Molecular and Cellular Biochemistry

, Volume 412, Issue 1–2, pp 1–10 | Cite as

Malignant transformation of bone marrow stromal cells induced by the brain glioma niche in rats

  • Qiuping He
  • Xifeng Zou
  • Deyi Duan
  • Yujun Liu
  • Qunyuan XuEmail author


Normal human embryonic stem cells (hESCs) can develop neoplastic cancer stem cell (CSC) properties after coculture with transformed hESCs in vitro. In the present study, the influence of the tumor microenvironment on malignant transformation of bone marrow stromal cells (BMSCs) was studied after allografting a mixture of enhanced green fluorescent protein (EGFP)-labeled BMSCs and C6 glioma cells into the rat brain to understand the influence of the cellular environment, especially the tumor environment, on the transformation of grafted BMSCs in the rat brain. We performed intracerebral transplantation in the rat brain using EGFP-labeled BMSCs coinjected with C6 tumor cells. After transplantation, the EGFP-labeled cells were isolated from the tumor using fluorescence-activated cell sorting, and the characteristics of the recovered cells were investigated. Glioma-specific biomarkers of the sorted cells and the biological characteristics of the tumors were analyzed. The BMSCs isolated from the cografts were transformed into glioma CSCs, as indicated by the marked expression of the glioma marker GFAP in glioma cells, and of Nestin and CD133 in neural stem cells and CSCs, as well as rapid cell growth, decreased level of the tumor suppressor gene p53, increased level of the oncogene murine double minute gene 2 (MDM2), and recapitulation of glioma tissues in the brain. These data suggest that BMSCs can be transformed into CSCs, which can be further directed toward glioma formation under certain conditions, supporting the notion that the tumor microenvironment is involved in transforming normal BMSCs into glial CSCs.


Bone marrow stromal cell Transformation Glioma Cancer stem cell C6 



Bone marrow stromal cells


Cancer stem cells


Enhanced green fluorescent protein


Fluorescence-activated cell sorting


Glial fibrillary acidic protein



This study was supported by a grant from the National Basic Research Program of China (No. 2007CB947704).

Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.


  1. 1.
    Delude C (2011) Tumorigenesis: testing ground for cancer stem cells. Nature 480:S43–45PubMedCrossRefGoogle Scholar
  2. 2.
    D’Angelo RC, Wicha MS (2010) Stem cells in normal development and cancer. Prog Mol Biol Transl Sci 95:113–158PubMedCrossRefGoogle Scholar
  3. 3.
    Gao JX (2008) Cancer stem cells: the lessons from pre-cancerous stem cells. J Cell Mol Med 12:67–96PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432:324–331PubMedCrossRefGoogle Scholar
  5. 5.
    Yang YM, Chang JW (2008) Current status and issues in cancer stem cell study. Cancer Invest 26:741–755PubMedCrossRefGoogle Scholar
  6. 6.
    Clarke MF, Fuller M (2006) Stem cells and cancer: two faces of eve. Cell 124:1111–1115PubMedCrossRefGoogle Scholar
  7. 7.
    Dirks P (2010) Cancer stem cells: invitation to a second round. Nature 466:40–41PubMedCrossRefGoogle Scholar
  8. 8.
    Ponti D, Costa A, Zaffaroni N, Pratesi G, Petrangolini G, Coradini D, Pilotti S, Pierotti MA, Daidone MG (2005) Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties. Cancer Res 65:5506–5511PubMedCrossRefGoogle Scholar
  9. 9.
    Meszoely IM, Means AL, Scoggins CR, Leach SD (2001) Developmental aspects of early pancreatic cancer. Cancer J 7:242–250PubMedGoogle Scholar
  10. 10.
    Hope KJ, Jin L, Dick JE (2004) Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol 5:738–743PubMedCrossRefGoogle Scholar
  11. 11.
    Sell S, Dunsford HA (1989) Evidence for the stem cell origin of hepatocellular carcinoma and cholangiocarcinoma. Am J Pathol 134:1347–1363PubMedPubMedCentralGoogle Scholar
  12. 12.
    Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65:10946–10951PubMedCrossRefGoogle Scholar
  13. 13.
    Doucette T, Rao G, Yang Y, Gumin J, Shinojima N, Bekele BN, Qiao W, Zhang W, Lang FF (2011) Mesenchymal stem cells display tumor-specific tropism in an RCAS/Ntv-a glioma model. Neoplasia 13:716–725PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Roger M, Clavreul A, Venier-Julienne MC, Passirani C, Sindji L, Schiller P, Montero-Menei C, Menei P (2010) Mesenchymal stem cells as cellular vehicles for delivery of nanoparticles to brain tumors. Biomaterials 31:8393–8401PubMedCrossRefGoogle Scholar
  15. 15.
    Liu C, Chen Z, Chen Z, Zhang T, Lu Y (2006) Multiple tumor types may originate from bone marrow-derived cells. Neoplasia 8:716–724PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Stiles CD, Rowitch DH (2008) Glioma stem cells: a midterm exam. Neuron 58:832–846PubMedCrossRefGoogle Scholar
  17. 17.
    Dirks PB (2010) Brain tumor stem cells: the cancer stem cell hypothesis writ large. Mol Oncol 4:420–430PubMedCrossRefGoogle Scholar
  18. 18.
    Glantz M, Kesari S, Recht L, Fleischhack G, Van Horn A (2009) Understanding the origins of gliomas and developing novel therapies: cerebrospinal fluid and subventricular zone interplay. Semin Oncol 36:S17–24PubMedCrossRefGoogle Scholar
  19. 19.
    Prockop DJ, Gregory CA, Spees JL (2003) One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A 100:11917–11923PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Studeny M, Marini FC, Dembinski JL, Zompetta C, Cabreira-Hansen M, Bekele BN, Champlin RE, Andreeff M (2004) Mesenchymal stem cells: potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents. J Natl Cancer Inst 96:1593–1603PubMedCrossRefGoogle Scholar
  21. 21.
    Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang FF (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318PubMedGoogle Scholar
  22. 22.
    Brazelton TR, Rossi FM, Keshet GI, Blau HM (2000) From marrow to brain: expression of neuronal phenotypes in adult mice. Science 290:1775–1779PubMedCrossRefGoogle Scholar
  23. 23.
    Williams AR, Hare JM (2011) Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res 109:923–940PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Salem HK, Thiemermann C (2010) Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28:585–596PubMedPubMedCentralGoogle Scholar
  25. 25.
    Saulnier N, Lattanzi W, Puglisi MA, Pani G, Barba M, Piscaglia AC, Giachelia M, Alfieri S, Neri G, Gasbarrini G, Gasbarrini A (2009) Mesenchymal stromal cells multipotency and plasticity: induction toward the hepatic lineage. Eur Rev Med Pharmacol Sci 13:71–78PubMedGoogle Scholar
  26. 26.
    Egusa H, Schweizer FE, Wang CC, Matsuka Y, Nishimura I (2005) Neuronal differentiation of bone marrow-derived stromal stem cells involves suppression of discordant phenotypes through gene silencing. J Biol Chem 280:23691–23697PubMedCrossRefGoogle Scholar
  27. 27.
    Jiang Y, Jahagirdar BN, Reinhardt RL et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedCrossRefGoogle Scholar
  28. 28.
    Sanchez-Ramos J, Song S, Cardozo-Pelaez F, Hazzi C, Stedeford T, Willing A, Freeman TB, Saporta S, Janssen W, Patel N, Cooper DR, Sanberg PR (2000) Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 164:247–256PubMedCrossRefGoogle Scholar
  29. 29.
    Roth TM, Ramamurthy P, Ebisu F, Lisak RP, Bealmear BM, Barald KF (2007) A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formation. Glia 55:1123–1133PubMedCrossRefGoogle Scholar
  30. 30.
    Serakinci N, Guldberg P, Burns JS, Abdallah B, Schrødder H, Jensen T, Kassem M (2004) Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 23:5095–5098PubMedCrossRefGoogle Scholar
  31. 31.
    Li H, Fan X, Kovi RC et al (2007) Spontaneous expression of embryonic factors and p53 point mutations in aged mesenchymal stem cells: a model of age-related tumorigenesis in mice. Cancer Res 67:10889–10898PubMedCrossRefGoogle Scholar
  32. 32.
    Xu W, Qian H, Zhu W, Chen Y, Shao Q, Sun X, Hu J, Han C, Zhang X (2004) A novel tumor cell line cloned from mutated human embryonic bone marrow mesenchymal stem cells. Oncol Rep 12:501–508PubMedGoogle Scholar
  33. 33.
    Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR, Wang TC (2004) Gastric cancer originating from bone marrow-derived cells. Science 306:1568–1571PubMedCrossRefGoogle Scholar
  34. 34.
    Bakhtiary M, Marzban M, Mehdizadeh M, Joghataei MT, Khoei S, Pirhajati Mahabadi V, Laribi B, Tondar M, Moshkforoush A (2010) Comparison of transplantation of bone marrow stromal cells (BMSC) and stem cell mobilization by granulocyte colony stimulating factor after traumatic brain injury in rat. Iran Biomed J 14:142–149PubMedPubMedCentralGoogle Scholar
  35. 35.
    Nishida H, Nakayama M, Tanaka H, Kitamura M, Hatoya S, Sugiura K, Harada Y, Suzuki Y, Ide C, Inaba T (2010) Safety of autologous bone marrow stromal cell transplantation in dogs with acute spinal cord injury. Vet Surg 41:437–442CrossRefGoogle Scholar
  36. 36.
    Badie B, Schartner JM (2000) Flow cytometric characterization of tumor-associated macrophages in experimental gliomas. Neurosurgery 46:957–961; discussion 961–952Google Scholar
  37. 37.
    Zurita M, Bonilla C, Otero L, Aguayo C, Vaquero J (2008) Neural transdifferentiation of bone marrow stromal cells obtained by chemical agents is a short-time reversible phenomenon. Neurosci Res 60:275–280PubMedCrossRefGoogle Scholar
  38. 38.
    Karaoz E, Aksoy A, Ayhan S, Sariboyaci AE, Kaymaz F, Kasap M (2009) Characterization of mesenchymal stem cells from rat bone marrow: ultrastructural properties, differentiation potential and immunophenotypic markers. Histochem Cell Biol 132:533–546PubMedCrossRefGoogle Scholar
  39. 39.
    Vinores SA, Marangos PJ, Bonnin JM, Rubinstein LJ (1984) Immunoradiometric and immunohistochemical demonstration of neuron-specific enolase in experimental rat gliomas. Cancer Res 44:2595–2599PubMedGoogle Scholar
  40. 40.
    Aizawa T, Hasegawa K, Ohkumo T, Haga S, Ikeda K, Yoshikawa K (2011) Neural stem cell-like gene expression in a mouse ependymoma cell line transformed by human BK polyomavirus. Cancer Sci 102:122–129PubMedCrossRefGoogle Scholar
  41. 41.
    Bexell D, Gunnarsson S, Tormin A, Darabi A, Gisselsson D, Roybon L, Scheding S, Bengzon J (2009) Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol Ther 17:183–190PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M (2003) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–901PubMedCrossRefGoogle Scholar
  43. 43.
    Rizvi AZ, Swain JR, Davies PS, Bailey AS, Decker AD, Willenbring H, Grompe M, Fleming WH, Wong MH (2006) Bone marrow-derived cells fuse with normal and transformed intestinal stem cells. Proc Natl Acad Sci U S A 103:6321–6325PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Qiuping He
    • 1
    • 2
  • Xifeng Zou
    • 1
    • 2
    • 3
  • Deyi Duan
    • 1
    • 2
  • Yujun Liu
    • 1
    • 2
  • Qunyuan Xu
    • 1
    • 2
    Email author
  1. 1.Beijing Institute for Brain Disorders, Beijing Centre for Neural Regeneration and Repair, Beijing Key Laboratory of Brain Major Disorders, Key Laboratory for Neurodegenerative Diseases of The Ministry of EducationCapital Medical UniversityBeijingChina
  2. 2.Department of NeurobiologyCapital Medical UniversityBeijingChina
  3. 3.Department of Neurosurgery, Xijing HospitalThe First Affiliated Hospital of the Fourth Military Medical UniversityXi’anChina

Personalised recommendations