Research Papers:

PEDF inhibits pancreatic tumorigenesis by attenuating the fibro-inflammatory reaction

Daniel R. Principe, Brian DeCant, Andrew M. Diaz, Riley J. Mangan, Rosa Hwang, Andrew Lowy, Brandon B. Shetuni, Bharath K. Sreekumar, Chuhan Chung, David J. Bentrem, Hidayatullah G. Munshi, Barbara Jung, Paul J. Grippo and Faraz Bishehsari _

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Oncotarget. 2016; 7:28218-28234. https://doi.org/10.18632/oncotarget.8587

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Daniel R. Principe1, Brian DeCant2, Andrew M. Diaz2, Riley J. Mangan2, Rosa Hwang3, Andrew Lowy4, Brandon B. Shetuni5, Bharath K. Sreekumar6, Chuhan Chung6, David J. Bentrem7, Hidayatullah G. Munshi7, Barbara Jung2, Paul J. Grippo2,*, Faraz Bishehsari8,*

1University of Illinois College of Medicine, Champaign, IL, USA

2Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

3Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4Department of Surgery, University of California San Diego, San Diego, CA, USA

5Northwestern Medicine, Central DuPage Hospital, Winfield, IL, USA

6Department of Medicine, Yale University School of Medicine, New Haven, CT, USA

7Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

8Department of Medicine, Rush University Medical Center, Chicago, IL, USA

*Paul J. Grippo and Faraz Bishehsari contributed equally to this manuscript and serve as joint senior authors

Correspondence to:

Faraz Bishehsari, email: [email protected]

Paul J. Grippo, email: [email protected]

Keywords: pancreatic cancer, PEDF, inflammation, fibrosis, KRAS

Received: November 02, 2015    Accepted: March 17, 2016    Published: April 5, 2016


Pancreatic cancer is characterized by a pronounced fibro-inflammatory reaction that has been shown to contribute to cancer progression. Previous reports have demonstrated that pigment epithelium-derived factor (PEDF) has potent tumor suppressive effects in pancreatic cancer, though little is known about the mechanisms by which PEDF limits pancreatic tumorigenesis. We therefore employed human specimens, as well as mouse and in vitro models, to explore the effects of PEDF upon the pancreatic microenvironment. We found that PEDF expression is decreased in human pancreatic cancer samples compared to non-malignant tissue. Furthermore, PEDF-deficient patients displayed increased intratumoral inflammation/fibrosis. In mice, genetic ablation of PEDF increased cerulein-induced inflammation and fibrosis, and similarly enhanced these events in the background of oncogenic KRAS. In vitro, recombinant PEDF neutralized macrophage migration as well as inhibited macrophage-induced proliferation of tumor cells. Additionally, recombinant PEDF suppressed the synthesis of pro-inflammatory/pro-fibrotic cytokines both in vivo and in vitro, and reduced collagen I deposition and TGFβ synthesis by pancreatic stellate cells, consistent with reduced fibrosis. Combined, our results demonstrate that PEDF limits pancreatic cancer progression by attenuating the fibro-inflammatory reaction, and makes restoration of PEDF signaling a potential therapeutic approach to study in pancreatic cancer.

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