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Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation

Oncogene volume 37, pages 3317–3328 (2018)Cite this article

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Abstract

Ionizing radiation is widely used for patient with glioblastoma (GBM). However, the effect of radiation on patient survival is marginal and upon recurrence tumors frequently shift toward mesenchymal subtype adopting invasiveness. Here, we show that ionizing radiation affects biomechanical tension in GBM microenvironment and provides proinvasive extracellular signaling cue, hyaluronic acid (HA)-rich condition. In response to radiation, HA production was increased in GBM cells by HA synthase-2 (HAS2) that was transcriptionally upregulated by NF-ĸB. Notably, NF-ĸB was persistently activated by IL-1α-feedback loop, making HA abundance in tumor microenvironment after radiation. Radiation-induced HA abundance causally has been linked to invasiveness of GBM cells by generating movement track as an extracellular matrix, and by acting as a signaling ligand for CD44 receptor, leading to SRC activation, which is sufficient for mesenchymal shift of GBM cells. Collectively, our findings provide an explanation for the frequent brain tumor relapse after radiotherapy, and potential therapeutic targets to block mesenchymal shift upon relapse.

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References

  1. Dunn GP, Rinne ML, Wykosky J, Genovese G, Quayle SN, Dunn IF, et al. Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev. 2012;26:756–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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;352:987–96.

    Article  CAS  Google Scholar 

  3. Dirks PB. Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol. 2008;26:2916–24.

    Article  PubMed  Google Scholar 

  4. Nguyen DH, Oketch-Rabah HA, Illa-Bochaca I, Geyer FC, Reis-Filho JS, Mao JH, et al. Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type. Cancer Cell. 2011;19:640–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Catton C, Milosevic M, Warde P, Bayley A, Crook J, Bristow R, et al. Recurrent prostate cancer following external beam radiotherapy: follow-up strategies and management. Urol Clin North Am. 2003;30:751–63.

    Article  PubMed  Google Scholar 

  6. Kim MJ, Kim RK, Yoon CH, An S, Hwang SG, Suh Y, et al. Importance of PKCdelta signaling in fractionated-radiation-induced expansion of glioma-initiating cells and resistance to cancer treatment. J Cell Sci. 2011;124:3084–94.

    Article  CAS  PubMed  Google Scholar 

  7. Kim YH, Yoo KC, Cui YH, Uddin N, Lim EJ, Kim MJ, et al. Radiation promotes malignant progression of glioma cells through HIF-1alpha stabilization. Cancer Lett. 2014;354:132–41.

    Article  CAS  PubMed  Google Scholar 

  8. Shankar A, Kumar S, Iskander AS, Varma NR, Janic B, deCarvalho A, et al. Subcurative radiation significantly increases cell proliferation, invasion, and migration of primary glioblastoma multiforme in vivo. Chin J Cancer. 2014;33:148–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol. 1999;58:1029–40.

    Article  CAS  PubMed  Google Scholar 

  10. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol. 2004;36:1046–69.

    Article  CAS  PubMed  Google Scholar 

  11. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73.

    Article  CAS  PubMed  Google Scholar 

  13. Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, et al. Gene expression profiling of gliomas strongly predicts survival. Cancer Res. 2004;64:6503–10.

    Article  CAS  PubMed  Google Scholar 

  14. Carro MS, Lim WK, Alvarez MJ, Bollo RJ, Zhao X, Snyder EY, et al. The transcriptional network for mesenchymal transformation of brain tumours. Nature. 2010;463:318–25.

    Article  CAS  PubMed  Google Scholar 

  15. Mao P, Joshi K, Li J, Kim SH, Li P, Santana-Santos L, et al. Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci USA. 2013;110:8644–9.

    Article  CAS  PubMed  Google Scholar 

  16. Hyc A, Osiecka-Iwan A, Niderla-Bielinska J, Jankowska-Steifer E, Moskalewski S. Pro- and anti-inflammatory cytokines increase hyaluronan production by rat synovial membrane in vitro. Int J Mol Med. 2009;24:579–85.

    CAS  PubMed  Google Scholar 

  17. Vigetti D, Genasetti A, Karousou E, Viola M, Moretto P, Clerici M, et al. Proinflammatory cytokines induce hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway. J Biol Chem. 2010;285:24639–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yoshida Y, Kumar A, Koyama Y, Peng H, Arman A, Boch JA, et al. Interleukin 1 activates STAT3/nuclear factor-kappaB cross-talk via a unique TRAF6- and p65-dependent mechanism. J Biol Chem. 2004;279:1768–76.

    Article  CAS  PubMed  Google Scholar 

  19. Tammi RH, Passi AG, Rilla K, Karousou E, Vigetti D, Makkonen K, et al. Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 2011;278:1419–28.

    Article  CAS  PubMed  Google Scholar 

  20. Bohrer LR, Chuntova P, Bade LK, Beadnell TC, Leon RP, Brady NJ, et al. Activation of the FGFR-STAT3 pathway in breast cancer cells induces a hyaluronan-rich microenvironment that licenses tumor formation. Cancer Res. 2014;74:374–86.

    Article  CAS  PubMed  Google Scholar 

  21. Entwistle J, Hall CL, Turley EA. HA receptors: regulators of signalling to the cytoskeleton. J Cell Biochem. 1996;61:569–77.

    Article  CAS  PubMed  Google Scholar 

  22. Bourguignon LY, Zhu H, Shao L, Chen YW. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem. 2001;276:7327–36.

    Article  CAS  PubMed  Google Scholar 

  23. Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A, et al. A multigene predictor of outcome in glioblastoma. Neuro Oncol. 2010;12:49–57.

    Article  CAS  PubMed  Google Scholar 

  24. Joseph JV, Conroy S, Pavlov K, Sontakke P, Tomar T, Eggens-Meijer E, et al. Hypoxia enhances migration and invasion in glioblastoma by promoting a mesenchymal shift mediated by the HIF1alpha-ZEB1 axis. Cancer Lett. 2015;359:107–16.

    Article  CAS  PubMed  Google Scholar 

  25. Du J, Bernasconi P, Clauser KR, Mani DR, Finn SP, Beroukhim R, et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nat Biotechnol. 2009;27:77–83.

    Article  CAS  PubMed  Google Scholar 

  26. de Groot J, Milano V. Improving the prognosis for patients with glioblastoma: the rationale for targeting Src. J Neurooncol. 2009;95:151–63.

    Article  PubMed  Google Scholar 

  27. Sun Z, Andersson R. NF-kappaB activation and inhibition: a review. Shock. 2002;18:99–106.

    Article  PubMed  Google Scholar 

  28. Hartupee J, Li X, Hamilton T. Interleukin 1alpha-induced NFkappaB activation and chemokine mRNA stabilization diverge at IRAK1. J Biol Chem. 2008;283:15689–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Saavalainen K, Tammi MI, Bowen T, Schmitz ML, Carlberg C. Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB. J Biol Chem. 2007;282:11530–9.

    Article  CAS  PubMed  Google Scholar 

  30. Bhat KP, Balasubramaniyan V, Vaillant B, Ezhilarasan R, Hummelink K, Hollingsworth F, et al. Mesenchymal differentiation mediated by NF-kappaB promotes radiation resistance in glioblastoma. Cancer Cell. 2013;24:331–46.

    Article  CAS  PubMed  Google Scholar 

  31. Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, et al. Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene. 2009;28:3949–59.

    Article  CAS  PubMed  Google Scholar 

  32. Hwang E, Yoo KC, Kang SG, Kim RK, Cui YH, Lee HJ, et al. PKCdelta activated by c-MET enhances infiltration of human glioblastoma cells through NOTCH2 signaling. Oncotarget. 2016;7:4890–902.

    PubMed  Google Scholar 

  33. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim YG, Jeon S, Sin GY, Shim JK, Kim BK, Shin HJ, et al. Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens. Child’s Nerv Syst. 2013;29:549–63.

    Article  Google Scholar 

  35. Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF. An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg. 2000;92:326–33.

    Article  CAS  PubMed  Google Scholar 

  36. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Akio Soeda (Department of Neurological Surgery, Gifu University, Japan) for providing patient-derived X01 GBM cells and Incheol Shin (Department of Life Science, Hanyang University, Korea) for vectors pBMN and pBMN-CD44.

Funding

This work was supported by the National Research Foundation (NRF) and Ministry of Science, ICT and Future Planning, Korean Government, through its National Nuclear Technology Program (NRF-2015M2A2A7A01044998 and NRF-2016R1E1A1A01942075).

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Author notes

  1. These authors contributed equally: Ki-Chun Yoo, Yongjoon Suh

Authors and Affiliations

  1. Department of Life Science, Research Institute for Natural Sciences, Hanyang University, Seoul, 04763, Korea

    Ki-Chun Yoo, Yongjoon Suh, Yoojeong An, Nizam Uddin, Yan-Hong Cui & Su-Jae Lee

  2. Division of Radiation Effect, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea

    Hae-June Lee & Ye Ji Jeong

  3. Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, 03722, Korea

    Tae-Hoon Roh, Jin-Kyoung Shim, Jong Hee Chang & Seok-Gu Kang

  4. Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, 10408, Korea

    Jong Bae Park

  5. Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Sciences, Seoul, 01812, Korea

    Min-Jung Kim

  6. Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon, 34057, Korea

    In-Gyu Kim

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Correspondence to Seok-Gu Kang or Su-Jae Lee.

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Yoo, KC., Suh, Y., An, Y. et al. Proinvasive extracellular matrix remodeling in tumor microenvironment in response to radiation. Oncogene 37, 3317–3328 (2018). https://doi.org/10.1038/s41388-018-0199-y

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