title: Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18.
abstract: The ST18 gene has been proposed to act either as a tumor suppressor or as an oncogene in different human cancers, but direct evidence for its role in tumorigenesis has been lacking thus far. Here, we demonstrate that ST18 is critical for tumor progression and maintenance in a mouse model of liver cancer, based on oncogenic transformation and adoptive transfer of primary precursor cells (hepatoblasts). ST18 messenger RNA (mRNA) and protein were detectable neither in normal liver nor in cultured hepatoblasts, but were readily expressed after subcutaneous engraftment and tumor growth. ST18 expression in liver cells was induced by inflammatory cues, including acute or chronic inflammation in vivo, as well as coculture with macrophages in vitro. Knocking down the ST18 mRNA in transplanted hepatoblasts delayed tumor progression. Induction of ST18 knockdown in pre-established tumors caused rapid tumor involution associated with pervasive morphological changes, proliferative arrest, and apoptosis in tumor cells, as well as depletion of tumor-associated macrophages, vascular ectasia, and hemorrhage. Reciprocally, systemic depletion of macrophages in recipient animals had very similar phenotypic consequences, impairing either tumor development or maintenance, and suppressing ST18 expression in hepatoblasts. Finally, RNA sequencing of ST18-depleted tumors before involution revealed down-regulation of inflammatory response genes, pointing to the suppression of nuclear factor kappa B-dependent transcription.
  
  
  
  ST18 expression in epithelial cells is induced by tumor-associated macrophages, contributing to the reciprocal feed-forward loop between both cell types in liver tumorigenesis. Our findings warrant the exploration of means to interfere with ST18-dependent epithelium-macrophage interactions in a therapeutic setting. (Hepatology 2017;65:1708-1719).
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Micol
authors.initials: M
authors.lastname: Ravà
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Aleco
authors.initials: A
authors.lastname: D'Andrea
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Mirko
authors.initials: M
authors.lastname: Doni
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Theresia R
authors.initials: TR
authors.lastname: Kress
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Ostuni
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Marco J
authors.initials: MJ
authors.lastname: Morelli
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Collino
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ghisletti
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Nicoli
authors.affiliation: Mouse & Animal Pathology Laboratory, Fondazione Filarete, Milan, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Recordati
authors.affiliation: Medical and Laboratory Genetics, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Iascone
authors.affiliation: Pathology Department, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Aurelio
authors.initials: A
authors.lastname: Sonzogni
authors.affiliation: Paediatric Liver, GI and Transplantation, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: D'Antiga
authors.affiliation: Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, United Kingdom.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Shukla
authors.affiliation: Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, United Kingdom.|Mater Research Institute, The University of Queensland, Translational Research Institute, Woolloongabba, Australia.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Faulkner
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Campaner
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia, Milan, Italy.|Department of Experimental Oncology, European Institute of Oncology, Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: C581556:Myt3 protein, mouse; D014157:Transcription Factors