportion of PDAC patients get the chance to receive surgical resection, which offers the only chance to cure.[1, 2] The www.impactjournals.com/oncotarget gemcitabine-based conventional chemotherapy remains the major option for most PDAC patients, it provides limited overall survival (OS)benefit.[5, 6]Tumor necrosis factor-alpha (TNF-α) is a master regulator of inflammation and a key player in the cytokine network. [7, 8]. Pancreatic adenocarcinoma (PDAC) is a lethal disease, evidenced by the around five months’ average survival time. Tumor necrosis factor-alpha (TNF-α) is a master regulator of inflammation and a key player in the cytokine network. TNF-α is a type II transmembrane protein with signaling potential as a membrane-integrated protein or a soluble cytokine released by proteolytic cleavage. [9,10,11] There are two TNF receptors: TNFR1, which is activated by soluble ligand and TNFR2 which primarily binds the transmembrane form. Anti-TNF-α antibodies and other TNF-α antagonists showed therapeutic activity in various experimental models of common epithelial cancers. 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. 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
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