title: The soluble form of the tumor suppressor Lrig1 potently inhibits in vivo glioma growth irrespective of EGF receptor status.
abstract: BACKGROUND
  Deregulated growth factor signaling is a major driving force in the initiation and progression of glioblastoma. The tumor suppressor and stem cell marker Lrig1 is a negative regulator of the epidermal growth factor receptor (EGFR) family. Here, we addressed the therapeutic potential of the soluble form of Lrig1 (sLrig1) in glioblastoma treatment and the mechanism of sLrig1-induced growth inhibition.
  
  
  METHODS
  With use of encapsulated cells, recombinant sLrig1 was locally delivered in orthotopic glioblastoma xenografts generated from freshly isolated patient tumors. Tumor growth and mouse survival were evaluated. The efficacy of sLrig1 and the affected downstream signaling was studied in vitro and in vivo in glioma cells displaying variable expression of wild-type and/or a constitutively active EGFR mutant (EGFRvIII).
  
  
  RESULTS
  Continuous interstitial delivery of sLrig1 in genetically diverse patient-derived glioma xenografts led to strong tumor growth inhibition. Glioma cell proliferation in vitro and tumor growth in vivo were potently inhibited by sLrig1, irrespective of EGFR expression levels. Of importance, tumor growth was also suppressed in EGFRvIII-driven glioma. sLrig1 induced cell cycle arrest without changing total receptor level or phosphorylation. Affected downstream effectors included MAP kinase but not AKT signaling. Of importance, local delivery of sLrig1 into established tumors led to a 32% survival advantage in treated mice.
  
  
  CONCLUSIONS
  To our knowledge, this is the first report demonstrating that sLrig1 is a potent inhibitor of glioblastoma growth in clinically relevant experimental glioma models and that this effect is largely independent of EGFR status. The potent anti-tumor effect of sLrig1, in combination with cell encapsulation technology for in situ delivery, holds promise for future treatment of glioblastoma.
authors.affiliation: NorLux Neuro-Oncology Laboratory, Department of Oncology, Centre de Recherche Public de la Santé, Luxembourg, Luxembourg, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.forename: Katja
authors.initials: K
authors.lastname: Tiemann
authors.forename: Amandine
authors.initials: A
authors.lastname: Bernard
authors.forename: Anna
authors.initials: A
authors.lastname: Golebiewska
authors.forename: Olivier
authors.initials: O
authors.lastname: Keunen
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Baofeng
authors.initials: B
authors.lastname: Wang
authors.forename: Håkan
authors.initials: H
authors.lastname: Hedman
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: C484445:LRIG1 protein, human; D008562:Membrane Glycoproteins; D066246:ErbB Receptors
keywords: EGFR; Lrig1; alginate; cell encapsulation; glioblastoma; glioma; tyrosine kinase receptors; xenograft models