title: Hypoxia stimulates pancreatic stellate cells to induce fibrosis and angiogenesis in pancreatic cancer.
abstract: Pancreatic cancer is characterized by excessive desmoplastic reaction and by a hypoxic microenvironment within the solid tumor mass. Chronic pancreatitis is also characterized by fibrosis and hypoxia. Fibroblasts in the area of fibrosis in these pathological settings are now recognized as activated pancreatic stellate cells (PSCs). Recent studies have suggested that a hypoxic environment concomitantly exists not only in pancreatic cancer cells but also in surrounding PSCs. This study aimed to clarify whether hypoxia affected the cell functions in PSCs. Human PSCs were isolated and cultured under normoxia (21% O(2)) or hypoxia (1% O(2)). We examined the effects of hypoxia and conditioned media of hypoxia-treated PSCs on cell functions in PSCs and in human umbilical vein endothelial cells. Hypoxia induced migration, type I collagen expression, and vascular endothelial growth factor (VEGF) production in PSCs. Conditioned media of hypoxia-treated PSCs induced migration of PSCs, which was inhibited by anti-VEGF antibody but not by antibody against hepatocyte growth factor. Conditioned media of hypoxia-treated PSCs induced endothelial cell proliferation, migration, and angiogenesis in vitro and in vivo. PSCs expressed several angiogenesis-regulating molecules including VEGF receptors, angiopoietin-1, and Tie-2. In conclusion, hypoxia induced profibrogenic and proangiogenic responses in PSCs. In addition to their established profibrogenic roles, PSCs might play proangiogenic roles during the development of pancreatic fibrosis, where they are subjected to hypoxia.
authors.affiliation: Div. of Gastroenterology, Tohoku Univ. Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. amasamune@int3.med.tohoku.ac.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Masamune
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kikuta
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Kennichi
authors.initials: K
authors.lastname: Satoh
authors.forename: Morihisa
authors.initials: M
authors.lastname: Hirota
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D017077:Culture Media, Conditioned; D005355:Fibrosis / Q000209:etiology; D006801:Humans; D009389:Neovascularization, Pathologic / Q000209:etiology*; D009593:Nitroimidazoles; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D017077:Culture Media, Conditioned; D009593:Nitroimidazoles; D042461:Vascular Endothelial Growth Factor A; C033815:pimonidazole