Phosphatidylserine is a marker of tumor vasculature and a potential target for cancer imaging and therapy

ArticleinInternational Journal of Radiation OncologyBiologyPhysics 54(5):1479-84 · January 2003with27 Reads
DOI: 10.1016/S0360-3016(02)03928-7 · Source: PubMed
  • 39.62 · Southern Illinois University School of Medicine
  • 42.27 · University of Texas Southwestern Medical Center
Abstract
(1) To determine whether exposure of phosphatidylserine (PS) occurs on vascular endothelium in solid tumors in mice. (2) To determine whether PS exposure can be induced on viable endothelial cells in tissue culture by conditions present in the tumor microenvironment. Externalized PS in vivo was detected by injecting mice with a monoclonal anti-PS antibody and examining frozen sections of tumors and normal tissues for anti-PS antibody bound to vascular endothelium. Apoptotic cells were identified by anti-active caspase-3 antibody or by TUNEL assay. PS exposure on cultured endothelial cells was determined by 125I-annexin V binding. Anti-PS antibody bound specifically to vascular endothelium in six tumor models. The percentage of PS-positive vessels ranged from 4% to 40% in different tumor types. Vascular endothelium in normal organs was unstained. Very few tumor vessels expressed apoptotic markers. Hypoxia/reoxygenation, acidity, inflammatory cytokines, thrombin, or hydrogen peroxide induced PS exposure on cultured endothelial cells without causing loss of viability. Vascular endothelial cells in tumors, but not in normal tissues, externalize PS. PS exposure might be induced by tumor-associated oxidative stress and activating cytokines. PS is an abundant and accessible marker of tumor vasculature and could be used for tumor imaging and therapy.
    • "Critically, the mechanisms by which cancer cells actually resist phagocytosis remain incompletely under- stood [9]. Compared with non-malignant cells, expression of PS on the cell surface is a consistent marker of malignancy in both primary and metastatic cell lines [6][7][8][9][10][11][12]. In their study focused on difficult-to-treat primary cancers, including metastatic melanoma, glioblastoma, and metastatic lesions, Riedl et al. [11] demonstrated the specificity of abundant externalized PS for malignant tumors. "
    [Show abstract] [Hide abstract] ABSTRACT: Unlike normal cells, cancer cells express high levels of phosphatidylserine on the extracellular leaflet of their cell membrane. Exploiting this characteristic, our lab developed a therapeutic agent that consists of the fusogenic protein, saposin C (SapC) which is embedded in dioleoylphosphatidylserine (DOPS) vesicles. These nanovesicles selectively target cancer cells and induce apoptosis. Here we review the data supporting use of SapC-DOPS to locate tumors for surgical resection or for treatment. In addition, there is important evidence suggesting that SapC-DOPS may also prove to be an effective novel cancer therapeutic reagent. Given that SapC-DOPS is easily labeled with lipophilic dyes, it has been combined with the far-red fluorescent dye, CellVue Maroon (CVM), for tumor targeting studies. We also have used contrast agents incorporated in the SapC-DOPS nanovesicles for computed tomography and magnetic resonance imaging, and review that data here. Administered intravenously, the fluorescently labeled SapC-DOPS traversed the blood–brain tumor barrier enabling identification of brain tumors. SapC-DOPS-CVM also detected a variety of other mouse tumors in vivo, rendering them observable by optical imaging using IVIS and multi-angle rotational optical imaging. Dye is detected within 30 min and remains within tumor for at least 7 days, whereas non-tumor tissues were unstained (some dye observed in the liver was transient, likely representing degradation products). Additionally, labeled SapC-DOPS ex vivo delineated tumors in human histological specimens. SapC-DOPS can also be labeled with contrast reagents for computed tomography or magnetic resonance imaging. In conclusion, labeled SapC-DOPS provides a convenient, specific, and nontoxic method for detecting tumors while concurrently offering a therapeutic benefit.
    Full-text · Article · Dec 2016
    • "Greater activity towards cancerous over healthy cells is likely to be due, in part, to an increase in affinity for the dysregulated tumour cell plasma membranes. The changes to the membrane include an increase in negatively charged phospholipids [189, 190] and glycoproteins [191, 192] in the outer leaflet, as well as increased surface area and fluidity [193, 194]. In contrast, murine β-defensins and human HBD-2 exert indirect anticancer activity via chemotactic and immunoadjuvant activities that promote adaptive immune responses [195][196][197]. "
    [Show abstract] [Hide abstract] ABSTRACT: Defensins are a well-characterised group of small, disulphide-rich, cationic peptides that are produced by essentially all eukaryotes and are highly diverse in their sequences and structures. Most display broad range antimicrobial activity at low micromolar concentrations, whereas others have other diverse roles, including cell signalling (e.g. immune cell recruitment, self/non-self-recognition), ion channel perturbation, toxic functions, and enzyme inhibition. The defensins consist of two superfamilies, each derived from an independent evolutionary origin, which have subsequently undergone extensive divergent evolution in their sequence, structure and function. Referred to as the cis- and trans-defensin superfamilies, they are classified based on their secondary structure orientation, cysteine motifs and disulphide bond connectivities, tertiary structure similarities and precursor gene sequence. The utility of displaying loops on a stable, compact, disulphide-rich core has been exploited by evolution on multiple occasions. The defensin superfamilies represent a case where the ensuing convergent evolution of sequence, structure and function has been particularly extreme. Here, we discuss the extent, causes and significance of these convergent features, drawing examples from across the eukaryotes.
    Full-text · Article · Aug 2016
    • "Normal membranes exhibit an outer leaflet that is mostly composed by zwitterionic PC and SM, while anionic PS along with most of the PE are usually comprised in the inner leaflet [23]. By contrast, a loss of this asymmetric distribution has been observed for several types of cancer [25, 26], which results in the exposure of the negatively charged PS on the surface of their membranes (Figure 1) [27, 28]. Since the flippase aminophospholipid translocases maintain the distribution of both PE and PS, evidences demonstrated that PE is also located in the membrane's outer leaflet of tumor endothelial cells [29]. "
    [Show abstract] [Hide abstract] ABSTRACT: Lipidomics has been proving that membrane lipids play a crucial role in several cell functions and are involved in several pathologies, including cancer. In fact, beyond a scaffold where proteins and other components are embedded, the cell membrane can also act as a barrier or a target for anticancer drugs. From this point of view, the development of new chemotherapeutic agents should also take into account the role of the membrane in their activity. This Review aims to highlight the importance of anticancer drug-membrane interactions as a powerful strategy to improve cancer therapy. Biophysical techniques emerge, therefore, as essential tools to unveil such interactions.
    Article · Jun 2016
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