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Glioma Stem/Progenitor Cells Contribute to Neovascularization via Transdifferentiation

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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.

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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

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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
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  2. Yaodong Zhao
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  3. Qiang Huang
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  7. Hong Xiao
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  9. Qing Lan
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  10. Xiaosong Gu
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Corresponding author

Correspondence to Qiang Huang.

Additional information

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

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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

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

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