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Article

Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis

Expression of Concern in: /10.3892/or.2025.8989
  • Authors:
    • Ying Wang
    • Tao Liu
    • Ning Yang
    • Shuo Xu
    • Xingang Li
    • Donghai Wang
  • View Affiliations / Copyright

    Affiliations: Department of Rehabilitation, Qilu Children's Hospital of Shandong University, Jinan, Shandong, P.R. China, Department of Neurosurgery, Qilu Hospital, Shandong University, Jinan, Shandong, P.R. China
  • Pages: 3522-3528
    |
    Published online on: October 13, 2016
       https://doi.org/10.3892/or.2016.5171
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Abstract

Glioblastoma (GBM) is a highly malignant brain tumor characterized by invasion tendency. Macrophage infiltration is associated with GBM invasion, but the mechanisms remain unclear. Hypoxia is an outstanding characteristic of GBM tissue. Hypoxia microenvironment modulates the biological behaviors of both tumor cells and infiltrated immune cells, including macrophages. In the present study, we analyzed the effects of hypoxia and macrophages on invasion of GBM cells and its potential mechanisms. We found that both hypoxia and macrophage supernatant promoted GBM cells invasion and matrix metalloproteinase (MMP)-9 expression, and hypoxia modulated the invasive activity of GBM cells by upregulating their CCR5 expression. The supernatant of hypoxic macrophages also showed greater pro-invasion effect than normoxic macrophages through the elevated secretion of CCL4. Moreover, we found that interferon regulatory factor-8 (IRF-8) was possibly involved in hypoxia-modulated CCL4 expression of macrophages. Taken together, the present study found that macrophages promoted GBM invasion by the CCL4-CCR5 axis, and hypoxia enhanced the interaction between these two types of cells by upregulating both CCL4 and CCR5 expression, respectively. The results of the present study suggested that hypoxia would be a potential target for the development of immune therapies of GBM.
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1 

Huse JT and Holland EC: Targeting brain cancer: Advances in the molecular pathology of malignant glioma and medulloblastoma. Nat Rev Cancer. 10:319–331. 2010. View Article : Google Scholar : PubMed/NCBI

2 

Davis FG, McCarthy BJ, Freels S, Kupelian V and Bondy ML: The conditional probability of survival of patients with primary malignant brain tumors: Surveillance, epidemiology, and end results (SEER) data. Cancer. 85:485–491. 1999. View Article : Google Scholar : PubMed/NCBI

3 

Meyer MA: Malignant gliomas in adults. N Engl J Med. 359:18502008. View Article : Google Scholar : PubMed/NCBI

4 

Kanu OO, Mehta A, Di C, Lin N, Bortoff K, Bigner DD, Yan H and Adamson DC: Glioblastoma multiforme: A review of therapeutic targets. Expert Opin Ther Targets. 13:701–718. 2009. View Article : Google Scholar : PubMed/NCBI

5 

Giese A, Bjerkvig R, Berens ME and Westphal M: Cost of migration: Invasion of malignant gliomas and implications for treatment. J Clin Oncol. 21:1624–1636. 2003. View Article : Google Scholar : PubMed/NCBI

6 

Hussain SF, Yang D, Suki D, Aldape K, Grimm E and Heimberger AB: The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neuro Oncol. 8:261–279. 2006. View Article : Google Scholar : PubMed/NCBI

7 

Graeber MB, Scheithauer BW and Kreutzberg GW: Microglia in brain tumors. Glia. 40:252–259. 2002. View Article : Google Scholar : PubMed/NCBI

8 

Kushchayev SV, Kushchayeva YS, Wiener PC, Scheck AC, Badie B and Preul MC: Monocyte-derived cells of the brain and malignant gliomas: The double face of Janus. World Neurosurg. 82:1171–1186. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Yang I, Han SJ, Kaur G, Crane C and Parsa AT: The role of microglia in central nervous system immunity and glioma immunology. J Clin Neurosci. 17:6–10. 2010. View Article : Google Scholar : PubMed/NCBI

10 

Charles NA, Holland EC, Gilbertson R, Glass R and Kettenmann H: The brain tumor microenvironment. Glia. 60:502–514. 2012. View Article : Google Scholar : PubMed/NCBI

11 

da Fonseca AC and Badie B: Microglia and macrophages in malignant gliomas: Recent discoveries and implications for promising therapies. Clin Dev Immunol. 2013:2641242013.PubMed/NCBI

12 

Ye XZ, Xu SL, Xin YH, Yu SC, Ping YF, Chen L, Xiao HL, Wang B, Yi L, Wang QL, et al: Tumor-associated microglia/macrophages enhance the invasion of glioma stem-like cells via TGF-β1 signaling pathway. J Immunol. 189:444–453. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Markovic DS, Vinnakota K, Chirasani S, Synowitz M, Raguet H, Stock K, Sliwa M, Lehmann S, Kälin R, van Rooijen N, et al: Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion. Proc Natl Acad Sci USA. 106:12530–12535. 2009. View Article : Google Scholar : PubMed/NCBI

14 

Lin HC, Song TY and Hu ML: S-Adenosylhomocysteine promotes the invasion of C6 glioma cells via increased secretion of matrix metalloproteinase-2 in murine microglial BV2 cells. Toxicol Sci. 112:322–330. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins K, Magarelli DP, Hahn SM, et al: Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res. 10:8177–8184. 2004. View Article : Google Scholar : PubMed/NCBI

16 

16. Kessler J, Hahnel A, Wichmann H, Rot S, Kappler M, Bache M and Vordermark D: HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: Effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer. 10:6052010. View Article : Google Scholar : PubMed/NCBI

17 

Yang L, Lin C, Wang L, Guo H and Wang X: Hypoxia and hypoxia-inducible factors in glioblastoma multiforme progression and therapeutic implications. Exp Cell Res. 318:2417–2426. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Shen Z, Kauttu T, Seppänen H, Vainionpää S, Ye Y, Wang S, Mustonen H and Puolakkainen P: Both macrophages and hypoxia play critical role in regulating invasion of gastric cancer in vitro. Acta Oncol. 52:852–860. 2013. View Article : Google Scholar : PubMed/NCBI

19 

Shen Z, Seppänen H, Vainionpää S, Ye Y, Wang S, Mustonen H and Puolakkainen P: IL10, IL11, IL18 are differently expressed in CD14+ TAMs and play different role in regulating the invasion of gastric cancer cells under hypoxia. Cytokine. 59:352–357. 2012. View Article : Google Scholar : PubMed/NCBI

20 

Mu L, Wang J, Chen Y, Li L, Guo X, Zheng S and Jing C: Hypoxia-inducible factor-1α and semaphorin4D genes involved with tumor-associated macrophage-induced metastatic behavior and clinical significance in colon cancer. Chin Med J. 127:3568–3575. 2014.PubMed/NCBI

21 

Zhao P, Gao D, Wang Q, Song B, Shao Q, Sun J, Ji C, Li X, Li P and Qu X: Response gene to complement 32 (RGC-32) expression on M2-polarized and tumor-associated macrophages is M-CSF-dependent and enhanced by tumor-derived IL-4. Cell Mol Immunol. 12:692–699. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Chen S, Han M, Chen W, He Y, Huang B, Zhao P, Huang Q, Gao L, Qu X and Li X: KIF1B promotes glioma migration and invasion via cell surface localization of MT1-MMP. Oncol Rep. 35:971–977. 2016.PubMed/NCBI

23 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Zhao L, Wang Y, Xue Y, Lv W, Zhang Y and He S: Critical roles of chemokine receptor CCR5 in regulating glioblastoma proliferation and invasion. Acta Biochim Biophys Sin. 47:890–898. 2015. View Article : Google Scholar : PubMed/NCBI

25 

Pham K, Luo D, Liu C and Harrison JK: CCL5, CCR1 and CCR5 in murine glioblastoma: Immune cell infiltration and survival rates are not dependent on individual expression of either CCR1 or CCR5. J Neuroimmunol. 246:10–17. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Lin S, Wan S, Sun L, Hu J, Fang D, Zhao R, Yuan S and Zhang L: Chemokine C-C motif receptor 5 and C-C motif ligand 5 promote cancer cell migration under hypoxia. Cancer Sci. 103:904–912. 2012. View Article : Google Scholar : PubMed/NCBI

27 

Zhang J, Sarkar S, Cua R, Zhou Y, Hader W and Yong VW: A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis. 33:312–319. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Zagzag D, Lukyanov Y, Lan L, Ali MA, Esencay M, Mendez O, Yee H, Voura EB and Newcomb EW: Hypoxia-inducible factor 1 and VEGF upregulate CXCR4 in glioblastoma: Implications for angiogenesis and glioma cell invasion. Lab Invest. 86:1221–1232. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Günthner R and Anders HJ: Interferon-regulatory factors determine macrophage phenotype polarization. Mediators Inflamm. 2013:7310232013. View Article : Google Scholar : PubMed/NCBI

30 

Génin P, Algarté M, Roof P, Lin R and Hiscott J: Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors. J Immunol. 164:5352–5361. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Liu J, Guan X and Ma X: Interferon regulatory factor 1 is an essential and direct transcriptional activator for interferon γ-induced RANTES/CCl5 expression in macrophages. J Biol Chem. 280:24347–24355. 2005. View Article : Google Scholar : PubMed/NCBI

32 

Yarilina A, Park-Min KH, Antoniv T, Hu X and Ivashkiv LB: TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat Immunol. 9:378–387. 2008. View Article : Google Scholar : PubMed/NCBI

33 

Holtschke T, Löhler J, Kanno Y, Fehr T, Giese N, Rosenbauer F, Lou J, Knobeloch KP, Gabriele L, Waring JF, et al: Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell. 87:307–317. 1996. View Article : Google Scholar : PubMed/NCBI

34 

Koh MY, Nguyen V, Lemos R Jr, Darnay BG, Kiriakova G, Abdelmelek M, Ho TH, Karam J, Monzon FA, Jonasch E, et al: Hypoxia-induced SUMOylation of E3 ligase HAF determines specific activation of HIF2 in clear-cell renal cell carcinoma. Cancer Res. 75:316–329. 2015. View Article : Google Scholar : PubMed/NCBI

35 

Sun L, Li H, Chen J, Iwasaki Y, Kubota T, Matsuoka M, Shen A, Chen Q and Xu Y: PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. J Cell Sci. 126:3939–3947. 2013. View Article : Google Scholar : PubMed/NCBI

36 

Wu YC, Ling TY, Lu SH, Kuo HC, Ho HN, Yeh SD, Shen CN and Huang YH: Chemotherapeutic sensitivity of testicular germ cell tumors under hypoxic conditions is negatively regulated by SENP1-controlled sumoylation of OCT4. Cancer Res. 72:4963–4973. 2012. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Wang Y, Liu T, Yang N, Xu S, Li X and Wang D: Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989. Oncol Rep 36: 3522-3528, 2016.
APA
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., & Wang, D. (2016). Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989. Oncology Reports, 36, 3522-3528. https://doi.org/10.3892/or.2016.5171
MLA
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., Wang, D."Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989". Oncology Reports 36.6 (2016): 3522-3528.
Chicago
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., Wang, D."Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989". Oncology Reports 36, no. 6 (2016): 3522-3528. https://doi.org/10.3892/or.2016.5171
Copy and paste a formatted citation
x
Spandidos Publications style
Wang Y, Liu T, Yang N, Xu S, Li X and Wang D: Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989. Oncol Rep 36: 3522-3528, 2016.
APA
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., & Wang, D. (2016). Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989. Oncology Reports, 36, 3522-3528. https://doi.org/10.3892/or.2016.5171
MLA
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., Wang, D."Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989". Oncology Reports 36.6 (2016): 3522-3528.
Chicago
Wang, Y., Liu, T., Yang, N., Xu, S., Li, X., Wang, D."Hypoxia and macrophages promote glioblastoma invasion by the CCL4-CCR5 axis Expression of Concern in /10.3892/or.2025.8989". Oncology Reports 36, no. 6 (2016): 3522-3528. https://doi.org/10.3892/or.2016.5171
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