title: Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness.
abstract: Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial mesenchymal transition (EMT) of tumor cells and their achievement of stem cell traits. We demonstrate that CAFs induce EMT and stemness through a proinflammatory signature, which exploits reactive oxygen species to drive a migratory and aggressive phenotype of prostate carcinoma cells. CAFs exert their propelling role for EMT in strict dependence on cycloxygenase-2 (COX-2), nuclear factor-κB, and hypoxia-inducible factor-1. CAF-secreted metalloproteases elicit in carcinoma cells a Rac1b/COX-2-mediated release of reactive oxygen species, which is mandatory for EMT, stemness, and dissemination of metastatic cells. Tumor growth is abolished, and metastasis formation is severely impaired by RNA interfering-mediated targeting of the proinflammatory signature, thereby supporting the therapeutic targeting of the circuitry COX-2/nuclear factor-κB /hypoxia-inducible factor-1 as a valuable antimetastatic tool affecting cancer cell malignancy.
authors.affiliation: Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D000818:Animals; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D045726:Metalloproteases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D045726:Metalloproteases; D020830:rac1 GTP-Binding Protein