Journal of Neuro-Oncology

, Volume 83, Issue 3, pp 241–247 | Cite as

Malignant gliomas actively recruit bone marrow stromal cells by secreting angiogenic cytokines

  • Tobias Birnbaum
  • Julia Roider
  • Christoph J. Schankin
  • Claudio S. Padovan
  • Christian Schichor
  • Roland Goldbrunner
  • Andreas Straube
Lab Investigation

Abstract

The transplantation of progenitor cells is a promising new approach for the treatment of gliomas. Marrow stromal cells (MSC) are possible candidates for such a cell-based therapy, since they are readily and autologously available and show an extensive tropism to gliomas in vitro and in vivo. However, the signals that guide the MSC are still poorly understood. In this study, we show that gliomas have the capacity to actively attract MSC by secreting a multitude of angiogenic cytokines. We demonstrate that interleukin-8 (IL-8), transforming growth factor-ß1 (TGF-ß1) and neurotrophin-3 (NT-3) contribute to this glioma-directed tropism of human MSC. Together with the finding that vascular endothelial growth factor (VEGF) is another MSC-attracting factor secreted by glioma cells, these data support the hypothesis that gliomas use their angiogenic pathways to recruit mesenchymal progenitor cells.

Keywords

Angiogenesis Glioma Interleukin-8 Marrow stromal cells Migration Neurotrophin-3 Transforming growth factor-ß1 

Notes

Acknowledgments

This work was supported by grants of the Förderprogramm für Forschung und Lehre, LMU Munich, Germany, and by grants of the Friedrich-Baur-Stiftung, Munich, Germany. Parts of this work are elements of one co-author´s dissertation (Julia Roider) presented to the Medical Faculty, LMU Munich, Germany.

References

  1. 1.
    Sathornsumetee S, Rich J (2006) New treatment strategies for malignant gliomas. Expert Rev Anticancer Ther 6:1087–1104PubMedCrossRefGoogle Scholar
  2. 2.
    Aboody K, Brown A, Rainov N, Bower K, Liu S, Yang W, Small J, Herrlinger U, Ourednik V, Black P, Breakefield X, Snyder E (2000) Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci USA 97:12846–12851PubMedCrossRefGoogle Scholar
  3. 3.
    Schichor C, Birnbaum T, Etminan N, Schnell O, Grau S, Miebach S, Aboody K, Padovan C, Straube A, Tonn J, Goldbrunner R (2006) Vascular endothelial growth factor A contributes to glioma-induced migration of human marrow stromal cells (hMSC). Exp Neurol 199:301–310PubMedCrossRefGoogle Scholar
  4. 4.
    Nakamizo A, Marini F, Amano T, Khan A, Studeny M, Gumin J, Chen J, Hentschel S, Vecil G, Dembinski J, Andreeff M, Lang F (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318PubMedGoogle Scholar
  5. 5.
    Nakamura K, Ito Y, Kawano Y, Kurozumi K, Kobune M, Tsuda H, Bizen A, Honmou O, Niitsu Y, Hamada H (2004) Antitumor effect of genetically engineered mesenchymal stem cells in a rat glioma model. Gene Ther 11:1155–1164PubMedCrossRefGoogle Scholar
  6. 6.
    Kargiotis O, Rao J, Kyritsis A (2006) Mechanisms of angiogenesis in gliomas. J Neurooncol 78:281–293PubMedCrossRefGoogle Scholar
  7. 7.
    Hamel W, Westphal M, Szönyi E, Escandón E, Nikolics K (1993) Neurotrophin gene expression by cell lines derived from human gliomas. J Neurosci Res 34:147–157PubMedCrossRefGoogle Scholar
  8. 8.
    Donovan M, Miranda R, Kraemer R, McCaffrey T, Tessarollo L, Mahadeo D, Sharif S, Kaplan D, Tsoulfas P, Parada L (1995) Neurotrophin and neurotrophin receptors in vascular smooth muscle cells. Regulation of expression in response to injury. Am J Pathol 147:309–324PubMedGoogle Scholar
  9. 9.
    Weis J, Schönrock L, Züchner S, Lie D, Sure U, Schul C, Stögbauer F, Ringelstein E, Halfter H (1999) CNTF and its receptor subunits in human gliomas. J Neurooncol 44:243–253PubMedCrossRefGoogle Scholar
  10. 10.
    Wiesenhofer B, Stockhammer G, Kostron H, Maier H, Hinterhuber H, Humpel C (2000) Glial cell line-derived neurotrophic factor (GDNF) and its receptor (GFR-alpha 1) are strongly expressed in human gliomas. Acta Neuropathol (Berl) 99:131–137CrossRefGoogle Scholar
  11. 11.
    Yamauchi J, Chan J, Shooter E (2003) Neurotrophin 3 activation of TrkC induces Schwann cell migration through the c-Jun N-terminal kinase pathway. Proc Natl Acad Sci U S A 100:14421–14426PubMedCrossRefGoogle Scholar
  12. 12.
    Padovan C, Jahn K, Birnbaum T, Reich P, Sostak P, Strupp M, Straube A (2003) Expression of neuronal markers in differentiated marrow stromal cells and CD133+ stem-like cells. Cell Transplant 12:839–848PubMedGoogle Scholar
  13. 13.
    Tabatabai G, Bähr O, Möhle R, Eyüpoglu I, Boehmler A, Wischhusen J, Rieger J, Blümcke I, Weller M, Wick W (2005) Lessons from the bone marrow: how malignant glioma cells attract adult haematopoietic progenitor cells. Brain 128:2200–2211PubMedCrossRefGoogle Scholar
  14. 14.
    Von Lüttichau I, Notohamiprodjo M, Wechselberger A, Peters C, Henger A, Seliger C, Djafarzadeh R, Huss R, Nelson P (2005) Human adult CD34- progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells Dev 14:329–336CrossRefGoogle Scholar
  15. 15.
    Honczarenko M, Le Y, Swierkowski M, Ghiran I, Glodek A, Silberstein L (2006) Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells 24:1030–1041PubMedCrossRefGoogle Scholar
  16. 16.
    Sordi V, Malosio M, Marchesi F, Mercalli A, Melzi R, Giordano T, Belmonte N, Ferrari G, Leone B, Bertuzzi F, Zerbini G, Allavena P, Bonifacio E, Piemonti L (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106:419–427PubMedCrossRefGoogle Scholar
  17. 17.
    Son B, Marquez-Curtis L, Kucia M, Wysoczynski M, Turner A, Ratajczak J, Ratajczak M, Janowska-Wieczorek A (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24:1254–1264PubMedCrossRefGoogle Scholar
  18. 18.
    Wang L, Li Y, Chen X, Chen J, Gautam S, Xu Y, Chopp M (2002) MCP-1, MIP-1, IL-8 and ischemic cerebral tissue enhance human bone marrow stromal cell migration in interface culture. Hematology 7:113–117PubMedCrossRefGoogle Scholar
  19. 19.
    Charalambous C, Pen L, Su Y, Milan J, Chen T, Hofman F (2005) Interleukin-8 differentially regulates migration of tumor-associated and normal human brain endothelial cells. Cancer Res 65:10347–10354PubMedCrossRefGoogle Scholar
  20. 20.
    Desbaillets I, Diserens A, de Tribolet N, Hamou M, Van Meir E (1999) Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene 18:1447–1456PubMedCrossRefGoogle Scholar
  21. 21.
    Platten M, Wick W, Weller M (2001) Malignant glioma biology: role for TGF-beta in growth, motility, angiogenesis, and immune escape. Microsc Res Tech 52:401–410PubMedCrossRefGoogle Scholar
  22. 22.
    Brat D, Bellail A, Van Meir E (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 7:122–133PubMedCrossRefGoogle Scholar
  23. 23.
    Silva G, Litovsky S, Assad J, Sousa A, Martin B, Vela D, Coulter S, Lin J, Ober J, Vaughn W, Branco R, Oliveira E, He R, Geng Y, Willerson J, Perin E (2005) Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a canine chronic ischemia model. Circulation 111:150–156PubMedCrossRefGoogle Scholar
  24. 24.
    Li Y, Chen J, Zhang C, Wang L, Lu D, Katakowski M, Gao Q, Shen L, Zhang J, Lu M, Chopp M (2005) Gliosis and brain remodeling after treatment of stroke in rats with marrow stromal cells. Glia 49:407–417PubMedCrossRefGoogle Scholar
  25. 25.
    Chen J, Li Y, Katakowski M, Chen X, Wang L, Lu D, Lu M, Gautam S, Chopp M (2003) Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res 73:778–786PubMedCrossRefGoogle Scholar
  26. 26.
    Tille J, Pepper M (2002) Mesenchymal cells potentiate vascular endothelial growth factor-induced angiogenesis in vitro. Exp Cell Res 280:179–191PubMedCrossRefGoogle Scholar
  27. 27.
    Majumdar M, Banks V, Peluso D, Morris E (2000) Isolation, characterization, and chondrogenic potential of human bone marrow-derived multipotential stromal cells. J Cell Physiol 185:98–106PubMedCrossRefGoogle Scholar
  28. 28.
    Reyes M, Verfaillie C (2001) Characterization of multipotent adult progenitor cells, a subpopulation of mesenchymal stem cells. Ann NY Acad Sci 938:231–233PubMedCrossRefGoogle Scholar
  29. 29.
    Conget P, Minguell J (1999) Phenotypical and functional properties of human bone marrow mesenchymal progenitor cells. J Cell Physiol 181:67–73PubMedCrossRefGoogle Scholar
  30. 30.
    De Ugarte D, Alfonso Z, Zuk P, Elbarbary A, Zhu M, Ashjian P, Benhaim P, Hedrick M, Fraser J (2003) Differential expression of stem cell mobilization-associated molecules on multi-lineage cells from adipose tissue and bone marrow. Immunol Lett 89:267–270PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Tobias Birnbaum
    • 1
  • Julia Roider
    • 1
  • Christoph J. Schankin
    • 1
  • Claudio S. Padovan
    • 1
  • Christian Schichor
    • 2
  • Roland Goldbrunner
    • 2
  • Andreas Straube
    • 1
  1. 1.Department of NeurologyLudwig-Maximilians-University, Klinikum GroßhadernMunichGermany
  2. 2.Department of NeurosurgeryLudwig-Maximilians-University, Klinikum GroßhadernMunichGermany

Personalised recommendations