Pathologic correlates of primary central nervous system lymphoma defined in an orthotopic xenograft model.
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.
Kadoch
Cigall
C
Division of Hematology/Oncology, Department of Neurological Surgery, University of California at San Francisco, San Francisco, California, USA.
Dinca
Eduard B
EB
Voicu
Ramona
R
Chen
Lingjing
L
Nguyen
Diana
D
Parikh
Seema
S
Karrim
Juliana
J
Shuman
Marc A
MA
Lowell
Clifford A
CA
Treseler
Patrick A
PA
James
C David
CD
Rubenstein
James L
JL
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
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