Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
- Tel Aviv University, Israel
- Freie Universität Berlin, Germany
- Tel Aviv Sourasky Medical Center, Israel
- Northwestern University, United States
- University of Maryland, United States
Abstract
Glioblastoma is a highly aggressive brain tumor. Current standard-of-care results in a marginal therapeutic outcome, partly due to acquirement of resistance and insufficient blood-brain barrier (BBB) penetration of chemotherapeutics. To circumvent these limitations, we conjugated the chemotherapy paclitaxel (PTX) to a dendritic polyglycerol sulfate (dPGS) nanocarrier. dPGS is able to cross the BBB, bind to P/L-selectins and accumulate selectively in intracranial tumors. We show that dPGS has dual targeting properties, as we found that P-selectin is not only expressed on tumor endothelium but also on glioblastoma cells. We delivered dPGS-PTX in combination with a peptidomimetic of the anti-angiogenic protein thrombospondin-1 (TSP-1 PM). This combination resulted in a remarkable synergistic anticancer effect on intracranial human and murine glioblastoma via induction of Fas and Fas-L, with no side effects compared to free PTX or temozolomide. This study shows that our unique therapeutic approach offers a viable alternative for the treatment of glioblastoma.
Article and author information
Author details
Ronit Satchi-Fainaro
Funding
H2020 European Research Council (617445)
- Ronit Satchi-Fainaro
Israel Science Foundation (918/14)
- Ronit Satchi-Fainaro
Israel Cancer Association (20150909)
- Ronit Satchi-Fainaro
Bundesministerium für Bildung und Forschung (13N11536)
- Rainer Haag
Bundesministerium für Bildung und Forschung (13N12561)
- Marcelo Calderón
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Charles L Sawyers, Memorial Sloan-Kettering Cancer Center, United States
Ethics
Animal experimentation: All animals were housed in the Tel Aviv University animal facility. The experiments were approved by the animal care and use committee (IACUC) of Tel Aviv University (approval no. 01-12-064, 01-12-065) and conducted in accordance with NIH guidelines.
Human subjects: Experiments involving human tissues were performed with the approval of the Institutional Review Board (IRB) and in compliance with all legal and ethical considerations for human subject research (approval no. 0735-13-TLV). Single human plasma was obtained from a healthy consented unmedicated donor according to German ethical guidelines.
Version history
- Received: January 23, 2017
- Accepted: October 3, 2017
- Accepted Manuscript published: October 4, 2017 (version 1)
- Version of Record published: October 17, 2017 (version 2)
- Version of Record updated: November 3, 2017 (version 3)
Copyright
© 2017, Ferber et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome
eLife 6:e25281.
https://doi.org/10.7554/eLife.25281
Further reading
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High-throughput vertebrate animal model systems for the study of patient-specific biology and new therapeutic approaches for aggressive brain tumors are currently lacking, and new approaches are urgently needed. Therefore, to build a patient-relevant in vivo model of human glioblastoma, we expressed common oncogenic variants including activated human EGFRvIII and PI3KCAH1047R under the control of the radial glial-specific promoter her4.1 in syngeneic tp53 loss-of-function mutant zebrafish. Robust tumor formation was observed prior to 45 days of life, and tumors had a gene expression signature similar to human glioblastoma of the mesenchymal subtype, with a strong inflammatory component. Within early stage tumor lesions, and in an in vivo and endogenous tumor microenvironment, we visualized infiltration of phagocytic cells, as well as internalization of tumor cells by mpeg1.1:EGFP+ microglia/macrophages, suggesting negative regulatory pressure by pro-inflammatory cell types on tumor growth at early stages of glioblastoma initiation. Furthermore, CRISPR/Cas9-mediated gene targeting of master inflammatory transcription factors irf7 or irf8 led to increased tumor formation in the primary context, while suppression of phagocyte activity led to enhanced tumor cell engraftment following transplantation into otherwise immune-competent zebrafish hosts. Altogether, we developed a genetically relevant model of aggressive human glioblastoma and harnessed the unique advantages of zebrafish including live imaging, high-throughput genetic and chemical manipulations to highlight important tumor-suppressive roles for the innate immune system on glioblastoma initiation, with important future opportunities for therapeutic discovery and optimizations.
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Establishing a zebrafish model of a deadly type of brain tumor highlights the role of the immune system in the early stages of the disease.
