Skip to main content

Advertisement

Springer Nature Link
Log in

Glioma Stem/Progenitor Cells Contribute to Neovascularization via Transdifferentiation

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Objective

Previous studies suggest that tumor cells might be the progenitor for tumor vasculature. Whether vascular tube formation from transdifferentiation of human glioma stem/progenitor cells (hGSPCs) contribute to angiogenesis of gliomas remain largely uncertain.

Methods

hGSPCs were isolated from thirteen surgical specimens of gliomas and cultured in medium favored for stem cell growth. In vitro transdifferentiation of hGSPCs was performed under hypoxia. Expression of vascular endothelial cells (VECs) markers CD31, CD34, kinase insert domain receptor (KDR), and von Willebrand factor (vWF) were analyzed with real-time quantitative RT-PCR and immunofluorescence techniques. Vasculogenic mimicry of hGSPCs was evaluated in a tumor stem cell xenograft model in vivo. Relationships between content of hGSPCs and expression levels of both VECs markers and proangiogenic factors in large number of clinical specimens were further investigated in glioma tissue microarray.

Results

In vitro, hGSPCs can transdifferentiate into VECs under hypoxia, they manifested typical “flagstone” pattern when cultivated in medium containing VEGF for a few days; when cultivated on Matrigel they were capable of forming capillary-like structures. Expression of VECs markers including CD31, CD34, KDR, and vWF were significantly up-regulated after transdifferentiation. Human leukocyte antigen (HLA) positively stained vessels were observed inside the xenograft tumors after intracerebral transplantation of hGSPCs in athymic nude mice, implied part of tumor cells with human origin were involved in formation of tumor vessels. In surgical specimens of human glioma, tumor vascular cells coexpressing the markers of early VECs (CD34) and markers of hGSPCs (ABCG2 and nestin) suggest that these vascular cells may stemmed from hGSPCs.

Conclusions

Our observations suggest the functional role of hGSPCs as endothelial progenitors, which have properties that give rise to VECs, and have the ability to form vascular endothelial tubes. However, unspecific markers (ABCG2, nestin) that stain for both endothelial as well as glioma stem cells, were found to be expressed in tumor vasculature of human specimen, and limit further interpretation of this finding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. Folkman, J. (1971). Tumor angiogenesis: therapeutic implications. The New England Journal of Medicine, 285(21), 1182–1186.

    Article  CAS  PubMed  Google Scholar 

  2. Fox, S. B., Gatter, K. C., & Harris, A. L. (1996). Tumour angiogenesis. The Journal of Pathology, 179(3), 232–237.

    Article  CAS  PubMed  Google Scholar 

  3. Maniotis, A. J., Folberg, R., Hess, A., et al. (1999). Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. The American Journal of Pathology, 155(3), 739–752.

    CAS  PubMed  Google Scholar 

  4. Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105–111.

    Article  CAS  PubMed  Google Scholar 

  5. Wicha, M. S., Liu, S., & Dontu, G. (2006). Cancer stem cells: an old idea-a paradigm shift. Cancer Research, 66(4), 1883–1890.

    Article  CAS  PubMed  Google Scholar 

  6. Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100(7), 3983–3988.

    Article  CAS  PubMed  Google Scholar 

  7. Bonnet, D., & Dick, J. E. (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Natural Medicines, 3(7), 730–737.

    Article  CAS  Google Scholar 

  8. Lapidot, T., Sirard, C., Vormoor, J., et al. (1994). A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature, 367(6464), 645–648.

    Article  CAS  PubMed  Google Scholar 

  9. Tang, C., Ang, B. T., & Pervaiz, S. (2007). Cancer stem cell: target for anti-cancer therapy. The FASEB Journal, 21(14), 3777–3785.

    Article  CAS  PubMed  Google Scholar 

  10. Monzani, E., & La Porta, C. A. (2008). Targeting cancer stem cells to modulate alternative vascularization mechanisms. Stem Cell Reviews, 4(1), 51–56.

    Article  PubMed  Google Scholar 

  11. Shen, R., Ye, Y., Chen, L., Yan, Q., Barsky, S. H., & Gao, J. X. (2008). Precancerous stem cells can serve as tumor vasculogenic progenitors. PLoS ONE, 3(2), e1652.

    Article  PubMed  Google Scholar 

  12. Bleau, A. M., Hambardzumyan, D., Ozawa, T., et al. (2009). PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell, 4(3), 226–35.

    Article  CAS  PubMed  Google Scholar 

  13. Huang, Q., Zhang, Q. B., Dong, J., et al. (2008). Glioma stem cells are more aggressive in recurrent tumors with malignant progression than in the primary tumor, and both can be maintained long-term in vitro. BMC Cancer, 8, 304.

    Article  PubMed  Google Scholar 

  14. Ji, X. Y., Huang, Q., Dong, J., Zhu, Y. D., Wang, A. D., & Lan, Q. (2006). Characteristics of morphology, differentiation related markers, and proliferation dynamics of differentiated brain tumor stem cells in vitro[in Chinese]. Zhonghua Yi Xue Za Zhi, 86(23), 1604–1609.

    CAS  PubMed  Google Scholar 

  15. Zhang, Q. B., Ji, X. Y., Huang, Q., Dong, J., Zhu, Y. D., & Lan, Q. (2006). Differentiation profile of brain tumor stem cells: a comparative study with neural stem cells. Cell Research, 16(12), 909–915.

    Article  CAS  PubMed  Google Scholar 

  16. Goldberg, M. P., & Choi, D. W. (1993). Combined oxygen and glucose deprivation in cortical cell culture: calcium-dependent and calcium-independent mechanisms of neuronal injury. The Journal of Neuroscience, 13(8), 3510–3524.

    CAS  PubMed  Google Scholar 

  17. Zhai, D. Z., Huang, Q., Zhu, Q., et al. (2007). Expression of cyclin-dependent kinase CDC2 and its significance in malignant progression of gliomas[in Chinese]. Zhonghua Bing Li Xue Za Zhi, 36(3), 196–197.

    CAS  PubMed  Google Scholar 

  18. Chang, Y. S., di Tomaso, E., McDonald, D. M., Jones, R., Jain, R. K., & Munn, L. L. (2000). Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proceedings of the National Academy of Sciences of the United States of America, 97(26), 14608–14613.

    Article  CAS  PubMed  Google Scholar 

  19. Folkman, J. (2001). Can mosaic tumor vessel facilitate molecular diagnosis of cancer? Proceedings of the National Academy of Sciences of the United States of America, 98(2), 398–400.

    Article  CAS  PubMed  Google Scholar 

  20. Singh, S. K., Clarke, I. D., Terasaki, M., et al. (2003). Identification of a cancer stem cell in human brain tumors. Cancer Research, 63(18), 5821–5828.

    CAS  PubMed  Google Scholar 

  21. Lin, C., McGough, R., Aswad, B., Block, J. A., & Terek, R. (2004). Hypoxia induces HIF-1alpha and VEGF expression in chondrosarcoma cells and chondrocytes. Journal of Orthopaedic Research, 22(6), 1175–1181.

    Article  CAS  PubMed  Google Scholar 

  22. Risau, W. (1997). Mechanisms of angiogenesis. Nature, 386(6626), 671–674.

    Article  CAS  PubMed  Google Scholar 

  23. Kim, M., Turnquist, H., Jackson, J., et al. (2002). The multidrug resistance transporter ABCG2 (breast cancer resistance protein 1) effluxes Hoechst 33342 and is overexpressed in hematopoietic stem cells. Clinical Cancer Research, 8(1), 22–28.

    CAS  PubMed  Google Scholar 

  24. Robey, R. W., Steadman, K., Polgar, O., et al. (2004). Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Research, 64(4), 1242–1246.

    Article  CAS  PubMed  Google Scholar 

  25. Scharenberg, C. W., Harkey, M. A., & Torok-Storb, B. (2002). The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature human hematopoietic progenitors. Blood, 99(2), 507–512.

    Article  CAS  PubMed  Google Scholar 

  26. Doyle, L. A., Yang, W., Abruzzo, L. V., et al. (1998). A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 95(26), 15665–15670.

    Article  CAS  PubMed  Google Scholar 

  27. Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., & Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine, 183(4), 1797–1806.

    Article  CAS  PubMed  Google Scholar 

  28. Zhou, S., Morris, J. J., Barnes, Y., Lan, L., Schuetz, J. D., & Sorrentino, B. P. (2002). Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo. Proceedings of the National Academy of Sciences of the United States of America, 99(19), 12339–12344.

    Article  CAS  PubMed  Google Scholar 

  29. Zhou, S., Schuetz, J. D., Bunting, K. D., et al. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Natural Medicines, 7(9), 1028–1034.

    Article  CAS  Google Scholar 

  30. Kondo, T., Setoguchi, T., & Taga, T. (2004). Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line. Proceedings of the National Academy of Sciences of the United States of America, 101(3), 781–786.

    Article  CAS  PubMed  Google Scholar 

  31. Abbott, B. L. (2006). ABCG2 (BCRP): a cytoprotectant in normal and malignant stem cells. Clinical Advances in Hematology & Oncology, 4(1), 63–72.

    Google Scholar 

  32. Dahlstrand, J., Zimmerman, L. B., McKay, R. D., & Lendahl, U. (1992). Characterization of the human nestin gene reveals a close evolutionary relationship to neurofilaments. Journal of Cell Science, 103(Pt 2), 589–597.

    CAS  PubMed  Google Scholar 

  33. Frederiksen, K., & McKay, R. D. (1988). Proliferation and differentiation of rat neuroepithelial precursor cells in vivo. The Journal of Neuroscience, 8(4), 1144–1151.

    CAS  PubMed  Google Scholar 

  34. Fuchs, E. (1994). Intermediate filaments and disease: mutations that cripple cell strength. The Journal of Cell Biology, 125(3), 511–516.

    Article  CAS  PubMed  Google Scholar 

  35. Hockfield, S., & McKay, R. D. (1985). Identification of major cell classes in the developing mammalian nervous system. The Journal of Neuroscience, 5(12), 3310–3328.

    CAS  PubMed  Google Scholar 

  36. Lendahl, U., Zimmerman, L. B., & Mckay, R. (1990). CNS stem cells express a new class of intermediate filament protein. Cell, 60(4), 585–595.

    Article  CAS  PubMed  Google Scholar 

  37. Dahlstrand, J., Collins, V. P., & Lendahl, U. (1992). Expression of the class VI intermediate filament nestin in human central nervous system tumors. Cancer Research, 52(19), 5334–5341.

    CAS  PubMed  Google Scholar 

  38. Gehling, U. M., Ergün, S., Schumacher, U., et al. (2000). In vitro differentiation of endothelial cells from AC133-positive progenitor cells. Blood, 95(10), 3106–3112.

    CAS  PubMed  Google Scholar 

  39. Hristov, M., Erl, W., & Weber, P. C. (2003). Endothelial progenitor cells: isolation and characterization. Trends in Cardiovascular Medicine, 13(5), 201–206.

    Article  CAS  PubMed  Google Scholar 

  40. Peichev, M., Naiyer, A. J., Pereira, D., et al. (2000). Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood, 95(3), 952–958.

    CAS  PubMed  Google Scholar 

  41. Aghi, M., Cohen, K. S., Klein, R. J., Scadden, D. T., & Chiocca, E. A. (2006). Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Research, 66(18), 9054–9064.

    Article  CAS  PubMed  Google Scholar 

  42. Alvarez-Dolado, M., Pardal, R., Garcia-Verdugo, J. M., et al. (2003). Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature, 425(6961), 968–973.

    Article  CAS  PubMed  Google Scholar 

  43. Chen, K. A., Laywell, E. D., Marshall, G., Walton, N., Zheng, T., & Steindler, D. A. (2006). Fusion of neural stem cells in culture. Experimental Neurology, 198(1), 129–135.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study is supported by National Basic Research Program of China (973 program, 2010CB529403), and National Natural Science Foundation of China (No. 30872654; 30973081).

Conflicts of interest

None

Author information

Authors and Affiliations

  1. Department of Neurosurgery, The 2nd Affiliated Hospital of Suzhou University, 1055 Sanxiang Road, Suzhou, 215004, People’s Republic of China

    Jun Dong, Yaodong Zhao, Qiang Huang, Xifeng Fei, Yi Diao, Yuntian Shen, Hong Xiao & Qing Lan

  2. Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong, 226001, China

    Tianyi Zhang & Xiaosong Gu

Authors
  1. Jun Dong
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Yaodong Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Qiang Huang
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Xifeng Fei
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Yi Diao
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yuntian Shen
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Hong Xiao
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Tianyi Zhang
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Qing Lan
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Xiaosong Gu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Qiang Huang.

Additional information

Jun Dong and Yaodong Zhao have contributed to this paper equally.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dong, J., Zhao, Y., Huang, Q. et al. Glioma Stem/Progenitor Cells Contribute to Neovascularization via Transdifferentiation. Stem Cell Rev and Rep 7, 141–152 (2011). https://doi.org/10.1007/s12015-010-9169-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-010-9169-7

Keywords