Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium

Jason H. Stafford, Philip E. Thorpe

Research output: Contribution to journalArticle

80 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)299-308
Number of pages10
JournalNeoplasia
Volume13
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Vascular Endothelium
Neoplasms
Phosphatidylserines
Endothelial Cells
Membranes
Biomarkers
phosphatidylethanolamine
Cell Hypoxia
Tumor Microenvironment
Optical Imaging
Blister
Drug Delivery Systems
Tumor Biomarkers
Prostate
Cultured Cells
Reactive Oxygen Species
Oxidative Stress
Carcinoma
Kidney
Peptides

ASJC Scopus subject areas

  • Cancer Research

Cite this

Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium. / Stafford, Jason H.; Thorpe, Philip E.

In: Neoplasia, Vol. 13, No. 4, 04.2011, p. 299-308.

Research output: Contribution to journalArticle

Stafford, Jason H. ; Thorpe, Philip E. / Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium. In: Neoplasia. 2011 ; Vol. 13, No. 4. pp. 299-308.
@article{3bded5664b18449e92ba45cce3442b9d,
title = "Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium",
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.",
author = "Stafford, {Jason H.} and Thorpe, {Philip E.}",
year = "2011",
month = "4",
doi = "10.1593/neo.101366",
language = "English (US)",
volume = "13",
pages = "299--308",
journal = "Neoplasia (United States)",
issn = "1522-8002",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Increased exposure of phosphatidylethanolamine on the surface of tumor vascular endothelium

AU - Stafford, Jason H.

AU - Thorpe, Philip E.

PY - 2011/4

Y1 - 2011/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79953695111&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79953695111&partnerID=8YFLogxK

U2 - 10.1593/neo.101366

DO - 10.1593/neo.101366

M3 - Article

C2 - 21472134

AN - SCOPUS:79953695111

VL - 13

SP - 299

EP - 308

JO - Neoplasia (United States)

JF - Neoplasia (United States)

SN - 1522-8002

IS - 4

ER -