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A blockade of PD-L1 produced antitumor and antimetastatic effects in an orthotopic mouse pancreatic cancer model via the PI3K/AkT/MTOR signaling pathway

Authors Zhao L, Li C, Liu F, Zhao Y, Liu J, Hua Y, Liu J, Huang J, Ge C

Received 17 December 2016

Accepted for publication 8 March 2017

Published 12 April 2017 Volume 2017:10 Pages 2115—2126

DOI https://doi.org/10.2147/OTT.S130481

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Akshita Wason

Peer reviewer comments 3

Editor who approved publication: Dr Carlos Vigil Gonzales

Lei Zhao,1 Cheng Li,2 Fei Liu,2 Yonghong Zhao,2 Jun Liu,2 Ye Hua,1 Jinyang Liu,1 Jiapeng Huang,1 Chunlin Ge1

1Department of Pancreatic and Biliary Surgery, The First Hospital of China Medical University, 2Department of Immunology, College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, People’s Republic of China

Background: Pancreatic cancer is one of the most aggressive and intractable malignant tumors, and most deaths from pancreatic cancer are related to metastases. It has been demonstrated in vitro that overexpression of programmed death-ligand 1 (PD-L1) correlates with a lack of phosphatase and tensin homologue (PTEN) expression in pancreatic cancer tissue. This loss of PTEN expression may aberrantly activate the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, and thereby promote tumor cell survival, proliferation, and disease progression. In this study, we investigated the potential therapeutic effect of blockading PD-L1 expression on the progression of pancreatic cancer and its spontaneous liver metastases in vivo by inhibiting the PI3K/Akt/mTOR signaling pathway.
Methods: We investigated the effect of blockading PD-L1 in an orthotopic pancreatic cancer mouse model. The pancreatic tumor weights and inhibition ratios were determined after treatment with antimouse PD-L1 antibody for 5 weeks. We used immunohistochemistry methods to investigate PD-L1 expression in pancreatic cancer tissue and spontaneous liver metastasis tissue. The levels of mRNA and protein expression for various components involved in the PI3K/Akt/mTOR signaling pathway as well as for matrix metalloproteinases-2 and -9 (MMP2 and MMP9) were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blot methods, respectively.
Results: Blockading PD-L1 significantly inhibited tumor growth and decreased the levels of PD-L1 expression in tumor tissue. Furthermore, the levels of PTEN mRNA and protein expression were elevated, while the levels of phospho-Akt (p-Akt) and phospho-mTOR (p-mTOR) protein were decreased in pancreatic cancer and liver metastasis tissues after establishing a PD-L1 blockade. In addition, a PD-L1 blockade decreased the levels of MMP2 and MMP9 mRNA and protein expression in tumor tissues.
Conclusion: Our results suggest that a blockade of PD-L1 may inhibit the growth and metastasis of pancreatic cancer by modulating the PI3K/Akt/mTOR pathway.

Keywords: PD-L1 blockade, pancreatic cancer, spontaneous liver metastasis, PI3K/Akt/mTOR pathway, PTEN, MMP2, MMP9
 

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