Elsevier

Neoplasia

Volume 13, Issue 4, April 2011, Pages 299-308, IN1-IN2
Neoplasia

Increased Exposure of Phosphatidylethanolamine on the Surface of Tumor Vascular Endothelium1,2

https://doi.org/10.1593/neo.101366Get rights and content
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open access

Abstract

We have previously shown that oxidative stress within the tumor microenvironment causes phosphatidylserine (PS) to redistribute from the inner to the outer membrane leaflet of the endothelial cells (EC) creating a highly specific marker for the tumor vasculature. Because the distribution of phosphatidylethanolamine (PE) and PS within the membrane is coregulated, we reasoned that PE would also be localized in the outer membrane leaflet of tumor EC. To demonstrate this, the PE-binding peptide duramycin was biotinylated and used to determine the distribution of PE on EC in vitro and in vivo. Exposure of cultured EC to hypoxia, acidity, reactive oxygen species, or irradiation resulted in the formation of membrane blebs that were intensely PE-positive. When biotinylated duramycin was intravenously injected into tumor-bearing mice, it preferentially localized to the luminal surface of the vascular endothelium. Depending on tumor type, 13% to 56% of the tumor vessels stained positive for PE. PE-positive vessels were observed in and around hypoxic regions of the tumor. With the exception of intertubular vessels of the kidney, normal vessels remained unstained. To test the potential of PE as a biomarker for imaging, duramycin was conjugated to the near-infrared fluorophore 800CW and used for optical imaging of RM-9 prostate carcinomas. The near-infrared probe was easily detected within tumors in live animals. These results show that PE, like PS, becomes exposed on tumor vascular endothelium of multiple types of tumors and holds promise as a biomarker for noninvasive imaging and drug targeting.

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1

This research was supported in part by a sponsored research agreement with Peregrine Pharmaceuticals, Inc. (Tustin, CA) and funding from the Gillson Longenbaugh Foundation (TX). Imaging was facilitated by the Southwestern Small Animal Imaging Resource (SW-SAIR), which is supported in part by the NCI U24 CA126608, the Harold C. Simmons Cancer Center, which is supported in part by an NCI Cancer Center Support Grant, CA142543-01, and the Department of Radiology.

2

This article refers to supplementary materials, which are designated by Figures W1 to W4 and are available online at www.neoplasia.com.