Abstract 190: Tumor endothelial cells as a targetable gateway that modulates access of drugs to cancer cells
Authors: Wu Yue , Greene Michael J. , Wang Jianmin , Smith Gary J. 
Published: August 2018

Abstract
Introduction: Human endothelial cells (EC) lining the tumor vasculature of human prostate adenocarcinoma are preserved in primary xenografts of intact surgical remnant tissue. Androgen deprivation (AD) causes de-endothelialization of primary xenografts that is followed by re-endothelialization with human endothelial cells in the absence of testosterone (T). This study determined the consequences of targeted perturbation of prostate endothelium on access of chemotherapeutic agents to prostate cancer (CaP) cells. Methods: SCID mice were castrated and implanted with a device for sustained delivery of T to establish “humanized” mice. Fresh surgical specimens of human CaP or benign human prostate were transplanted onto the “humanized” mice and allowed 30 days to engraft before the integrity of the human microvascular EC barrier was perturbed by removal of the T delivery device, T-deprivation (T-D). Cisplatin (Cis-Pt) was investigated because it is excluded effectively by the membrane pumps/transporters in human prostate ECs, and it effectively kills slowly/non-proliferating cancer cells. Fresh prostate cancer tissue, benign prostate tissue, or xenografts after various times/treatments were enzymatically disaggregated and EC and CaP cells isolated using cell type-specific antibody-conjugated magnetic beads. Transcriptomes of isolated cells were acquired using RNASeq. Cis-Pt-DNA adducts in the xenografts or isolated cells were analyzed using immunohistochemistry (IHC) or Cytof, respectively. Results: Enhanced access to the xenograft tissue of circulating imaging markers during the interval of the compromised EC barrier, and after re-endothelialization, was demonstrated by: MRI (contrast dyes); MS (nanoparticles); 3) IHC (lectins); and Photo-Acoustic Imaging (hemoglobin). Cis-Pt-DNA adducts in xenografts treated during the T-D induced “window” were at greater levels than xenografts treated in intact mice. Genes classically associated with epithelial or endothelial cells demonstrated the effectiveness of the enrichment of cell types. Global transcriptome analyses revealed comparable gene expression profiles of the same cell type isolated from fresh tissue or pre-T-D xenografts. T-D induced dynamic changes in gene transcriptomes of endothelial cells, epithelial cells and stromal cells, and the transcriptomes evolved over the time after T-D. Transcriptomes of endothelial cells before T-D and after re-endothelialization were significantly different. The profile of uptake transporters and efflux pumps varies between epithelial, endothelial and stromal cells, and the expression pattern within the individual populations also evolved in response to T-D. Conclusions: Primary xenografts provide a unique tool for analysis of the roles of targeted microvascular damage in organ-specific therapies, and of the evolution of the EC compartment in response to iatrogenic intervention.
Citation Format: Yue Wu, Michael J. Greene, Jianmin Wang, Gary J. Smith. Tumor endothelial cells as a targetable gateway that modulates access of drugs to cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 190.