Force-mediated proinvasive matrix remodeling driven by tumor-associated mesenchymal stem-like cells in glioblastoma

  • Lim, Eun-Jung (Department of Life Science, Research Institute for Natural Sciences, Hanyang University) ;
  • Suh, Yongjoon (Department of Life Science, Research Institute for Natural Sciences, Hanyang University) ;
  • Kim, Seungmo (Department of Life Science, Research Institute for Natural Sciences, Hanyang University) ;
  • Kang, Seok-Gu (Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine) ;
  • Lee, Su-Jae (Department of Life Science, Research Institute for Natural Sciences, Hanyang University)
  • Received : 2017.09.15
  • Accepted : 2017.12.04
  • Published : 2018.04.30


In carcinoma, cancer-associated fibroblasts participate in force-mediated extracellular matrix (ECM) remodeling, consequently leading to invasion of cancer cells. Likewise, the ECM remodeling actively occurs in glioblastoma (GBM) and the consequent microenvironmental stiffness is strongly linked to migration behavior of GBM cells. However, in GBM the stromal cells responsible for force-mediated ECM remodeling remain unidentified. We show that tumor-associated mesenchymal stem-like cells (tMSLCs) provide a proinvasive matrix condition in GBM by force-mediated ECM remodeling. Importantly, CCL2-mediated Janus kinase 1 (JAK1) activation increased phosphorylation of myosin light chain 2 in tMSLCs and led to collagen assembly and actomyosin contractility. Collectively, our findings implicate tMSLCs as stromal cells providing force-mediated proinvasive ECM remodeling in the GBM microenvironment, and reminiscent of fibroblasts in carcinoma.


Actomyosin contractility;Glioblastoma;Proinvasive extracellular matrix remodeling;Tumor-associated mesenchymal stem-like cells


Supported by : Hanyang University, National Research Foundation (NRF)


  1. Dunn GP, Rinne ML, Wykosky J et al (2012) Emerging insights into the molecular and cellular basis of glioblastoma. Genes Dev 26, 756-784
  2. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352, 987-996
  3. Dirks PB (2008) Brain tumor stem cells: bringing order to the chaos of brain cancer. J Clin Oncol 26, 2916-2924
  4. Mahesparan R, Read TA, Lund-Johansen M, Skaftnesmo KO, Bjerkvig R and Engebraaten O (2003) Expression of extracellular matrix components in a highly infiltrative in vivo glioma model. Acta Neuropathol 105, 49-57
  5. Bellail AC, Hunter SB, Brat DJ, Tan C and Van Meir EG (2004) Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 36, 1046-1069
  6. Umesh V, Rape AD, Ulrich TA and Kumar S (2014) Microenvironmental stiffness enhances glioma cell proliferation by stimulating epidermal growth factor receptor signaling. PLoS One 9, e101771
  7. Grundy TJ, De Leon E, Griffin KR et al (2016) Differential response of patient-derived primary glioblastoma cells to environmental stiffness. Sci Rep 6, 23353
  8. Nakada M, Nakada S, Demuth T, Tran NL, Hoelzinger DB and Berens ME (2007) Molecular targets of glioma invasion. Cell Mol Life Sci 64, 458-478
  9. Albrengues J, Bourget I, Pons C et al (2014) LIF mediates proinvasive activation of stromal fibroblasts in cancer. Cell Rep 7, 1664-1678
  10. Sanz-Moreno V, Gaggioli C, Yeo M et al (2011) ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20, 229-245
  11. Gaggioli C, Hooper S, Hidalgo-Carcedo C et al (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9, 1392-1400
  12. Butcher DT, Alliston T and Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9, 108-122
  13. Unsgaard G, Rygh OM, Selbekk T et al (2006) Intraoperative 3D ultrasound in neurosurgery. Acta Neurochir (Wien) 148, 235-253; discussion 253
  14. Ulrich TA, de Juan Pardo EM and Kumar S (2009) The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res 69, 4167-4174
  15. Calvo F, Ege N, Grande-Garcia A et al (2013) Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancerassociated fibroblasts. Nat Cell Biol 15, 637-646
  16. Ho CM, Chang SF, Hsiao CC, Chien TY and Shih DT (2012) Isolation and characterization of stromal progenitor cells from ascites of patients with epithelial ovarian adenocarcinoma. J Biomed Sci 19, 23
  17. Kim SM, Kang SG, Park NR et al (2011) Presence of glioma stroma mesenchymal stem cells in a murine orthotopic glioma model. Childs Nerv Syst 27, 911-922
  18. Kwak J, Shin HJ, Kim SH et al (2013) Isolation of tumor spheres and mesenchymal stem-like cells from a single primitive neuroectodermal tumor specimen. Childs Nerv Syst 29, 2229-2239
  19. Lim HY, Kim KM, Kim BK et al (2013) Isolation of mesenchymal stem-like cells in meningioma specimens. Int J Oncol 43, 1260-1268
  20. Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A and Leroux MA (2012) Concise review: role of mesenchymal stem cells in wound repair. Stem Cells Transl Med 1, 142-149
  21. Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71-74
  22. Kim YG, Jeon S, Sin GY et al (2013) Existence of glioma stroma mesenchymal stemlike cells in Korean glioma specimens. Childs Nerv Syst 29, 549-563
  23. Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315-317
  24. Lim EJ, Suh Y, Yoo KC et al (2017) Tumor-associated mesenchymal stem-like cells provide extracellular signaling cue for invasiveness of glioblastoma cells. Oncotarget 8, 1438-1448
  25. Chang AL, Miska J, Wainwright DA et al (2016) CCL2 Produced by the Glioma Microenvironment Is Essential for the Recruitment of Regulatory T Cells and Myeloid-Derived Suppressor Cells. Cancer Res 76, 5671-5682
  26. Zhang J, Sarkar S, Cua R, Zhou Y, Hader W and Yong VW (2012) A dialog between glioma and microglia that promotes tumor invasiveness through the CCL2/CCR2/interleukin-6 axis. Carcinogenesis 33, 312-319
  27. Hossain A, Gumin J, Gao F et al (2015) Mesenchymal Stem Cells Isolated From Human Gliomas Increase Proliferation and Maintain Stemness of Glioma Stem Cells Through the IL-6/gp130/STAT3 Pathway. Stem Cells 33, 2400-2415
  28. Yoon SJ, Shim JK, Chang JH et al (2016) Tumor Mesenchymal Stem-Like Cell as a Prognostic Marker in Primary Glioblastoma. Stem Cells Int 2016, 6756983
  29. Xu WT, Bian ZY, Fan QM, Li G and Tang TT (2009) Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett 281, 32-41
  30. Bourkoula E, Mangoni D, Ius T et al (2013) Gliomaassociated stem cells: A novel class of tumor-supporting cells able to predict prognosis of human low-grade gliomas. Stem Cells 32, 1239-1253
  31. Behnan J, Isakson P, Joel M et al (2014) Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells 32, 1110-1123
  32. Otsu K, Das S, Houser SD, Quadri SK, Bhattacharya S and Bhattacharya J (2009) Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood 113, 4197-4205
  33. Khakoo AY, Pati S, Anderson SA et al (2006) Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 203, 1235-1247
  34. Soeda A, Park M, Lee D et al (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28, 3949-3959

Cited by

  1. Proinvasive extracellular matrix remodeling for tumor progression vol.42, pp.1, 2019,