title: Pathologic correlates of primary central nervous system lymphoma defined in an orthotopic xenograft model.
abstract: OBJECTIVE
  The prospect for advances in the treatment of patients with primary central nervous system lymphoma (PCNSL) is likely dependent on the systematic evaluation of its pathobiology. Animal models of PCNSL are needed to facilitate the analysis of its molecular pathogenesis and for the efficient evaluation of novel therapeutics.
  
  
  METHODS
  We characterized the molecular pathology of CNS lymphoma tumors generated by the intracerebral implantation of Raji B lymphoma cells in athymic mice. Lymphoma cells were modified for bioluminescence imaging to facilitate monitoring of tumor growth and response to therapy. In parallel, we identified molecular features of lymphoma xenograft histopathology that are evident in human PCNSL specimens.
  
  
  RESULTS
  Intracerebral Raji tumors were determined to faithfully reflect the molecular pathogenesis of PCNSL, including the predominant immunophenotypic state of differentiation of lymphoma cells and their reactive microenvironment. We show the expression of interleukin-4 by Raji and other B lymphoma cell lines in vitro and by Raji tumors in vivo and provide evidence for a role of this cytokine in the M2 polarization of lymphoma macrophages both in the murine model and in diagnostic specimens of human PCNSL.
  
  
  CONCLUSIONS
  Intracerebral implantation of Raji cells results in a reproducible and invasive xenograft model, which recapitulates the histopathology and molecular features of PCNSL, and is suitable for preclinical testing of novel agents. We also show for the first time the feasibility and accuracy of tumor bioluminescence in the monitoring of a highly infiltrative brain tumor.
authors.affiliation: Division of Hematology/Oncology, Department of Neurological Surgery, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Cigall
authors.initials: C
authors.lastname: Kadoch
authors.forename: Eduard B
authors.initials: EB
authors.lastname: Dinca
authors.forename: Ramona
authors.initials: R
authors.lastname: Voicu
authors.forename: Lingjing
authors.initials: L
authors.lastname: Chen
authors.forename: Diana
authors.initials: D
authors.lastname: Nguyen
authors.forename: Seema
authors.initials: S
authors.lastname: Parikh
authors.forename: Juliana
authors.initials: J
authors.lastname: Karrim
authors.forename: Marc A
authors.initials: MA
authors.lastname: Shuman
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Treseler
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: James L
authors.initials: JL
authors.lastname: Rubenstein
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D016764:Cell Polarity; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics; D008163:Luminescent Measurements; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D050800:STAT6 Transcription Factor / Q000378:metabolism; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D025521:Tumor Suppressor Proteins; D015847:Interleukin-4; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide