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Published in: BMC Medicine 1/2021

01-12-2021 | Glioma | Research article

Telomerase-positive circulating tumor cells are associated with poor prognosis via a neutrophil-mediated inflammatory immune environment in glioma

Authors: Wen Zhang, Tiancheng Qin, Zhenrong Yang, Liyuan Yin, Changyun Zhao, Lin Feng, Song Lin, Binlei Liu, Shujun Cheng, Kaitai Zhang

Published in: BMC Medicine | Issue 1/2021

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Abstract

Background

Gliomas are the most common aggressive cancer in the central nervous system. Considering the difficulty in monitoring glioma response and progression, an approach is needed to evaluate the progression or survival of patients with glioma. We propose an application to facilitate clinical detection and treatment monitoring in glioma patients by using telomerase-positive circulating tumor cells (CTCs) and to further evaluate the relationship between the immune microenvironment and CTCs in glioma patients.

Methods

From October 2014 to June 2017, 106 patients newly diagnosed with glioma were enrolled. We used the telomerase reverse transcriptase CTC detection method to detect and analyze the CTC statuses of glioma patients before and after surgery. FlowSight and FISH confirmed the CTCs detected by the telomerase-based method. To verify the correlation between CTCs and the immune response, peripheral white blood cell RNA sequencing was performed.

Results

CTCs were common in the peripheral blood of glioma patients and were not correlated with the pathological classification or grade of patients. The results showed that the presence of postoperative CTCs but not preoperative CTCs in glioma patients was a poor prognostic factor. The level of postoperative CTCs, which predicts a poor prognosis after surgery, may be associated with neutrophils. RNA sequencing suggested that postoperative CTCs were positively correlated with innate immune responses, especially the activation of neutrophils and the generation of neutrophil extracellular traps, but negatively correlated with the cytotoxic response.

Conclusions

Our results showed that telomerase-positive CTCs can predict a poor prognosis of patients with glioma. Our results also showed a correlation between CTCs and the immune macroenvironment, which provides a new perspective for the treatment of glioma.
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Literature
2.
go back to reference Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709-722. https://doi.org/https://doi.org/10.1056/NEJMoa1308345. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709-722. https://​doi.​org/​https://​doi.​org/​10.​1056/​NEJMoa1308345.
4.
go back to reference Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. https://doi.org/https://doi.org/10.1056/NEJMoa043330. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. https://​doi.​org/​https://​doi.​org/​10.​1056/​NEJMoa043330.
5.
go back to reference Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100-1108. https://doi.org/https://doi.org/10.1016/S1470-2045(14)70379-1. Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, et al. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(10):1100-1108. https://​doi.​org/​https://​doi.​org/​10.​1016/​S1470-2045(14)70379-1.
10.
go back to reference Zhang W, Bao L, Yang S, Qian Z, Dong M, Yin L, et al. Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells. Oncotarget. 2016;7(26):39768-39783. https://doi.org/https://doi.org/10.18632/oncotarget.9465. Zhang W, Bao L, Yang S, Qian Z, Dong M, Yin L, et al. Tumor-selective replication herpes simplex virus-based technology significantly improves clinical detection and prognostication of viable circulating tumor cells. Oncotarget. 2016;7(26):39768-39783. https://​doi.​org/​https://​doi.​org/​10.​18632/​oncotarget.​9465.
14.
go back to reference Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. https://doi.org/10.1038/s41467-019-09234-6. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523. https://​doi.​org/​10.​1038/​s41467-019-09234-6.​
15.
go back to reference Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550. https://doi.org/https://doi.org/10.1073/pnas.0506580102. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545-15550. https://​doi.​org/​https://​doi.​org/​10.​1073/​pnas.​0506580102.
17.
go back to reference Racle J, de Jonge K, Baumgaertner P, Speiser DE, Gfeller D. Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife. 2017;6:e26476. https://doi.org/https://doi.org/10.7554/eLife.26476. Racle J, de Jonge K, Baumgaertner P, Speiser DE, Gfeller D. Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data. Elife. 2017;6:e26476. https://​doi.​org/​https://​doi.​org/​10.​7554/​eLife.​26476.
23.
go back to reference de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309. https://doi.org/https://doi.org/10.1158/1078-0432.CCR-08-0872. de Bono JS, Scher HI, Montgomery RB, Parker C, Miller MC, Tissing H, et al. Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clin Cancer Res. 2008;14(19):6302-6309. https://​doi.​org/​https://​doi.​org/​10.​1158/​1078-0432.​CCR-08-0872.
24.
go back to reference Bang-Christensen SR, Pedersen RS, Pereira MA, Clausen TM, Løppke C, Sand NT, et al. Capture and Detection of Circulating Glioma Cells Using the Recombinant VAR2CSA Malaria Protein. Cells. 2019;8(9):998. https://doi.org/https://doi.org/10.3390/cells8090998. Bang-Christensen SR, Pedersen RS, Pereira MA, Clausen TM, Løppke C, Sand NT, et al. Capture and Detection of Circulating Glioma Cells Using the Recombinant VAR2CSA Malaria Protein. Cells. 2019;8(9):998. https://​doi.​org/​https://​doi.​org/​10.​3390/​cells8090998.
25.
26.
27.
go back to reference Sareen H, Garrett C, Lynch D, Powter B, Brungs D, Cooper A, et al. The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients. Cancers (Basel). 2020;12(7):1831. https://doi.org/https://doi.org/10.3390/cancers12071831. Sareen H, Garrett C, Lynch D, Powter B, Brungs D, Cooper A, et al. The Role of Liquid Biopsies in Detecting Molecular Tumor Biomarkers in Brain Cancer Patients. Cancers (Basel). 2020;12(7):1831. https://​doi.​org/​https://​doi.​org/​10.​3390/​cancers12071831.
28.
go back to reference Adamczyk LA, Williams H, Frankow A, Ellis HP, Haynes HR, Perks C, et al. Current Understanding of Circulating Tumor Cells - Potential Value in Malignancies of the Central Nervous System. Front Neurol. 2015;6:174. https://doi.org/https://doi.org/10.3389/fneur.2015.00174. Adamczyk LA, Williams H, Frankow A, Ellis HP, Haynes HR, Perks C, et al. Current Understanding of Circulating Tumor Cells - Potential Value in Malignancies of the Central Nervous System. Front Neurol. 2015;6:174. https://​doi.​org/​https://​doi.​org/​10.​3389/​fneur.​2015.​00174.
29.
go back to reference Komata T, Kondo Y, Kanzawa T, Ito H, Hirohata S, Koga S, et al. Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells. Hum Gene Ther. 2002;13(9):1015-1025. https://doi.org/https://doi.org/10.1089/104303402753812421. Komata T, Kondo Y, Kanzawa T, Ito H, Hirohata S, Koga S, et al. Caspase-8 gene therapy using the human telomerase reverse transcriptase promoter for malignant glioma cells. Hum Gene Ther. 2002;13(9):1015-1025. https://​doi.​org/​https://​doi.​org/​10.​1089/​1043034027538124​21.
31.
go back to reference Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26(13):2192-2197. https://doi.org/https://doi.org/10.1200/JCO.2007.14.8163. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26(13):2192-2197. https://​doi.​org/​https://​doi.​org/​10.​1200/​JCO.​2007.​14.​8163.
33.
36.
37.
go back to reference Dinallo V, Marafini I, Di Fusco D, Laudisi F, Franzè E, Di Grazia A, et al. Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis. J Crohns Colitis. 2019;13(6):772-784. https://doi.org/https://doi.org/10.1093/ecco-jcc/jjy215. Dinallo V, Marafini I, Di Fusco D, Laudisi F, Franzè E, Di Grazia A, et al. Neutrophil Extracellular Traps Sustain Inflammatory Signals in Ulcerative Colitis. J Crohns Colitis. 2019;13(6):772-784. https://​doi.​org/​https://​doi.​org/​10.​1093/​ecco-jcc/​jjy215.
38.
go back to reference Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O'Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134(4):395-406. https://doi.org/10.1182/blood.2018892752. Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O'Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. 2019;134(4):395-406. https://​doi.​org/​10.​1182/​blood.​2018892752.​
40.
go back to reference Lynch D, Powter B, Po J.W, Cooper A, Garrett C, Koh E.-S, et al. Isolation of Circulating Tumor Cells from Glioblastoma Patients by Direct Immunomagnetic Targeting. Appl. Sci. 2020;10(9):3338. https://doi.org/https://doi.org/10.3390/app10093338. Lynch D, Powter B, Po J.W, Cooper A, Garrett C, Koh E.-S, et al. Isolation of Circulating Tumor Cells from Glioblastoma Patients by Direct Immunomagnetic Targeting. Appl. Sci. 2020;10(9):3338. https://​doi.​org/​https://​doi.​org/​10.​3390/​app10093338.
41.
go back to reference Ott M, Tomaszowski KH, Marisetty A, Kong LY, Wei J, et al. Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration. JCI Insight. 2020;5(17):e134386. https://doi.org/https://doi.org/10.1172/jci.insight.134386. Ott M, Tomaszowski KH, Marisetty A, Kong LY, Wei J, et al. Profiling of patients with glioma reveals the dominant immunosuppressive axis is refractory to immune function restoration. JCI Insight. 2020;5(17):e134386. https://​doi.​org/​https://​doi.​org/​10.​1172/​jci.​insight.​134386.
42.
go back to reference Marinari E, Allard M, Gustave R, Widmer V, Philippin G, Merkler D, et al. Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma. Oncoimmunology. 2020;9(1):1779990. https://doi.org/https://doi.org/10.1080/2162402X.2020.1779990. Marinari E, Allard M, Gustave R, Widmer V, Philippin G, Merkler D, et al. Inflammation and lymphocyte infiltration are associated with shorter survival in patients with high-grade glioma. Oncoimmunology. 2020;9(1):1779990. https://​doi.​org/​https://​doi.​org/​10.​1080/​2162402X.​2020.​1779990.
43.
go back to reference De Boeck A, Ahn BY, D'Mello C, Lun X, Menon SV, Alshehri MM, et al. Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression. Nat Commun. 2020;11(1):4997. https://doi.org/https://doi.org/10.1038/s41467-020-18569-4. De Boeck A, Ahn BY, D'Mello C, Lun X, Menon SV, Alshehri MM, et al. Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression. Nat Commun. 2020;11(1):4997. https://​doi.​org/​https://​doi.​org/​10.​1038/​s41467-020-18569-4.
44.
go back to reference Song L, Quan X, Su L, Wang K, Wang H, Wu L, et al. Inflammation and behavioral symptoms in preoperational glioma patients: Is depression, anxiety, and cognitive impairment related to markers of systemic inflammation? Brain Behav. 2020;10(9):e01771. https://doi.org/https://doi.org/10.1002/brb3.1771. Song L, Quan X, Su L, Wang K, Wang H, Wu L, et al. Inflammation and behavioral symptoms in preoperational glioma patients: Is depression, anxiety, and cognitive impairment related to markers of systemic inflammation? Brain Behav. 2020;10(9):e01771. https://​doi.​org/​https://​doi.​org/​10.​1002/​brb3.​1771.
Metadata
Title
Telomerase-positive circulating tumor cells are associated with poor prognosis via a neutrophil-mediated inflammatory immune environment in glioma
Authors
Wen Zhang
Tiancheng Qin
Zhenrong Yang
Liyuan Yin
Changyun Zhao
Lin Feng
Song Lin
Binlei Liu
Shujun Cheng
Kaitai Zhang
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-021-02138-7

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