Sungho Lee1,2, Khatri Latha2, Ganiraju Manyam3, Yuhui Yang2, Arvind Rao4, Ganesh Rao1. 1. Department of Neurosurgery, Baylor College of Medicine, Houston, Texas. 2. Departments of Neurosurgery. 3. Bioinformatics, and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas (G.M.). 4. Departments of Computational Medicine and Bioinformatics, Radiation Oncology, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
Abstract
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.
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.
Authors: Ling-Yuan Kong; Adam S Wu; Tiffany Doucette; Jun Wei; Waldemar Priebe; Gregory N Fuller; Wei Qiao; Raymond Sawaya; Ganesh Rao; Amy B Heimberger Journal: Clin Cancer Res Date: 2010-10-04 Impact factor: 12.531
Authors: Ki-Wook Kim; Alexandra Vallon-Eberhard; Ehud Zigmond; Julia Farache; Elias Shezen; Guy Shakhar; Andreas Ludwig; Sergio A Lira; Steffen Jung Journal: Blood Date: 2011-09-27 Impact factor: 22.113
Authors: Martin C Tom; Deborah Y J Park; Kailin Yang; C Marc Leyrer; Wei Wei; Xuefei Jia; Vamsi Varra; Jennifer S Yu; Samuel T Chao; Ehsan H Balagamwala; John H Suh; Michael A Vogelbaum; Gene H Barnett; Richard A Prayson; Glen H J Stevens; David M Peereboom; Manmeet S Ahluwalia; Erin S Murphy Journal: Int J Radiat Oncol Biol Phys Date: 2019-08-25 Impact factor: 7.038
Authors: D Moatti; S Faure; F Fumeron; M el-W Amara; P Seknadji; D H McDermott; P Debré; M C Aumont; P M Murphy; D de Prost; C Combadière Journal: Blood Date: 2001-04-01 Impact factor: 22.113
Authors: Krishna P L Bhat; Katrina L Salazar; Veerakumar Balasubramaniyan; Khalida Wani; Lindsey Heathcock; Faith Hollingsworth; Johanna D James; Joy Gumin; Kristin L Diefes; Se Hoon Kim; Alice Turski; Yasaman Azodi; Yuhui Yang; Tiffany Doucette; Howard Colman; Erik P Sulman; Frederick F Lang; Ganesh Rao; Sjef Copray; Brian D Vaillant; Kenneth D Aldape Journal: Genes Dev Date: 2011-12-15 Impact factor: 11.361
Authors: Amy B Heimberger; Mohamed Abou-Ghazal; Chantal Reina-Ortiz; David S Yang; Wei Sun; Wei Qiao; Nobuyoshi Hiraoka; Gregory N Fuller Journal: Clin Cancer Res Date: 2008-08-15 Impact factor: 12.531
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Michael Platten; Alexandra Kretz; Ulrike Naumann; Steffen Aulwurm; Kensuke Egashira; Stefan Isenmann; Michael Weller Journal: Ann Neurol Date: 2003-09 Impact factor: 10.422