Research Papers:

Failure of anti tumor-derived endothelial cell immunotherapy depends on augmentation of tumor hypoxia

Annalisa Pezzolo _, Danilo Marimpietri, Lizzia Raffaghello, Claudia Cocco, Angela Pistorio, Claudio Gambini, Michele Cilli, Alberto Horenstein, Fabio Malavasi and Vito Pistoia

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Oncotarget. 2014; 5:10368-10381. https://doi.org/10.18632/oncotarget.2015

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Annalisa Pezzolo1, Danilo Marimpietri1, Lizzia Raffaghello1, Claudia Cocco1, Angela Pistorio2, Claudio Gambini3, Michele Cilli4, Alberto Horenstein5, Fabio Malavasi5 and Vito Pistoia1

1 Laboratorio di Oncologia, Istituto Giannina Gaslini, Genova, Italy

2 Unità di Epidemiologia e Biostatistica Istituto Giannina Gaslini, Genova, Italy

3 Laboratorio di Anatomia Patologica Istituto Giannina Gaslini, Genova, Italy

4 Animal Research Facility, IRCCS-AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy

5 Laboratorio di Immunogenetica, Università di Torino, Italy


Annalisa Pezzolo, email:

Keywords: epithelial-mesenchymal transition, hypoxia, neuroblastoma, tumor-derived endothelial cells, vascular mimicry

Received: March 14, 2014 Accepted: May 26, 2014 Published: May 26, 2014


We have previously demonstrated that Tenascin-C (TNC)+ human neuroblastoma (NB) cells transdifferentiate into tumor-derived endothelial cells (TDEC), which have been detected both in primary tumors and in tumors formed by human NB cell lines in immunodeficient mice. TDEC are genetically unstable and may favor tumor progression, suggesting that their elimination could reduce tumor growth and dissemination. So far, TDEC have never been targeted by antibody-mediated immunotherapy in any of the tumor models investigated.

To address this issue, immunodeficient mice carrying orthotopic NB formed by the HTLA-230 human cell line were treated with TDEC-targeting cytotoxic human (h)CD31, that spares host-derived endothelial cells, or isotype-matched mAbs. hCD31 mAb treatment did not affect survival of NB-bearing mice, but increased significantly hypoxia in tumor microenvironment, where apoptotic and proliferating TDEC coexisted, indicating the occurrence of vascular remodeling.

Tumor cells from hCD31 mAb treated mice showed i) up-regulation of epithelial-mesenchymal transition (EMT)-related and vascular mimicry (VM)-related gene expression, ii) expression of endothelial (i.e. CD31 and VE-cadherin) and EMT-associated (i.e. Twist-1, N-cadherin and TNC) immunophenotypic markers, and iii) up-regulation of high mobility group box-1 (HMGB-1) expression. In vitro experiments with two NB cell lines showed that hypoxia was the common driver of all the above phenomena and that human recombinant HMGB-1 amplified EMT and TDEC trans-differentiation.

In conclusion, TDEC targeting with hCD31 mAb increases tumor hypoxia, setting the stage for the occurrence of EMT and of new waves of TDEC trans-differentiation. These adaptive responses to the changes induced by immunotherapy in the tumor microenvironment allow tumor cells to escape from the effects of hCD31 mAb.

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