Human CD34 + cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature

Cristiana Lavazza, Carmelo Carlo-Stella, Arianna Giacomini, Loredana Cleris, Marco Righi, Daniela Sia, Massimo Di Nicola, Michele Magni, Paolo Longoni, Marco Milanesi, Maura Francolini, Annunziata Gloghini, Antonino Carbone, Franca Formelli, Alessandro M. Gianni

Research output: Contribution to journalArticle

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Abstract

Adenovirus-transduced CD34 + cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL + cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL + cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45 + cells per 10 5 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL + cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL + cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL + cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL + cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL + cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling + endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL + cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

Original languageEnglish
Pages (from-to)2231-2240
Number of pages10
JournalBlood
Volume115
Issue number11
DOIs
Publication statusPublished - Mar 18 2010

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Tumors
Tumor Necrosis Factor-alpha
Cells
Apoptosis
Ligands
Membranes
Neoplasms
Labeling
Necrosis
Computer aided analysis
Chemokine CXCL12
Vascular Cell Adhesion Molecule-1
Endothelial cells
Proteome
Cell membranes
Biotin
Machinery
Tumor Burden
Adenoviridae
Intravenous Injections

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Human CD34 + cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature. / Lavazza, Cristiana; Carlo-Stella, Carmelo; Giacomini, Arianna; Cleris, Loredana; Righi, Marco; Sia, Daniela; Di Nicola, Massimo; Magni, Michele; Longoni, Paolo; Milanesi, Marco; Francolini, Maura; Gloghini, Annunziata; Carbone, Antonino; Formelli, Franca; Gianni, Alessandro M.

In: Blood, Vol. 115, No. 11, 18.03.2010, p. 2231-2240.

Research output: Contribution to journalArticle

Lavazza, C, Carlo-Stella, C, Giacomini, A, Cleris, L, Righi, M, Sia, D, Di Nicola, M, Magni, M, Longoni, P, Milanesi, M, Francolini, M, Gloghini, A, Carbone, A, Formelli, F & Gianni, AM 2010, 'Human CD34 + cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature', Blood, vol. 115, no. 11, pp. 2231-2240. https://doi.org/10.1182/blood-2009-08-239632
Lavazza, Cristiana ; Carlo-Stella, Carmelo ; Giacomini, Arianna ; Cleris, Loredana ; Righi, Marco ; Sia, Daniela ; Di Nicola, Massimo ; Magni, Michele ; Longoni, Paolo ; Milanesi, Marco ; Francolini, Maura ; Gloghini, Annunziata ; Carbone, Antonino ; Formelli, Franca ; Gianni, Alessandro M. / Human CD34 + cells engineered to express membrane-bound tumor necrosis factor-related apoptosis-inducing ligand target both tumor cells and tumor vasculature. In: Blood. 2010 ; Vol. 115, No. 11. pp. 2231-2240.
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abstract = "Adenovirus-transduced CD34 + cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL + cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL + cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45 + cells per 10 5 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL + cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL + cells and soluble (s)TRAIL significantly reduced tumor volume by 40{\%} and 29{\%}, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL + cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL + cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL + cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling + endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL + cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.",
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AU - Cleris, Loredana

AU - Righi, Marco

AU - Sia, Daniela

AU - Di Nicola, Massimo

AU - Magni, Michele

AU - Longoni, Paolo

AU - Milanesi, Marco

AU - Francolini, Maura

AU - Gloghini, Annunziata

AU - Carbone, Antonino

AU - Formelli, Franca

AU - Gianni, Alessandro M.

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N2 - Adenovirus-transduced CD34 + cells expressing membrane-bound tumor necrosis factor-related apoptosis-inducing ligand (CD34-TRAIL + cells) exert potent antitumor activity. To further investigate the mechanism(s) of action of CD34-TRAIL + cells, we analyzed their homing properties as well as antitumor and antivascular effects using a subcutaneous myeloma model in immunodeficient mice. After intravenous injection, transduced cells homed in the tumor peaking at 48 hours when 188 plus or minus 25 CD45 + cells per 10 5 tumor cells were detected. Inhibition experiments showed that tumor homing of CD34-TRAIL + cells was largely mediated by vascular cell adhesion molecule-1 and stromal cell-derived factor-1. Both CD34-TRAIL + cells and soluble (s)TRAIL significantly reduced tumor volume by 40% and 29%, respectively. Computer-aided analysis of TdT-mediated dUTP nick end-labeling-stained tumor sections demonstrated significantly greater effectiveness for CD34-TRAIL + cells in increasing tumor cell apoptosis and necrosis over sTRAIL. Proteome array analysis indicated that CD34-TRAIL + cells and sTRAIL activate similar apoptotic machinery. In vivo staining of tumor vasculature with sulfosuccinimidyl-6-(biotinamido) hexanoate-biotin revealed that CD34-TRAIL + cells but not sTRAIL significantly damaged tumor vasculature, as shown by TdT-mediated dUTP nick end-labeling + endothelial cells, appearance of hemorrhagic areas, and marked reduction of endothelial area. These results demonstrate that tumor homing of CD34-TRAIL + cells induces early vascular disruption, resulting in hemorrhagic necrosis and tumor destruction.

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