TY - JOUR
T1 - Role of CX3CR1 signaling in malignant transformation of gliomas
AU - Lee, Sungho
AU - Latha, Khatri
AU - Manyam, Ganiraju
AU - Yang, Yuhui
AU - Rao, Arvind
AU - Rao, Ganesh
N1 - Funding Information:
This work was supported by the National Institutes of Health (R01NS094615 to G.R. and R25NS070694 to S.L.); Tumor SPORE (P50CA127001 to G.R.); and Marnie Rose Foundation (G.R.). The
Funding Information:
Sequencing and Microarray Facility is funded by NCI Grant CA016672.
Publisher Copyright:
© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
PY - 2020
Y1 - 2020
N2 - Background. Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods. Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results. LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions. CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.
AB - Background. Chemokine signaling may contribute to progression of low-grade gliomas (LGGs) by altering tumor behavior or impacting the tumor microenvironment. In this study, we investigated the role of CX3C chemokine receptor 1 (CX3CR1) signaling in malignant transformation of LGGs. Methods. Ninety patients with LGGs were genotyped for the presence of common CX3CR1 V249I polymorphism and examined for genotype-dependent alterations in survival, gene expression, and tumor microenvironment. A genetically engineered mouse model was leveraged to model endogenous intracranial gliomas with targeted expression of CX3C ligand 1 (CX3CL1) and CX3CR1, individually or in combination. Results. LGG patients who were heterozygous (V/I; n = 43) or homozygous (I/I; n = 2) for the CX3CR1 V249I polymorphism had significantly improved median overall (14.8 vs 9.8 y, P < 0.05) and progression-free survival (8.6 vs 6.5 y, P < 0.05) compared with those with the wild type genotype (V/V; n = 45). Tumors from the V/I + I/I group exhibited significantly decreased levels of CCL2 and MMP9 transcripts, correlating with reduced intratumoral M2 macrophage infiltration and microvessel density. In an immunocompetent mouse model of LGGs, coexpression of CX3CL1 and CX3CR1 promoted a more malignant tumor phenotype characterized by increased microglia/macrophage infiltration and microvessel density, resulting in shorter survival. Conclusions. CX3CR1 V249I polymorphism is associated with improved overall and progression-free survival in LGGs. CX3CR1 signaling enhances accumulation of tumor associated microglia/macrophages and angiogenesis during malignant transformation.
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U2 - 10.1093/neuonc/noaa075
DO - 10.1093/neuonc/noaa075
M3 - Article
C2 - 32236410
AN - SCOPUS:85084800137
SN - 1522-8517
VL - 22
SP - 1463
EP - 1473
JO - Neuro-oncology
JF - Neuro-oncology
IS - 10
ER -