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Epidermal Growth Factor, Latrophilin, and Seven Transmembrane Domain-Containing Protein 1 Marker, a Novel Angiogenesis Marker

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Epidermal Growth Factor, Latrophilin, and Seven Transmembrane Domain-Containing Protein 1 Marker, a Novel Angiogenesis Marker Journal name: OncoTargets and Therapy Article Designation: Review Year: 2015 Volume: 8 OncoTargets and Therapy Dovepress Running head verso: Serban et al Running head recto: ELTD1 structure, function, and its role in angiogenesis open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S93843 Open Access Full Text Article REVIEW Epidermal growth factor, latrophilin, and seven transmembrane domain-containing protein 1 marker, a novel angiogenesis marker Florentina Serban Abstract: Epidermal growth factor, latrophilin, and seven transmembrane domain-containing Stefan-Alexandru Artene protein 1 on chromosome 1 (ELTD1), an orphan adhesion G-protein coupled receptor, was Ada Maria Georgescu reported as a regulator of angiogenesis, also involved in cancer progression and development. Stefana Oana Purcaru More recently, ELTD1 was identified as a potential new tumor marker for high-grade glioma. Daniela Elise Tache ELTD1, belongs to the G-protein coupled receptor superfamily that comprises the biggest Oana Alexandru receptor family in the human genome. Following the discovery of ELTD1 almost a decade ago, only a few research groups have attempted to find its role in normal and tumor cells, important Anica Dricu information about this receptor remaining still unknown. The ELTD1 ligand has not currently Department of Biochemistry, been identified and intracellular signaling studies have not yet been performed in normal or University of Medicine and Pharmacy For personal use only. of Craiova, Craiova, Romania tumor cells. Although the current published data on ELTD1 function and structure are rather limited, this receptor seems to be very important, not only as biomarker, but also as molecular target in glioblastoma. This review summarizes and discusses the current knowledge on ELTD1 structure, function, and its role in both physiological and tumoral angiogenesis. Keywords: ELTD1, angiogenesis, glioma, biomarker Introduction Since the early ages of oncology, medical researchers have strived to discover new biomarkers, which can be correlated with early stages of cancer development, tumor progression, and resistance to therapy. With the discovery of targeted therapy, some of OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.191.40.80 on 10-Sep-2017 these markers became interesting therapeutic targets due to their implication in intricate pathophysiological processes involved in cancer growth, invasion, or resistance to curative approaches. One of the most studied pathophysiological events involved in cancer development and progression is angiogenesis. Depriving nascent cancer cells of their nutrients provided by aberrant, newly formed blood vessels became an attrac- tive approach that, in theory, could deter or even reverse neoplastic growth. However, both early and more recent trials have yielded limited results due to the complex nature of microvasculature in each cancer type, the multiple pathways implicated in cell signaling, and the vast number of genes responsible for both normal and cancer angiogenesis.1–5 Together, these variables can confer both natural and acquired resis- tance to anti-angiogenic therapy, leading to mixed clinical results.6–8 Many angiogenic inhibitors, designated for cancer treatment, are currently in preclinical and clinical use. The vascular endothelial growth factor receptor family is a well-studied angiogenic Correspondence: Anica Dricu Department of Biochemistry, University class of receptors9–11 that have been constantly used to develop new cancer therapies of Medicine and Pharmacy of Craiova, for quite a while now.12–14 The therapeutic results, however, for many malignant dis- Petru Rares 2, 200349, Craiova, Romania Email [email protected] eases, in which vascular endothelial growth factor receptor dysfunction is believed submit your manuscript | www.dovepress.com OncoTargets and Therapy 2015:8 3767–3774 3767 Dovepress © 2015 Serban et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/OTT.S93843 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Serban et al Dovepress to drive tumor angiogenesis, have been ineffective. Future as part of the secretin family, but was later revealed to be a approaches should include inhibition of multiple pathways distinct group. As a particular feature, this family presents an involved in cancer microvasculature formation or the dis- unusually elongated N-terminal ectodomain, which is often covery of new angiogenesis markers, more specific for each perceived as combinations of different adhesion-linked motifs: cancer type.15–18 cadherins,34 thrombospondins,35,36 leucine-rich repeats,37 and One such possible candidate is epidermal growth factor, epithelial growth factor (EGF)-like domain.38,39 Members latrophilin, and seven transmembrane domain-containing of the adhesion family are implicated in multiple cellular protein 1 on chromosome 1 (ELTD1), a biomarker recently functions such as cytoskeletal regulation,40–43 planar cell linked to both normal and pathological angiogenesis.19,20 polarity,42,44,45 cell adhesion and migration,46–48 cellular pro- An editorial article linked ELTD1 levels to how the human liferation and death,35,49,50 hematopoiesis, immunity,51–53 and organism responds to hematopoietic stem cell transplant by angiogenesis.19,54–57 The adhesion family includes the latrophi- developing graft-versus-host disease.21 Using complementary lin-like subfamily, with its four members: the orphan ELTD1 DNA microarray, another study also found that ELTD1 was receptor, as well as the latrophilin 1, 2, and 3 receptors.58 significantly upregulated in patients with ulcerative colitis Nechiporuk et al27 mapped the ELTD1 gene on the with dysplastic lesions when compared with normal, nondys- 1p33–p32 band, belonging to chromosome 1. The gene plastic, and colic mucosa.22 Upregulation of the ELTD1 gene contains 15 exons having two splice variants: a full-length was observed in studies describing genomic adaption to high version and a shorter variant represented by a fraction of a altitudes in the Andean population,23 cannabis use disorders,24 transmembrane domain.59 The gene encodes a 3,527 nucle- genetic predisposition for obesity in both humans and pigs,25 otide transcript, which further translates into a 690 amino acid and even resistance to therapy in cattle afflicted by ticks.26 protein. The ELTD1 receptor is formed of a large extracel- Initially mentioned in 2001, as a receptor normally lular domain, a seven transmembrane domain coupled with a regulated in the human heart,27 ELTD1 has been recently short cytoplasmic tail. The extracellular domain contains an linked to the progression and development of glioblastoma N-terminal region, an EGF-like domain, a calcium-binding For personal use only. multiforme (GBM),28,29 a particularly aggressive brain tumor EGF domain, and a GPCR proteolysis site. The cytoplasmic with a very bleak prognosis. domain contains a tyrosine kinase phosphorylation site, Although it was discovered 14 years ago,27 in the scientific suggested to be involved in receptor intracellular signaling literature, only a few published works have dealt directly with (Figure 1).27 Unfortunately, no information is yet available this topic. The current review is an analysis of the information in current literature on the downstream signaling pathways currently available on ELTD1. implicated in signal transduction or the ligands that bind to the ELTD1 receptor. Origin and structure of the ELTD1 receptor ELTD1 implication in angiogenesis Ontogenetically, ELTD1 belongs to the G-protein coupled Due to the low number of studies concerning ELTD1, its OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.191.40.80 on 10-Sep-2017 receptor (GPCR) superfamily, which comprises the big- roles in both physiological and pathological angiogenesis gest receptor family in the human genome. Also called are quite unknown. In the first study published in this area, the 7α-helicases transmembrane receptors, the GPCR Nechiporuk et al27 asserted that the ELTD1 receptor was superfamily transducts signals from the extracellular to the highly expressed in cardiomyocytes and smooth muscle cells intracellular domain using guanine-binding proteins. The of both blood vessels and bronchi, in murine models. ELTD1 GPCR superfamily is involved in a multitude of human regulation was also linked to the switch between hyperplastic physiological processes, pertaining to different areas such and hypertrophic evolution in the development of cardio- as chemotaxis, smell, hormone secretion, taste, vision, or myocytes during the physiological differentiation process, inflammation.30–32 in both human and rat models. The receptor’s presence Containing over 900 members, the GPCR superfamily in the coronary arteries also raises further question marks comprises five major families: glutamate (22 members), regarding its implication in coronary angiogenesis.27 More rhodopsin (701 members), adhesion
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