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Increased invasive phenotype of CSF-1R expression in glioma cells via the ERK1/2 signaling pathway

Cancer Gene Therapy volume 26, pages 136–144 (2019)Cite this article

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Abstract

Glioma is a common malignant tumor of the central nervous system (CNS) that has no effective treatment. In this study, we report that colony-stimulating factor-1 receptor (CSF-1R) is a key mediator of malignant features in glioma via modulation of the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. In general, CSF-1R upregulation in glioma is associated with poor histologic grade and sursvival. Enforced expression of CSF-1R is sufficient to enhance cell growth, migration, invasion, and epithelial–mesenchymal transition, while CSF-1R silencing suppresses the above-described malignant phenotypes. Mechanistic investigations show that CSF-1R promotes activation of the ERK1/2 signaling pathway. Inhibition of the ERK1/2 pathway by SCH772984 reduces CSF-1R-induced migration, invasion, and lung metastasis of glioma cells, thus establishing a role of the ERK1/2 signaling pathway in mediating the CSF-1R effect. In summary, our results suggest that CSF-1R overexpression in gliomas contributes to the malignant behaviors of cancer cells.

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References

  1. Davis ME. Glioblastoma: overview of disease and treatment. Clin J Oncol Nurs. 2016;20 Suppl:S2–8.

    Article  Google Scholar 

  2. Reifenberger G, Wirsching HG, Knobbe-Thomsen CB, Weller M. Advances in the molecular genetics of gliomas—implications for classification and therapy. Nat Rev Clin Oncol. 2017;14:434–52.

    Article  CAS  Google Scholar 

  3. Coniglio SJ, Segall JE. Review: molecular mechanism of microglia stimulated glioblastoma invasion. Matrix Biol. 2013;32:372–80.

    Article  CAS  Google Scholar 

  4. Urbanczyk H, Straczynska-Niemiec A, Glowacki G, Lange D, Miszczyk L. Case presentation—a five-year survival of the patient with glioblastoma brain tumor. Rep Pract Oncol Radiother. 2014;19:347–51.

    Article  Google Scholar 

  5. Delgado-Lopez PD, Corrales-Garcia EM. Survival in glioblastoma: a review on the impact of treatment modalities. Clin Transl Oncol. 2016;18:1062–71.

    Article  CAS  Google Scholar 

  6. Noroxe DS, Poulsen HS, Lassen U. Hallmarks of glioblastoma: a systematic review. ESMO Open. 2016;1:e000144.

    Article  Google Scholar 

  7. Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor Perspect Biol. 2014;6:a021857.

    Article  Google Scholar 

  8. Hume DA, MacDonald KP. Therapeutic applications of macrophage colony-stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signaling. Blood. 2012;119:1810–20.

    Article  CAS  Google Scholar 

  9. Hamilton JA, Cook AD, Tak PP. Anti-colony-stimulating factor therapies for inflammatory and autoimmune diseases. Nat Rev Drug Discov. 2016;16:53–70.

    Article  Google Scholar 

  10. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10:58.

    Article  Google Scholar 

  11. Ao JY, Zhu XD, Chai ZT, Cai H, Zhang YY, Zhang KZ, et al. Colony-stimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol Cancer Ther. 2017;16:1544–54.

    Article  CAS  Google Scholar 

  12. Cannarile MA, Ries CH, Hoves S, Ruttinger D. Targeting tumor-associated macrophages in cancer therapy and understanding their complexity. Oncoimmunology. 2014;3:e955356.

    Article  Google Scholar 

  13. Weischenfeldt J, Porse B. Bone marrow-derived macrophages (BMM): isolation and applications. CSH Protoc. 2008;2008:pdbprot5080.

    Google Scholar 

  14. Mousa A, Cui C, Song A, Myneni VD, Sun H, Li JJ, et al. Transglutaminases factor XIII-A and TG2 regulate resorption, adipogenesis and plasma fibronectin homeostasis in bone and bone marrow. Cell Death Differ. 2017;24:844–54.

    Article  CAS  Google Scholar 

  15. Muraille E, Leo O, Moser M. TH1/TH2 paradigm extended: macrophage polarization as an unappreciated pathogen-driven escape mechanism? Front Immunol. 2014;5:603.

    PubMed  PubMed Central  Google Scholar 

  16. Almatroodi SA, McDonald CF, Darby IA, Pouniotis DS. Characterization of M1/M2 tumour-associated macrophages (TAMs) and Th1/Th2 cytokine profiles in patients with NSCLC. Cancer Microenviron. 2016;9:1–11.

    Article  CAS  Google Scholar 

  17. Sielska M, Przanowski P, Wylot B, Gabrusiewicz K, Maleszewska M, Kijewska M, et al. Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response. J Pathol. 2013;230:310–21.

    Article  CAS  Google Scholar 

  18. Lou J, Low-Nam ST, Kerkvliet JG, Hoppe AD. Delivery of CSF-1R to the lumen of macropinosomes promotes its destruction in macrophages. J Cell Sci. 2014;127 Part 24:5228–39.

    Article  Google Scholar 

  19. Wiehagen KR, Girgis NM, Yamada DH, Smith AA, Chan SR, Grewal IS, et al. Combination of CD40 agonism and CSF-1R blockade reconditions tumor-associated macrophages and drives potent antitumor immunity. Cancer Immunol Res. 2017;5:1109–21.

    Article  CAS  Google Scholar 

  20. Tong J, Wang P, Tan S, Chen D, Nikolovska-Coleska Z, Zou F, et al. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Res. 2017;77:2512–21.

    Article  CAS  Google Scholar 

  21. Tong J, Tan S, Zou F, Yu J, Zhang L. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene. 2017;36:787–96.

    Article  CAS  Google Scholar 

  22. Yu YX, Wu HJ, Tan BX, Qiu C, Liu HZ. CSF-1R regulates non-small cell lung cancer cells dissemination through Wnt3a signaling. Am J Cancer Res. 2017;7:2144–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang L, Xu X, Hao Y, Chen J, Li L, Cheng J, et al. Overexpression of CSF-1R in nasopharyngeal carcinoma. Rev Roum Morphol Embryol. 2015;56:1279–83.

    Google Scholar 

  24. Cho MJ, Lee JY, Shin MG, Kim HJ, Choi YJ, Rho SB, et al. TSC-22 inhibits CSF-1R function and induces apoptosis in cervical cancer. Oncotarget. 2017;8:97990–8003.

    PubMed  PubMed Central  Google Scholar 

  25. Ryder M, Gild M, Hohl TM, Pamer E, Knauf J, Ghossein R, et al. Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS ONE. 2013;8:e54302.

    Article  CAS  Google Scholar 

  26. Huynh J, Kwa MQ, Cook AD, Hamilton JA, Scholz GM. CSF-1 receptor signalling from endosomes mediates the sustained activation of Erk1/2 and Akt in macrophages. Cell Signal. 2012;24:1753–61.

    Article  CAS  Google Scholar 

  27. Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, et al. The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas. Science. 2016;352:aad3018.

    Article  Google Scholar 

  28. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19:1264–72.

    Article  CAS  Google Scholar 

  29. Huang L, Xu X, Hao Y. The possible mechanisms of tumor progression via CSF-1/CSF-1R pathway activation. Rev Roum Morphol Embryol. 2014;55 Suppl:501–6.

    Google Scholar 

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Acknowledgements

We thank our lab members for critical reading of the manuscript.

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Authors and Affiliations

  1. Department of Neurosurgery, China-Japan Union Hospital of Jilin University, 130033, Changchun, China

    Libo Sun, Huaxin Liang, Weidong Yu & Xingyi Jin

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  1. Libo Sun
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  2. Huaxin Liang
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Correspondence to Xingyi Jin.

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Sun, L., Liang, H., Yu, W. et al. Increased invasive phenotype of CSF-1R expression in glioma cells via the ERK1/2 signaling pathway. Cancer Gene Ther 26, 136–144 (2019). https://doi.org/10.1038/s41417-018-0053-y

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