title: Angiogenin secretion from hepatoma cells activates hepatic stellate cells to amplify a self-sustained cycle promoting liver cancer.
abstract: Hepatocellular carcinoma (HCC) frequently develops in a pro-inflammatory and pro-fibrogenic environment with hepatic stellate cells (HSCs) remodeling the extracellular matrix composition. Molecules secreted by liver tumors contributing to HSC activation and peritumoral stromal transformation remain to be fully identified. Here we show that conditioned medium from HCC cell lines, Hep3B and HepG2, induced primary mouse HSCs transdifferentiation, characterized by profibrotic properties and collagen modification, with similar results seen in the human HSC cell line LX2. Moreover, tumor growth was enhanced by coinjection of HepG2/LX2 cells in a xenograft murine model, supporting a HCC-HSC crosstalk in liver tumor progression. Protein microarray secretome analyses revealed angiogenin as the most robust and selective protein released by HCC compared to LX2 secreted molecules. In fact, recombinant angiogenin induced in vitro HSC activation requiring its nuclear translocation and rRNA transcriptional stimulation. Moreover, angiogenin antagonism by blocking antibodies or angiogenin inhibitor neomycin decreased in vitro HSC activation by conditioned media or recombinant angiogenin. Finally, neomycin administration reduced tumor growth of HepG2-LX2 cells coinjected in mice. In conclusion, angiogenin secretion by HCCs favors tumor development by inducing HSC activation and ECM remodeling. These findings indicate that targeting angiogenin signaling may be of potential relevance in HCC management.
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bárcena
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Milica
authors.initials: M
authors.lastname: Stefanovic
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Tutusaus
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Martinez-Nieto
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martinez
authors.affiliation: 1] Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain [2] Liver Unit-Hospital Clínic, CIBERehd, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
authors.affiliation: Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain.
authors.forename: Alvaro
authors.initials: A
authors.lastname: de Mingo
authors.affiliation: Liver Unit-Hospital Clínic, CIBERehd, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Caballeria
authors.affiliation: 1] Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain [2] Liver Unit-Hospital Clínic, CIBERehd, Barcelona, Spain [3] Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
authors.forename: José C
authors.initials: JC
authors.lastname: Fernandez-Checa
authors.affiliation: 1] Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain [2] Liver Unit-Hospital Clínic, CIBERehd, Barcelona, Spain.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.affiliation: 1] Department of Cell Death and Proliferation, IIBB-CSIC, IDIBAPS, Barcelona, Spain [2] Liver Unit-Hospital Clínic, CIBERehd, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D056945:Hep G2 Cells; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D012259:Ribonuclease, Pancreatic / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; C046366:angiogenin; D012259:Ribonuclease, Pancreatic