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      Selecting Targets for Tumor Imaging: An Overview of Cancer-Associated Membrane Proteins

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          Abstract

          Tumor targeting is a booming business: The global therapeutic monoclonal antibody market accounted for more than $78 billion in 2012 and is expanding exponentially. Tumors can be targeted with an extensive arsenal of monoclonal antibodies, ligand proteins, peptides, RNAs, and small molecules. In addition to therapeutic targeting, some of these compounds can also be applied for tumor visualization before or during surgery, after conjugation with radionuclides and/or near-infrared fluorescent dyes. The majority of these tumor-targeting compounds are directed against cell membrane-bound proteins. Various categories of targetable membrane-bound proteins, such as anchoring proteins, receptors, enzymes, and transporter proteins, exist. The functions and biological characteristics of these proteins determine their location and distribution on the cell membrane, making them more, or less, accessible, and therefore, it is important to understand these features. In this review, we evaluate the characteristics of cancer-associated membrane proteins and discuss their overall usability for cancer targeting, especially focusing on imaging applications.

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          Most cited references182

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          G-protein-coupled receptors and cancer.

          G-protein-coupled receptors (GPCRs), the largest family of cell-surface molecules involved in signal transmission, have recently emerged as crucial players in tumour growth and metastasis. Malignant cells often hijack the normal physiological functions of GPCRs to survive, proliferate autonomously, evade the immune system, increase their blood supply, invade their surrounding tissues and disseminate to other organs. This Review will address our current understanding of the many roles of GPCRs and their signalling circuitry in tumour progression and metastasis. We will also discuss how interfering with GPCRs might provide unique opportunities for cancer prevention and treatment.
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            Targeted drug delivery via the folate receptor.

            The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its gamma-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.
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              RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis.

              The integrin α(v)β(3) plays an important role in angiogenesis. It is expressed on tumoral endothelial cells as well as on some tumor cells. RGD peptides are well-known to bind preferentially to the α(v)β(3) integrin. In this context, targeting tumor cells or tumor vasculature by RGD-based strategies is a promising approach for delivering anticancer drugs or contrast agents for cancer therapy and diagnosis. RGD-based strategies include antagonist drugs (peptidic or peptidomimetic) of the RGD sequence, RGD-conjugates, and the grafting of the RGD peptide or peptidomimetic, as targeting ligand, at the surface of nanocarriers. Although all strategies are overviewed, this review aims to particularly highlight the position of RGD-based nanoparticles in cancer therapy and imaging. This review is divided into three parts: the first one describes the context of angiogenesis, the role of the integrin α(v)β(3), and the binding of the RGD peptide to this integrin; the second one focuses on RGD-based strategies in cancer therapy; while the third one focuses on RGD-based strategies in cancer diagnosis.
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                Author and article information

                Journal
                Biomark Cancer
                Biomark Cancer
                Biomarkers in Cancer
                Biomarkers in Cancer
                Libertas Academica
                1179-299X
                2016
                27 September 2016
                : 8
                : 119-133
                Affiliations
                [1 ]Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
                [2 ]Department of Gastroenterology, Leiden University Medical Center, Leiden, the Netherlands.
                [3 ]Antibodies for Research Applications BV, Gouda, the Netherlands.
                Author notes
                Article
                bic-8-2016-119
                10.4137/BIC.S38542
                5040425
                27721658
                a8b581a7-5416-4050-b8da-819a262d5e6f
                © 2016 the author(s), publisher and licensee Libertas Academica Ltd.

                This is an open access article published under the Creative Commons CC-BY-NC 3.0 license.

                History
                : 05 July 2016
                : 05 September 2016
                : 06 September 2016
                Categories
                Review

                cancer imaging,biomarker,transmembrane,adhesion protein,receptor,gpi anchor

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