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Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells

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Abstract

The proapoptotic death receptor 5 (DR5) expressed by tumor associated endothelial cells (TECs) mediates vascular disrupting effects of human CD34+ cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34−TRAIL+ cells) in mice. Indeed, lack of DR5 on TECs causes resistance to CD34−TRAIL+ cells. By xenografting in nonobese diabetic/severe combined immunodeficient mice the TRAIL-resistant lymphoma cell line SU-DHL-4V, which generates tumors lacking endothelial DR5 expression, here we demonstrate for the first time that the Akt inhibitor perifosine induces in vivo DR5 expression on TECs, thereby overcoming tumor resistance to the vascular disruption activity of CD34−TRAIL+ cells. In fact, CD34−TRAIL+ cells combined with perifosine, but not CD34−TRAIL+ cells alone, exerted marked antivascular effects and caused a threefold increase of hemorrhagic necrosis in SU-DHL-4V tumors. Consistent with lack of DR5 expression, CD34−TRAIL+ cells failed to affect the growth of SU-DHL-4V tumors, but CD34−TRAIL+ cells plus perifosine reduced tumor volumes by 60 % compared with controls. In view of future clinical studies using membrane-bound TRAIL, our results highlight a strategy to rescue patients with primary or acquired resistance due to the lack of DR5 expression in tumor vasculature.

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Acknowledgments

We are indebted to Prof. Marco Presta (Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy) for continuous support and critical revision of the manuscript. This work was supported in part by grants from the Ministry of Education, University and Research (Rome, Italy), the Ministry of Health (Ricerca Finalizzata 2010 to C.C.-S.), and the Italian Association for Cancer Research (MCO - 9998 to C.C.-S. and A.M.G.).

Conflict of interest

The authors declare no competing financial interests.

Ethical standards

Animal experiments were performed according to the Italian laws (D.L. 116/92 and following additions) that enforce the EU 86/109 Directive and were approved by the institutional Ethical Committee for Animal Experimentation.

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Authors and Affiliations

  1. Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089, Rozzano, Milan, Italy

    Arianna Giacomini, Silvia L. Locatelli & Carmelo Carlo-Stella

  2. Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy

    Arianna Giacomini, Marco Righi, Silvia L. Locatelli & Carmelo Carlo-Stella

  3. National Research Council, Institute of Neuroscience, Milan, Italy

    Marco Righi

  4. Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy

    Loredana Cleris & Maria Grazia Daidone

  5. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy

    Stefania Mitola

  6. Medical Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133, Milan, Italy

    Alessandro M. Gianni

  7. Department of Medical Physiopathology and Transplants, University of Milan, Milan, Italy

    Alessandro M. Gianni

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  1. Arianna Giacomini
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Correspondence to Alessandro M. Gianni or Carmelo Carlo-Stella.

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Giacomini, A., Righi, M., Cleris, L. et al. Induction of death receptor 5 expression in tumor vasculature by perifosine restores the vascular disruption activity of TRAIL-expressing CD34+ cells. Angiogenesis 16, 707–722 (2013). https://doi.org/10.1007/s10456-013-9348-7

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