Increased Exposure of Phosphatidylethanolamine on the Surface of Tumor Vascular Endothelium 1 2

Department of Pharmacology and Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 04/2011; 13(4):299-308. DOI: 10.1593/neo.101366
Source: PubMed


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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    • "The oxidative stress in tumour cells caused exposure of phosphatidylserine on the surface of the vascular endothelium of blood vessels in tumours but not on normal cells [139]. The fusion protein (FP) consisting of L-methionase linked to human annexin-V injected into the bloodstream will bind to the marker on vascular endothelial cells of the tumour only. "
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    ABSTRACT: Cancer is an increasing cause of mortality and morbidity throughout the world. L-methionase has potential application against many types of cancers. L-Methionase is an intracellular enzyme in bacterial species, an extracellular enzyme in fungi, and absent in mammals. L-Methionase producing bacterial strain(s) can be isolated by 5,5'-dithio-bis-(2-nitrobenzoic acid) as a screening dye. L-Methionine plays an important role in tumour cells. These cells become methionine dependent and eventually follow apoptosis due to methionine limitation in cancer cells. L-Methionine also plays an indispensable role in gene activation and inactivation due to hypermethylation and/or hypomethylation. Membrane transporters such as GLUT1 and ion channels like Na(2+), Ca(2+), K(+), and Cl(-) become overexpressed. Further, the α-subunit of ATP synthase plays a role in cancer cells growth and development by providing them enhanced nutritional requirements. Currently, selenomethionine is also used as a prodrug in cancer therapy along with enzyme methionase that converts prodrug into active toxic chemical(s) that causes death of cancerous cells/tissue. More recently, fusion protein (FP) consisting of L-methionase linked to annexin-V has been used in cancer therapy. The fusion proteins have advantage that they have specificity only for cancer cells and do not harm the normal cells.
    BioMed Research International 08/2014; 2014:506287. DOI:10.1155/2014/506287 · 2.71 Impact Factor
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    • "We found that their activity is not only governed by electrostatics and amphiphilicity as most AMP, but by a specific affinity to bind and rupture membranes that carry phosphatidylethanolamine lipids (Burman et al., 2011; Henriques et al., 2012). This phospholipid is not part of the composition of the outer leaflet of healthy human cell membranes, but predominant amongst tumour cells as they lose their ability to uphold this asymmetry (Stafford and Thorpe, 2011), and amongst most bacteria without which fitness is dramatically reduced (Rietveld et al., 1993). This combination of qualities have made cyclotides a special focus of our research and are good examples of the range of qualities that can be found in peptide pharmacognosy, rather than confining research to the traditional low-molecular-weight compounds. "
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    Phytochemical Analysis 01/2014; 25(1). DOI:10.1002/pca.2468 · 2.34 Impact Factor
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    • "When cells undergo apoptosis, as do tumor cells responding to chemotherapy, PS becomes exposed on their outer membrane surface through one or more calcium-dependent mechanisms [3,4]. PS exposure is also induced on the viable vascular endothelium in tumors by oxidative stresses within the tumor microenvironment [5-7] and increased PS exposure levels on the endothelium are consistently seen in tumors responding to therapy [8-11]. Since PS exposure on tumor endothelium and tumor cells correlates with tumor growth inhibition [8,9,12], it provides an excellent marker for predicting tumor response to therapy. "
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    ABSTRACT: Phosphatidylserine (PS) is an attractive target for imaging agents that identify tumors and assess their response to therapy. PS is absent from the surface of most cell types, but becomes exposed on tumor cells and tumor vasculature in response to oxidative stresses in the tumor microenvironment and increases in response to therapy. To image exposed PS, we used a fully human PS-targeting antibody fragment, PGN635 F(ab')2, that binds to complexes of PS and β2-glycoprotein I. PGN635 F(ab')2 was labeled with the positron-emitting isotope iodine-124 ((124)I) and the resulting probe was injected into nude mice bearing subcutaneous or orthotopic human PC3 prostate tumors. Biodistribution studies showed that (124)I-PGN635 F(ab')2 localized with remarkable specificity to the tumors with little uptake in other organs, including the liver and kidneys. Clear delineation of the tumors was achieved by PET 48 hours after injection. Radiation of the tumors with 15 Gy or systemic treatment of the mice with 10 mg/kg docetaxel increased localization in the tumors. Tumor-to-normal (T/N) ratios were inversely correlated with tumor growth measured over 28 days. These data indicate that (124)I-PGN635 F(ab')2 is a promising new imaging agent for predicting tumor response to therapy.
    PLoS ONE 12/2013; 8(12):e84864. DOI:10.1371/journal.pone.0084864 · 3.23 Impact Factor
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