Resveratrol Ameliorates the Malignant Progression of Pancreatic Cancer by Inhibiting Hypoxia-induced Pancreatic Stellate Cell Activation
Authors: Ying Xiao
Liankang Sun
Weikun Qian
Xuqi Li
Jianjun Lei
Jiguang Ma
Zheng Wang
Jie Li
Qinhong Xu
Tao Qin
Wanxing Duan
Qingyong Ma
Journal: Cell Transplantation (2020)
Discipline: CLINICAL MEDICINE
Keywords: PSCs; hypoxia; pancreatic cancer; resveratrol; stromal desmoplasia.
Affiliations: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Both the authors contributed equally to this article., Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China., Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Abstract:  Pancreatic cancer is characterized by a hypoxic tumor microenvironment, which is primarily caused by massive fibrosis with pancreatic stellate cells (PSCs) as a main component. Our previous studies have shown that resveratrol can significantly inhibit pancreatic cancer. However, whether resveratrol can inhibit hypoxia-induced cancer development remains unclear. The objective of this study was to explore whether PSCs and hypoxia synergistically mediate aggressiveness in pancreatic cancer and detect the potential pleiotropic protective effects of resveratrol on hypoxia-induced pancreatic cancer progression. Human PSCs were treated with vehicle or resveratrol under normoxic or hypoxic conditions (3% O2), and PSC activation was assessed by immunofluorescence staining. SiRNA was used to silence hypoxia-inducible factor 1 (HIF-1) expression. The invasive capacity of Panc-1 and Mia Paca-2 cells cocultured with conditioned medium from PSCs was assessed by Transwell assays. To examine tumor formation kinetics, KPC (LSL-KrasG12D/+, Trp53fl/+, and Pdx1-Cre) mice were sacrificed at different time points. To investigate the antitumor effects of resveratrol in vivo, 8-wk-old KPC mice were divided into two groups and treated daily with or without 50 mg/kg resveratrol. Our data indicate that hypoxia induces PSC activation via HIF-1 and that the interleukin 6, vascular endothelial growth factor A, and stromal cell-derived factor 1 derived from activated PSCs promote both invasion and the epithelial-mesenchymal transition and inhibit apoptosis in pancreatic cancer cells. However, resveratrol inhibits hypoxia-induced PSC activation, blocks the interplay between PSCs and pancreatic cancer cells, and suppresses the malignant progression of pancreatic cancer and stromal desmoplasia in a KPC mouse model. Our data highlight that activated PSCs and intratumoral hypoxia are essential targets for novel strategies to prevent tumor-microenvironment interactions. Furthermore, the polyphenolic compound resveratrol effectively ameliorates the malignant progression of pancreatic ductal adenocarcinoma. 

Retracted: No

PubPeer comments:
 Figures 2 and 3 of this paper appear to have some image overlaps ![file] ![file] , 
 Thank you for pointing out the error! As a co-corresponding author, I am sorry for this error that might have occurred during composing picture. We took 10 pictures of each group. There may be a small number of pictures with repeated parts during shooting. As the results of Transwell, some of these pictures looks very similar. So we mistakenly put the picture of the Hypoxia+RSV group as the Hypoxia+siHIF1u03b1 group in Figure2 and put the picture of the CM group as the CM+RSV group in Figure 3. The invaded cells were quantified by counting the number of cells in 10 random fields. Therefore, our statistical results are basically unaffected. We have communicated with the editor of Cell Transplantation and hope to solve this affair as soon as possible. ,