title: Hypoxia-induced endoplasmic reticulum stress characterizes a necrotic phenotype of pancreatic cancer.
abstract: 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.
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Raulefs
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.|Department of Surgery, Koc University School of Medicine, Istanbul, Turkey.
authors.forename: Mert
authors.initials: M
authors.lastname: Erkan
authors.affiliation: Institute of Pathology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Surgery, Technische Universität München (TUM), Munich, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.affiliation: Department of Surgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Michalski
mesh_terms: D000818:Animals; D017209:Apoptosis; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000473:pathology*; D049109:Cell Proliferation; D059865:Endoplasmic Reticulum Stress; D006801:Humans; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D007124:Immunoenzyme Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009336:Necrosis; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000473:pathology*; D010641:Phenotype; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: ER stress; VEGFA; hypoxia; necrosis; pancreatic cancer