Elsevier

EBioMedicine

Volume 42, April 2019, Pages 408-419
EBioMedicine

Patient-specific organotypic blood vessels as an in vitro model for anti-angiogenic drug response testing in renal cell carcinoma

https://doi.org/10.1016/j.ebiom.2019.03.026Get rights and content
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open access

Abstract

Background

Anti-angiogenic treatment failure is often attributed to drug resistance, unsuccessful drug delivery, and tumor heterogeneity. Recent studies have speculated that anti-angiogenic treatments may fail due to characteristics inherent to tumor-associated blood vessels. Tumor-associated blood vessels are phenotypically different from their normal counterparts, having defective or permeable endothelial monolayers, abnormal sprouts, and abnormal vessel hierarchy. Therefore, to predict the efficacy of anti-angiogenic therapies in an individual patient, in vitro models that mirror individual patient's tumor vascular biology and response to anti-angiogenic treatment are needed.

Methods

We used a microfluidic in vitro organotypic model to create patient-specific biomimetic blood vessels from primary patient-specific tumor endothelial cells (TEnCs) and normal endothelial cells (NEnC). We assessed number of sprouts and vessel organization via microscopy imaging and image analysis. We characterized NEnC and TEnC vessel secretions via multiplex bead-based ELISA.

Findings

Using this model, we found that TEnC vessels exhibited more angiogenic sprouts than NEnC vessels. We also found a more disorganized and gap-filled endothelial monolayer. NEnCs and TEnC vessels exhibited heterogeneous functional drug responses across the five patients screened, as described in the clinic.

Interpretation

Our model recapitulated hallmarks of TEnCs and NEnCs found in vivo and captured the functional and structural differences between TEnC and NEnC vessels. This model enables a platform for therapeutic drug screening and assessing patient-specific responses with great potential to inform personalized medicine approaches.

Funding

NIH grants R01 EB010039, R33 CA225281, R01CA186134 University of Wisconsin Carbone Cancer Center (CA014520), and University of Wisconsin Hematology training grant T32 HL07899.

Keywords

Organotypic
Lumen
Model
Anti-angiogenic
Renal
Carcinoma

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1

These authors have contributed to this work equally.