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Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy.

ABSTRACT: Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Consequently, RAPTA-T pre-treatment followed by the application of cisplatin or liposomal cisplatin (Lipoplatin) leads to increased levels of the cytotoxin in the tumor and enhanced mesothelioma growth inhibition. We demonstrate that the vascular changes induced by RAPTA-T are related, in part, to the inhibition of poly-(ADP-ribose) polymerase 1 (PARP-1) which is associated to tumor vascular stabilization. These findings suggest novel therapeutic implications for RAPTA-T to create conditions for superior drug uptake and efficacy of approved cytotoxic anti-cancer drugs in malignant pleural mesothelioma and potentially other chemoresistant tumors.

SUBMITTER: Riedel T

PROVIDER: S-EPMC6035176 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy.

Riedel Tina T Cavin Sabrina S van den Bergh Hubert H Krueger Thorsten T Liaudet Lucas L Ris Hans-Beat HB Dyson Paul J PJ Perentes Jean Y JY

Scientific reports 20180706 1

Human pleural mesothelioma is an incurable and chemoresistant cancer. Using a nude mouse xenograft model of human pleural mesothelioma, we show that RAPTA-T, a compound undergoing preclinical evaluation, enhances tumor vascular function by decreasing blood vessel tortuosity and dilation, while increasing the coverage of endothelial cells by pericytes and vessel perfusion within tumors. This in turn significantly reduces the interstitial fluid pressure and increases oxygenation in the tumor. Cons ...[more]

PMID: 29980753

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Project description:Tumor Endothelial Marker 8/Anthrax Toxin Receptor 1 (TEM8/ANTXR1) expression is induced in the vascular compartment of multiple tumors and therefore, is a candidate molecule to target tumor therapies. This cell surface molecule mediates anthrax toxin internalization, however, its physiological function in blood vessels remains largely unknown. We identified the chicken chorioallantoic membrane (CAM) as a model system to study the endogenous function of TEM8 in blood vessels as we found that TEM8 expression was induced transiently between day 10 and 12 of embryonic development, when the vascular tree is undergoing final development and growth. We used the cell-binding component of anthrax toxin, Protective Antigen (PA), to engage endogenous TEM8 receptors and evaluate the effects of PA-TEM8 complexes on vascular development. PA applied at the time of highest TEM8 expression reduced vascular density and disrupted hierarchical branching as revealed by quantitative morphometric analysis of the vascular tree after 48h. PA-dependent reduced branching phenotype was partially mimicked by Wnt3a application and ameliorated by the Wnt antagonist, Dikkopf-1. These results implicate TEM8 expression in endothelial cells in regulating the canonical Wnt signaling pathway at this day of CAM development. Consistent with this model, PA increased beta catenin levels acutely in CAM blood vessels in vivo and in TEM8 transfected primary human endothelial cells in vitro. TEM8 expression in Hek293 cells, which neither express endogenous PA-binding receptors nor Wnt ligands, stabilized beta catenin levels and amplified beta catenin-dependent transcriptional activity induced by Wnt3a. This agonistic function is supported by findings in the CAM, where the increase in TEM8 expression from day 10 to day 12 and PA application correlated with Axin 2 induction, a universal reporter gene for canonical Wnt signaling. We postulate that the developmentally controlled expression of TEM8 modulates endothelial cell response to canonical Wnt signaling to regulate vessel patterning and density.

Dataset Information

Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy.

Publications

Chemo-manipulation of tumor blood vessels by a metal-based anticancer complex enhances antitumor therapy.

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