Systematic Analysis of Chemokines Reveals CCL18 is a Prognostic Biomarker in Glioblastoma

Background Glioblastoma (GBM) is the most common and aggressive brain tumor in adults, in which chemokines are often upregulated and may play pivotal roles in their development and progression. Chemokines are a large subfamily of cytokines with leukocyte chemotactic activities involved in various tumor progression. However, gene expression patterns of the chemokines on a global scale were not known in GBM. Methods Differentially expressed chemokine genes in glioma and normal samples were screened by using The Cancer Genome Atlas (TCGA) database. Cox regression identified the prognosis-related genes in each glioma subtype. The protein expression levels of chemokines in 72 glioma tissues were detected by ELISA. Results We found that the transcripts of seven chemokines, including CCL2, CCL8, CCL18, CCL28, CXCL1, CXCL5, and CXCL13, were highly expressed in GBM that evidenced by involving immune cell infiltration regulation and accompanied with worse outcomes of GBM patients. The prognostic nomogram construction demonstrated that CCL18 held the highest risk score in patients with GBM. Furthermore, experiments on 72 glioma tissue samples confirmed that CCL18 protein expression was positively associated with tumor grade and IDH1 status but inversely with glioma patients’ overall survival (OS). Conclusion Our study reveals comprehensive and comparable roles of chemokine members in glioblastoma, and identified CCL18 as a critical driver of GBM malignant behaviors, therefore providing a potential target for developing prognosis and therapy in human glioblastoma.

[1]  Sagar M. Utturkar,et al.  Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells , 2021, Proceedings of the National Academy of Sciences.

[2]  Truc-Vien T. Nguyen,et al.  Identifying GPSM Family Members as Potential Biomarkers in Breast Cancer: A Comprehensive Bioinformatics Analysis , 2021, Biomedicines.

[3]  Wei Yu,et al.  CCL2: An Important Mediator Between Tumor Cells and Host Cells in Tumor Microenvironment , 2021, Frontiers in Oncology.

[4]  H. Daldrup-Link,et al.  Glioblastoma Multiforme (GBM): An overview of current therapies and mechanisms of resistance. , 2021, Pharmacological research.

[5]  P. Vajkoczy,et al.  Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma , 2021, Cancers.

[6]  B. Mroczko,et al.  Pro- and Antiangiogenic Factors in Gliomas: Implications for Novel Therapeutic Possibilities , 2021, International journal of molecular sciences.

[7]  Ji Zhang,et al.  Correlation of Tim-3 expression with chemokine levels for predicting the prognosis of patients with glioblastoma , 2021, Journal of Neuroimmunology.

[8]  K. Huang,et al.  Development of a prognostic index based on immunogenomic landscape analysis in glioma , 2021, Immunity, inflammation and disease.

[9]  M. Kavallaris,et al.  Frontiers in the treatment of glioblastoma: Past, present and emerging. , 2021, Advanced drug delivery reviews.

[10]  D. Bedognetti,et al.  Cytokine-chemokine network driven metastasis in esophageal cancer; promising avenue for targeted therapy , 2021, Molecular cancer.

[11]  J. Harrison,et al.  Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy. , 2020, Pharmacology & therapeutics.

[12]  J. Barnholtz-Sloan,et al.  CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2013-2017. , 2020, Neuro-oncology.

[13]  P. Dzięgiel,et al.  CCL18 in the Progression of Cancer , 2020, International journal of molecular sciences.

[14]  A. Marabelle,et al.  Chemokine biology on immune checkpoint-targeted therapies. , 2020, European journal of cancer.

[15]  Xue-Ting Deng,et al.  CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target , 2020, Cancer communications.

[16]  X. Jia,et al.  CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis , 2020, Molecular Cancer.

[17]  H. Kettenmann,et al.  Microglia/Brain Macrophages as Central Drivers of Brain Tumor Pathobiology , 2019, Neuron.

[18]  B. Fazi,et al.  The Expression of the Chemokine CXCL14 Correlates with Several Aggressive Aspects of Glioblastoma and Promotes Key Properties of Glioblastoma Cells , 2019, International journal of molecular sciences.

[19]  R. Bonecchi,et al.  Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy , 2019, Front. Immunol..

[20]  A. Richmond,et al.  Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy , 2019, Front. Immunol..

[21]  Damian Szklarczyk,et al.  STRING v11: protein–protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets , 2018, Nucleic Acids Res..

[22]  L. Pusztai,et al.  Immunological differences between primary and metastatic breast cancer , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[23]  X. Breakefield,et al.  Multidimensional communication in the microenvirons of glioblastoma , 2018, Nature Reviews Neurology.

[24]  M. Weller,et al.  Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[25]  P. Wesseling,et al.  WHO 2016 Classification of gliomas , 2018, Neuropathology and applied neurobiology.

[26]  Weiping Zou,et al.  Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy , 2017, Nature Reviews Immunology.

[27]  G. Lenz,et al.  The Epithelial‐to‐Mesenchymal Transition‐Like Process in Glioblastoma: An Updated Systematic Review and In Silico Investigation , 2017, Medicinal research reviews.

[28]  Yang Liu,et al.  Bioinformatic profiling identifies an immune-related risk signature for glioblastoma , 2016, Neurology.

[29]  K. Kelsey,et al.  Serum macrophage‐derived chemokine/CCL22 levels are associated with glioma risk, CD4 T cell lymphopenia and survival time , 2015, International journal of cancer.

[30]  Z. Trajanoski,et al.  Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer. , 2013, Immunity.

[31]  P. Wesseling Classification of Gliomas , 2013 .

[32]  Justin Guinney,et al.  GSVA: gene set variation analysis for microarray and RNA-Seq data , 2013, BMC Bioinformatics.

[33]  A. Zlotnik,et al.  The chemokine superfamily revisited. , 2012, Immunity.

[34]  Guangchuang Yu,et al.  clusterProfiler: an R package for comparing biological themes among gene clusters. , 2012, Omics : a journal of integrative biology.

[35]  M. Ewen,et al.  CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. , 2011, Cancer cell.

[36]  David T. W. Jones,et al.  IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas. , 2009, Neuro-oncology.

[37]  Julia L. Wilson,et al.  The chemokine network: a target in cancer biology? , 2006, Advanced drug delivery reviews.

[38]  M. Baggiolini Chemokines and leukocyte traffic , 1998, Nature.

[39]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[40]  C. N. Brorn,et al.  WHO? , 1896 .