Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model
15 Mar 2009-Clinical Cancer Research (American Association for Cancer Research)-Vol. 15, Iss: 6, pp 1989-1997
TL;DR: 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.
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TL;DR: In this paper, the authors used multiplex immunofluorescence and digital imaging analysis to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 primary central nervous system lymphoma (PCNSL) patients.
Abstract: Primary central nervous system lymphoma (PCNSL) is an aggressive and rare malignancy with poor prognosis. However, there are no reliable prognostic biomarkers for PCNSL in clinical practice. Here, we aimed to identify a reliable prognostic biomarker for predicting the survival of PCNSL patients. In this study, multiplex immunofluorescence and digital imaging analysis were used to characterize tumor-associated macrophages (TAMs) immunophenotypes and the expression of programmed cell death ligand 1 on TAMs, with regard to prognosis from diagnostic tumor tissue samples of 59 PCNSL patients. We found that the M2-to-M1 ratio was a more reliable prognostic biomarker for PCNSL than M1-like or M2-like macrophage infiltration. In addition, the combination of programmed death-ligand 1 (PD-L1) expression on TAMs and the M2-to-M1 ratio in PCNSL demonstrated improved performance in prognostic discrimination than PD-L1-positive TAMs or M2-to-M1 ratio. To validate the prognostic significance of the combined TAMs associated biomarkers, they were integrated into the International Extranodal Lymphoma Study Group (IELSG) index and termed as IELSG-M index. Kaplan-Meier plots showed that the IELSG-M index could discriminate patients into low-, intermediate- or high-risk subgroups, better than IELSG, in terms of prognosis. The areas under the receiver operating characteristic curves of IELSG-M was 0.844 for overall survival; superior to the IELSG model (0.580). Taken together, this study's findings showed that the combination of PD-L1 on TAMs and the M2-to-M1 ratio could be strong prognostic predictive biomarkers for PCNSL and the IELSG-M index had improved prognostic significance than the IELSG index.
1 citations
TL;DR: Results indicated that B7-H4 level was clearly enhanced in CRSwNP patients and associated with postoperative recurrence, and it might serve as a simple and convenient biomarker for early predicting postoperatively recurrence in CRw NP patients.
Abstract: Background Chronic rhinosinusitis with polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinuses with a high rate of postoperative recurrence. In this study, we aim to investigate the expression of B7-H4 in CRSwNP and its association with postoperative recurrence. Methods A total of 80 CRSwNP patients, including 40 primary CRSwNP (pCRSwNP) patients and 40 recurrent CRSwNP (rCRSwNP) patients, 27 chronic rhinosinusitis without polyps (CRSsNP) and 32 healthy controls (HC) were enrolled in this study, and the serum, nasal polyps and middle turbinate tissue samples were collected. Peripheral and tissue B7-H4 expressions were detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence, and their clinical values in predicting postoperative recurrence of CRSwNP were evaluated. Results We identified significantly higher tissue B7-H4 mRNA levels in the CRSwNP group than in the HC group, and elevated B7-H4 levels were associated with tissue eosinophil count and percentage (r = 0.469, P < 0.001; r = 0.521, P < 0.001). B7-H4 mRNA and protein levels were significantly higher in the rCRSwNP group than the pCRSwP group. Multivariate analysis and receiver operating characteristic (ROC) curves showed that tissue B7-H4 levels were associated with postoperative recurrence in patients with CRSwNP (P < 0.05). In addition, serum B7-H4 levels were significantly increased in the CRSwNP group than the CRS and HC groups, especially in the rCRSwNP group (P < 0.05), and the ROC curve presented a predictive ability of serum B7-H4 in predicting postoperative recurrence. Conclusion Our results indicated that B7-H4 level was clearly enhanced in CRSwNP patients and associated with postoperative recurrence. Serum B7-H4 might serve as a simple and convenient biomarker for early predicting postoperative recurrence in CRwNP patients.
1 citations
01 Jan 2012
TL;DR: Insights into the biology of primary central nervous system lymphoma (PCNSL) are essential to facilitate the development of more effective treatment for this uncommon variant of extranodal non-Hodgkin lymphoma.
Abstract: Insights into the biology of primary central nervous system lymphoma (PCNSL) are essential to facilitate the development of more effective treatment for this uncommon variant of extranodal non-Hodgkin lymphoma (NHL). An accumulating body of evidence suggests that the molecular pathogenesis of PCNSL is distinct from systemic lymphomas of the same histological type. First, 90% of NHL cases that present in the central nervous system (CNS) will, upon staging, prove to be confined to the brain, leptomeninges, optic nerves, and intraocular structures and thus be classified as PCNSL. Over the natural history of the disease, it is rare for PCNSL tumors to recur outside of the brain, underscoring this unique tropism for the CNS. Second, PCNSL tumors are associated with an inferior prognosis compared to other localized extranodal NHL tumors confined to a single extranodal site, such as bone. Third, CNS lymphomas tend to exhibit a heightened responsiveness to high-dose methotrexate-based therapy compared to systemic lymphomas with a concomitant diminished responsiveness to adriamycin-based chemotherapy regimens [1].
1 citations
Cites background from "Pathologic Correlates of Primary Ce..."
...recently provided evidence for the M2 polarization of tumor macrophages in diagnostic specimens of PCNSL [25]....
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TL;DR: Under normal conditions, the brain maintains a relatively quiescent immunologic state, however in the setting of CNS lymphoma, a robust inflammatory response is often detectable in diagnostic species.
Abstract: Under normal conditions, the brain maintains a relatively quiescent immunologic state, however in the setting of CNS lymphoma, a robust inflammatory response is often detectable in diagnostic speci...
1 citations
Cites background from "Pathologic Correlates of Primary Ce..."
...response is often detectable in diagnostic specimens, consisting predominantly of infiltrating activated macrophages and reactive T cells [1,2]....
[...]
...Expression of interleukin-4, another immunosuppressive Th2 cytokine, has also been demonstrated by B-cells in PCNSL and in an experimental model system of CNS lymphoma [2,18]....
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TL;DR: Wang et al. as mentioned in this paper investigated the expression of B7-H4 in chronic rhinosinusitis with polyps (CRSwNP) and its association with postoperative recurrence.
Abstract: Chronic rhinosinusitis with polyps (CRSwNP) is a common chronic inflammatory disease of the nasal cavity and sinuses with a high rate of postoperative recurrence. In this study, we aim to investigate the expression of B7-H4 in CRSwNP and its association with postoperative recurrence.A total of 80 CRSwNP patients, including 40 primary CRSwNP (pCRSwNP) patients and 40 recurrent CRSwNP (rCRSwNP) patients, 27 chronic rhinosinusitis without polyps (CRSsNP) and 32 healthy controls (HC) were enrolled in this study, and the serum, nasal polyps and middle turbinate tissue samples were collected. Peripheral and tissue B7-H4 expressions were detected by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence, and their clinical values in predicting postoperative recurrence of CRSwNP were evaluated.We identified significantly higher tissue B7-H4 mRNA levels in the CRSwNP group than in the HC group, and elevated B7-H4 levels were associated with tissue eosinophil count and percentage (r = 0.469, P < 0.001; r = 0.521, P < 0.001). B7-H4 mRNA and protein levels were significantly higher in the rCRSwNP group than the pCRSwP group. Multivariate analysis and receiver operating characteristic (ROC) curves showed that tissue B7-H4 levels were associated with postoperative recurrence in patients with CRSwNP (P < 0.05). In addition, serum B7-H4 levels were significantly increased in the CRSwNP group than the CRS and HC groups, especially in the rCRSwNP group (P < 0.05), and the ROC curve presented a predictive ability of serum B7-H4 in predicting postoperative recurrence.Our results indicated that B7-H4 level was clearly enhanced in CRSwNP patients and associated with postoperative recurrence. Serum B7-H4 might serve as a simple and convenient biomarker for early predicting postoperative recurrence in CRwNP patients.
1 citations
References
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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.
Abstract: background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.
6,018 citations
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.
Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
5,930 citations
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.
Abstract: Heterogeneity of the macrophage lineage has long been recognized and, in part, is a result of the specialization of tissue macrophages in particular microenvironments. Circulating monocytes give rise to mature macrophages and are also heterogeneous themselves, although the physiological relevance of this is not completely understood. However, as we discuss here, 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. These advances in our understanding have implications for the development of therapeutic strategies that are targeted to modify particular subpopulations of monocytes.
4,861 citations
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.
4,728 citations
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.
Abstract: Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.
2,836 citations