1. Cancer Biology
Download icon

Co-targeting the tumor endothelium and P-selectin-expressing glioblastoma cells leads to a remarkable therapeutic outcome

  1. Shiran Ferber
  2. Galia Tiram
  3. Ana Sousa-Herves
  4. Anat Eldar-Boock
  5. Adva Krivitsky
  6. Anna Scomparin
  7. Eilam Yeini
  8. Paula Ofek
  9. Dikla Ben-Shushan
  10. Laura Isabel Vossen
  11. Kai Licha
  12. Rachel Grossman
  13. Zvi Ram
  14. Jack Henkin
  15. Eytan Ruppin
  16. Noam Auslander
  17. Rainer Haag
  18. Marcelo Calderón
  19. Ronit Satchi-Fainaro  Is a corresponding author
  1. Tel Aviv University, Israel
  2. Freie Universität Berlin, Germany
  3. Tel Aviv Sourasky Medical Center, Israel
  4. Northwestern University, United States
  5. University of Maryland, United States
Research Article
  • Cited 28
  • Views 3,088
  • Annotations
Cite this article as: eLife 2017;6:e25281 doi: 10.7554/eLife.25281

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

  1. Shiran Ferber

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  2. Galia Tiram

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  3. Ana Sousa-Herves

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anat Eldar-Boock

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  5. Adva Krivitsky

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  6. Anna Scomparin

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  7. Eilam Yeini

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  8. Paula Ofek

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  9. Dikla Ben-Shushan

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  10. Laura Isabel Vossen

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Kai Licha

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Rachel Grossman

    Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  13. Zvi Ram

    Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  14. Jack Henkin

    Chemistry of Life Processes Institute, Northwestern University, Evanston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Eytan Ruppin

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    Competing interests
    The authors declare that no competing interests exist.
  16. Noam Auslander

    Department of Computer science, University of Maryland, College Park, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Rainer Haag

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  18. Marcelo Calderón

    Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  19. Ronit Satchi-Fainaro

    Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    For correspondence
    ronitsf@post.tau.ac.il
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7360-7837

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.

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.

Reviewing Editor

  1. Charles L Sawyers, Memorial Sloan-Kettering Cancer Center, United States

Publication history

  1. Received: January 23, 2017
  2. Accepted: October 3, 2017
  3. Accepted Manuscript published: October 4, 2017 (version 1)
  4. Version of Record published: October 17, 2017 (version 2)
  5. 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.

Metrics

  • 3,088
    Page views
  • 452
    Downloads
  • 28
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cancer Biology
    2. Neuroscience
    Susu Pan et al.
    Research Article

    Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, eg. celastrol, might be a novel strategy for colorectal cancer treatment.

    1. Cancer Biology
    2. Cell Biology
    Lauren K Williams et al.
    Research Article Updated

    The abscission checkpoint regulates the ESCRT membrane fission machinery and thereby delays cytokinetic abscission to protect genomic integrity in response to residual mitotic errors. The checkpoint is maintained by Aurora B kinase, which phosphorylates multiple targets, including CHMP4C, a regulatory ESCRT-III subunit necessary for this checkpoint. We now report the discovery that cytoplasmic abscission checkpoint bodies (ACBs) containing phospho-Aurora B and tri-phospho-CHMP4C develop during an active checkpoint. ACBs are derived from mitotic interchromatin granules, transient mitotic structures whose components are housed in splicing-related nuclear speckles during interphase. ACB formation requires CHMP4C, and the ESCRT factor ALIX also contributes. ACB formation is conserved across cell types and under multiple circumstances that activate the checkpoint. Finally, ACBs retain a population of ALIX, and their presence correlates with delayed abscission and delayed recruitment of ALIX to the midbody where it would normally promote abscission. Thus, a cytoplasmic mechanism helps regulate midbody machinery to delay abscission.