title: Ligand-dependent activation of EGFR in follicular dendritic cells sarcoma is sustained by local production of cognate ligands.
abstract: OBJECTIVE
  The aim of this study was to investigate the biological and clinical significance of epidermal growth factor receptor (EGFR) signaling pathway in follicular dendritic cell sarcoma (FDC-S).
  
  
  METHODS
  Expression of EGFR and cognate ligands as well as activation of EGFR signaling components was assessed in clinical samples and in a primary FDC-S short-term culture (referred as FDC-AM09). Biological effects of the EGFR antagonists cetuximab and panitumumab and the MEK inhibitor UO126 on FDC-S cells were determined in vitro on FDC-AM09. Direct sequencing of KRAS, BRAF, and PI3KCA was conducted on tumor DNA.
  
  
  RESULTS
  We found a strong EGFR expression on dysplastic and neoplastic FDCs. On FDC-AM09, we could show that engagement of surface EGFR by cognate ligands drives the survival and proliferation of FDC-S cells, by signaling to the nucleus mainly via MAPK and STAT pathways. Among EGFR ligands, heparin-binding EGF-like growth factor, TGF-α and Betacellulin (BTC) are produced in the tumor microenvironment of FDC-S at RNA level. By extending this finding at protein level we found that BTC is abundantly produced by FDC-S cells and surrounding stromal cells. Finally, direct sequencing of tumor-derived genomic DNA showed that mutations in KRAS, NRAS, BRAF, and PI3KCA, which predicts resistance to anti-EGFR MoAb in other cancer models, are not observed in FDC-S.
  
  
  CONCLUSIONS
  Activation of EGFR by cognate ligands produced in the tumor microenvironment sustain viability and proliferation of FDC-S indicating that the receptor blockade might be clinically relevant in this neoplasm.
authors.affiliation: Authors' Affiliations: Department of Molecular and Translational Medicine, Section of Anatomic Pathology, Oncology and Experimental immunology, University of Brescia, Brescia; Department of Physiopathology, Experimental Medicine and Public Health, University of Siena, Siena; Department of Pathology, San Raffaele Scientific Institute, Milan; Center of Predictive Molecular Medicine, Center of Excellence on Aging University-Foundation, Chieti; Unita' Operativa di Anatomia Patologica, Azienda Arcispedale S. Maria Nuova/IRCCS, Reggio Emilia; Hematopathology Section, Policlinico S. Orsola, University of Bologna, Bologna; Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri; and Humanitas Clinical and Research Center.
authors.forename: William
authors.initials: W
authors.lastname: Vermi
authors.forename: Emanuele
authors.initials: E
authors.lastname: Giurisato
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.forename: Piera
authors.initials: P
authors.lastname: Balzarini
authors.forename: Elisa
authors.initials: E
authors.lastname: Rossi
authors.forename: Daniela
authors.initials: D
authors.lastname: Medicina
authors.forename: Daniela
authors.initials: D
authors.lastname: Bosisio
authors.forename: Silvano
authors.initials: S
authors.lastname: Sozzani
authors.forename: Wilma
authors.initials: W
authors.lastname: Pellegrini
authors.forename: Claudio
authors.initials: C
authors.lastname: Doglioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Giulio
authors.initials: G
authors.lastname: Rossi
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D000068818:Cetuximab; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D020566:Dendritic Cells, Follicular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D008024:Ligands; D009570:Nitriles / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics; D000077544:Panitumumab; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002070:Butadienes; D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D008024:Ligands; D009570:Nitriles; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C113580:U 0126; D000077544:Panitumumab; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab