A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

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A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

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Author(s): Yonghong Zhang ¹ ^, ² , Xinlin Sun ¹ , Min Huang ¹ , Yiquan Ke ¹ , Jihui Wang ¹ , Xiao Liu ¹

Publication date (Electronic): 11 June 2015

Journal: Drug Design, Development and Therapy

Publisher: Dove Medical Press

Keywords: bispecific immunotoxin, human mesenchymal stem cells, ephrin A1, VEGF165, malignant glioma

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Abstract

Background

In previous years, immunotoxins have been shown to be a greatly promising therapeutic tool for brain malignancies, such as gliomas. Human mesenchymal stem cells (hMSCs) exhibit tropism to tumor tissue. However, the effect of bispecific immunotoxins in malignant gliomas is still unknown. The aim of this study was to investigate the function of bispecific immunotoxins in human malignant gliomas.

Materials and methods

In the present study, the bispecific immunotoxin VEGF ₁₆₅-ephrin A1-PE38KDEL was established using deoxyribonucleic acid shuffling and cloning techniques. The VEGF ₁₆₅-ephrin A1-PE38KDEL was delivered by hMSCs to mouse malignant gliomas. The effects of the bispecific immunotoxins on glioma-derived blood vessels and vasculogenic mimicry to elucidate the molecular mechanisms underlying the antitumorigenic effects of immunotoxins were examined in vivo.

Results

In vitro, transfected hMSCs significantly inhibited the cell viability of gliomas cell lines U87 and U251 in a dose-dependent manner compared with untransfected hMSCs ( P<0.01). In vivo, the intratumoral injection of engineered hMSCs was effective at inhibiting tumor growth in a malignant glioma tumor model.

Conclusion

The bispecific immunotoxin secreted from hMSCs acts as a novel strategy for improving treatment options for malignant gliomas in the clinic.

Most cited references 27

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Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.

A. Maniotis, R Folberg, A. Hess … (1999)

Tissue sections from aggressive human intraocular (uveal) and metastatic cutaneous melanomas generally lack evidence of significant necrosis and contain patterned networks of interconnected loops of extracellular matrix. The matrix that forms these loops or networks may be solid or hollow. Red blood cells have been detected within the hollow channel components of this patterned matrix histologically, and these vascular channel networks have been detected in human tumors angiographically. Endothelial cells were not identified within these matrix-embedded channels by light microscopy, by transmission electron microscopy, or by using an immunohistochemical panel of endothelial cell markers (Factor VIII-related antigen, Ulex, CD31, CD34, and KDR[Flk-1]). Highly invasive primary and metastatic human melanoma cells formed patterned solid and hollow matrix channels (seen in tissue sections of aggressive primary and metastatic human melanomas) in three-dimensional cultures containing Matrigel or dilute Type I collagen, without endothelial cells or fibroblasts. These tumor cell-generated patterned channels conducted dye, highlighting looping patterns visualized angiographically in human tumors. Neither normal melanocytes nor poorly invasive melanoma cells generated these patterned channels in vitro under identical culture conditions, even after the addition of conditioned medium from metastatic pattern-forming melanoma cells, soluble growth factors, or regimes of hypoxia. Highly invasive and metastatic human melanoma cells, but not poorly invasive melanoma cells, contracted and remodeled floating hydrated gels, providing a biomechanical explanation for the generation of microvessels in vitro. cDNA microarray analysis of highly invasive versus poorly invasive melanoma tumor cells confirmed a genetic reversion to a pluripotent embryonic-like genotype in the highly aggressive melanoma cells. These observations strongly suggest that aggressive melanoma cells may generate vascular channels that facilitate tumor perfusion independent of tumor angiogenesis.

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Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

Akira Nakamizo, Frank Marini, Toshiyuki Amano … (2005)

The poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor. Because it has been suggested that circulating bone marrow-derived stem cells can be recruited into solid organs in response to tissue stresses, we hypothesized that human bone marrow-derived mesenchymal stem cells (hMSC) may have a tropism for brain tumors and thus could be used as delivery vehicles for glioma therapy. To test this, we isolated hMSCs from bone marrow of normal volunteers, fluorescently labeled the cells, and injected them into the carotid artery of mice bearing human glioma intracranial xenografts (U87, U251, and LN229). hMSCs were seen exclusively within the brain tumors regardless of whether the cells were injected into the ipsilateral or contralateral carotid artery. In contrast, intracarotid injections of fibroblasts or U87 glioma cells resulted in widespread distribution of delivered cells without tumor specificity. To assess the potential of hMSCs to track human gliomas, we injected hMSCs directly into the cerebral hemisphere opposite an established human glioma and showed that the hMSCs were capable of migrating into the xenograft in vivo. Likewise, in vitro Matrigel invasion assays showed that conditioned medium from gliomas, but not from fibroblasts or astrocytes, supported the migration of hMSCs and that platelet-derived growth factor, epidermal growth factor, or stromal cell-derived factor-1alpha, but not basic fibroblast growth factor or vascular endothelial growth factor, enhanced hMSC migration. To test the potential of hMSCs to deliver a therapeutic agent, hMSCs were engineered to release IFN-beta (hMSC-IFN-beta). In vitro coculture and Transwell experiments showed the efficacy of hMSC-IFN-beta against human gliomas. In vivo experiments showed that treatment of human U87 intracranial glioma xenografts with hMSC-IFN-beta significantly increase animal survival compared with controls (P < 0.05). We conclude that hMSCs can integrate into human gliomas after intravascular or local delivery, that this engraftment may be mediated by growth factors, and that this tropism of hMSCs for human gliomas can be exploited to therapeutic advantage.

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Mechanisms of glioma-associated neovascularization.

Matthew Hardee, David Zagzag (2012)

Glioblastomas (GBMs), the most common primary brain tumor in adults, are characterized by resistance to chemotherapy and radiotherapy. One of the defining characteristics of GBM is an abundant and aberrant vasculature. The processes of vascular co-option, angiogenesis, and vasculogenesis in gliomas have been extensively described. Recently, however, it has become clear that these three processes are not the only mechanisms by which neovascularization occurs in gliomas. Furthermore, it seems that these processes interact extensively, with potential overlap among them. At least five mechanisms by which gliomas achieve neovascularization have been described: vascular co-option, angiogenesis, vasculogenesis, vascular mimicry, and (the most recently described) glioblastoma-endothelial cell transdifferentiation. We review these mechanisms in glioma neovascularization, with a particular emphasis on the roles of hypoxia and glioma stem cells in each process. Although some of these processes are well established, others have been identified only recently and will need to be further investigated for complete validation. We also review strategies to target glioma neovascularization and the development of resistance to these therapeutic strategies. Finally, we describe how these complex processes interlink and overlap. A thorough understanding of the contributing molecular processes that control the five modalities reviewed here should help resolve the treatment resistance that characterizes GBMs. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Des Devel Ther

Journal ID (iso-abbrev): Drug Des Devel Ther

Journal ID (publisher-id): Drug Design, Development and Therapy

Title: Drug Design, Development and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1177-8881

Publication date Collection: 2015

Publication date (Electronic): 11 June 2015

Volume: 9

Pages: 2947-2959

Affiliations

[1 ]National Key Clinic Specialty, Neurosurgery Institute of Guangdong Province, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou, People’s Republic of China

[2 ]Department of Neurosurgery, First Hospital of Lanzhou University, Lanzhou, People’s Republic of China

Author notes

Correspondence: Yiquan Ke, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, 253 Gongye Road, Guangzhou, Guangdong 510282, People’s Republic of China, Tel/fax +86 20 6164 3266, Email zjkeyiquan@ 123456yeah.net

Article

Publisher ID: dddt-9-2947

DOI: 10.2147/DDDT.S79475

PMC ID: 4468939

SO-VID: c5ef2e56-b47b-4928-b4fb-2282eb355a76

License:

The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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A novel bispecific immunotoxin delivered by human bone marrow-derived mesenchymal stem cells to target blood vessels and vasculogenic mimicry of malignant gliomas

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Abstract

Background

Materials and methods

Results

Conclusion

Most cited references 27

Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry.

Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas.

Mechanisms of glioma-associated neovascularization.

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