Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer
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Bo Kong1, Tao Cheng1, Weiwei Wu1, Ivonne Regel1, Susanne Raulefs1, Helmut Friess1, Mert Erkan1,3, Irene Esposito2, Jörg Kleeff1,*, Christoph W. Michalski4,*
1Department of Surgery, Technische Universität München (TUM), Munich, Germany
2Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria
3Department of Surgery, Koc University School of Medicine, Istanbul, Turkey
4Department of Surgery, University of Heidelberg, Heidelberg, Germany
*These authors have contributed equally to this work
Christoph W. Michalski, e-mail: email@example.com
Keywords: ER stress, VEGFA, hypoxia, necrosis, pancreatic cancer
Received: May 27, 2015 Accepted: August 14, 2015 Published: October 05, 2015
Stromal fibrosis and tissue necrosis are major histological sequelae of hypoxia. The hypoxia-to-fibrosis sequence is well-documented in pancreatic ductal adenocarcinoma (PDAC). However, hypoxic and necrotic PDAC phenotypes are insufficiently characterized. Recently, reduction of tuberous sclerosis expression in mice together with oncogenic Kras demonstrated a rapidly metastasizing phenotype with histologically eccentric necrosis, transitional hypoxia and devascularisation. We established cell lines from these tumors and transplanted them orthotopically into wild-type mice to test their abilities to recapitulate the histological features of the primary lesions. Notably, the necrotic phenotype was reproduced by only a subset of cell lines while others gave rise to dedifferentiated tumors with significantly reduced necrosis. In vitro analysis of the necrotic tumor-inducing cell lines revealed that these cells released a significant amount of vascular endothelial growth factor A (VEGFA). However, its release was not further increased under hypoxic conditions. Defective hypoxia-induced VEGFA secretion was not due to impaired VEGFA transcription or hypoxia-inducible factor 1-alpha activation, but rather a result of hypoxia-induced endoplasmic reticulum (ER) stress. We thus identified hypoxia-induced ER stress as an important pathway in PDACs with tissue necrosis and rapid metastasis.
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