Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model
Cigall Kadoch,Eduard B. Dinca,Ramona Voicu,Lingjing Chen,Diana Nguyen,Seema Parikh,Juliana Karrim,Marc A. Shuman,Clifford A. Lowell,Patrick A. Treseler,C. David James,James L. Rubenstein +11 more
TLDR
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.Abstract:
Purpose: 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. Experimental Design: 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. Conclusion: 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.read more
Citations
More filters
Journal ArticleDOI
Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice
TL;DR: The immunophenotype of the CNS as well as tumor cell characteristics and intracerebral interactions may create a micromilieu particularly conducive to PCNSL that may foster aggression of tumor cells and accelerate the fatal course of disease.
Journal ArticleDOI
Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma
TL;DR: There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects.
Journal ArticleDOI
Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma
Cigall Kadoch,Jing Li,Valerie S. Wong,Lingjing Chen,Soonmee Cha,Pamela N. Munster,Clifford A. Lowell,Marc A. Shuman,James L. Rubenstein +8 more
TL;DR: The first evidence of C3 activation within the neuroaxis with intraventricular immunotherapy is provided and it is suggested that complement may contribute to immunotherapeutic responses of rituximab in CNS lymphoma.
Journal ArticleDOI
Prognostic implications of tumor-infiltrating macrophages, M2 macrophages, regulatory T-cells, and indoleamine 2,3-dioxygenase-positive cells in primary diffuse large B-cell lymphoma of the central nervous system.
Soo Jeong Nam,Soo Jeong Nam,Sehui Kim,Dohee Kwon,Hannah Kim,So Yeon Kim,Eun Young Lee,Tae Min Kim,Tae Min Kim,Dae Seog Heo,Dae Seog Heo,Sung Hye Park,Megan S. Lim,Chul Woo Kim,Chul Woo Kim,Yoon Kyung Jeon,Yoon Kyung Jeon +16 more
TL;DR: It was shown that an increase in CD204+ cell numbers, suggestive of M2 macrophages, was associated with poor clinical outcome in CNS-DLBCL, whereas increased CD68+ or IDO- cell numbers were related to a favorable prognosis.
Journal ArticleDOI
Imaging and Therapy with Rituximab Anti-CD20 Immunotherapy in an Animal Model of Central Nervous System Lymphoma
Leslie L. Muldoon,Seth J. Lewin,Edit Dósa,Dale F. Kraemer,Michael A. Pagel,Nancy D. Doolittle,Edward A. Neuwelt,Edward A. Neuwelt +7 more
TL;DR: Rituximab was effective at decreasing tumor volume and improving survival in a model of CNS lymphoma and was not affected by combination with methotrexate or by BBBD.
References
More filters
Journal ArticleDOI
MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma
Monika E. Hegi,Annie-Claire Diserens,Thierry Gorlia,Marie-France Hamou,Nicolas de Tribolet,Nicolas de Tribolet,Michael Weller,Johan M. Kros,Johannes A. Hainfellner,Warren P. Mason,Luigi Mariani,Jacoline E C Bromberg,Peter Hau,René O. Mirimanoff,J. Gregory Cairncross,Robert C. Janzer,Roger Stupp +16 more
TL;DR: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylation of theMGMT promoter did notHave such a benefit and were assigned to only radiotherapy.
Journal ArticleDOI
Alternative activation of macrophages
TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.
Journal ArticleDOI
Monocyte and macrophage heterogeneity
Siamon Gordon,Philip R. Taylor +1 more
TL;DR: Recent studies have shown that monocyte heterogeneity is conserved in humans and mice, allowing dissection of its functional relevance: the different monocyte subsets seem to reflect developmental stages with distinct physiological roles, such as recruitment to inflammatory lesions or entry to normal tissues.
Journal ArticleDOI
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Alberto Mantovani,Silvano Sozzani,Silvano Sozzani,Massimo Locati,Paola Allavena,Antonio Sica +5 more
TL;DR: These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
Journal ArticleDOI
Macrophage activation and polarization.
TL;DR: The main functions of polarized macrophages are reviewed and the perspectives of this field are discussed, which include high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion.