肿瘤细胞具有较强的增殖和扩散转移能力,肿瘤细胞的增殖和转移受细胞表达的整合素所调节。其中,整合素αvβ3是被研究和讨论最为集中的细胞外基质粘附受体之一。因为αvβ3在肿瘤新生血管中的高表达,使其成为肿瘤诊断和抗肿瘤药物研究的重要靶点。αvβ3的天然配体中都含有一段精氨酸–甘氨酸–天冬氨酸(RGD)序列,参与肿瘤细胞的增殖和转移等活动。RGD的此特性可用于为体外构建肿瘤诊断的分子成像探针和用于靶向治疗的药物。基于整合素αvβ3在肿瘤诊断和治疗中所起到的关键性作用,本文对αvβ3的结构功能以及在癌症诊断和治疗中的作用进行简要概述。 The general characteristics of tumor cells are strong proliferation and metastasis, which are regulated by integrin expression in tumor cells. Integrin αvβ3 is one of the most intensively studied and discussed extracellular matrix adhesion receptors. Because of the high expression of αvβ3 in tumor neovascularization, it has become an important target for tumor diagnosis and anti-tumor drug research. Natural ligands of αvβ3 contain a section of arginine-glycine-aspartic acid (RGD) sequence, which is involved in the proliferation and metastasis of tumor cells. This property of RGD can be used to construct molecular imaging probes in vitro for tumor diagnosis and drugs for targeted therapy. Based on the critical role of integrin αvβ3 in the diagnosis and treatment of cancer, the structure and function of αvβ3 and its role in the diagnosis and treatment of cancer are briefly reviewed.
韩田振,纪雪梅,刘 煜. 整合素αvβ3在肿瘤诊断与治疗中的研究进展Advances in Research of Integrin αvβ3 in Tu-mor Diagnosis and Treatment[J]. 药物资讯, 2019, 08(03): 79-87. https://doi.org/10.12677/PI.2019.83010
参考文献ReferencesMadrazo, E., Conde, A.C. and Redondo-Munoz, J. (2017) Inside the Cell: Integrins as New Governors of Nuclear Alterations? Can-cers, 9, 82. <br>https://doi.org/10.3390/cancers9070082Schips, T.G., Vanhoutte, D., Vo, A., et al. (2019) Thrombospondin-3 Augments Injury-Induced Cardiomyopathy by Intracellular Integrin Inhibition and Sarcolemmal Instability. Nature Communications, 10, 76.
<br>https://doi.org/10.1038/s41467-018-08026-8Niu, J. and Li, Z. (2017) The Roles of Integrin Alphavbeta6 in Cancer. Cancer Letters, 403, 128-137.
<br>https://doi.org/10.1016/j.canlet.2017.06.012Xiong, J.P., Stehle, T., Diefenbach, B., et al. (2001) Crystal Structure of the Extracellular Segment of Integrin Alpha Vbeta3. Science, 294, 339-345. <br>https://doi.org/10.1126/science.1064535Holtke, C. (2018) isoDGR-Peptides for Integrin Targeting: Is the Time Up for RGD? Journal of Medicinal Chemistry, 61, 7471-7473. <br>https://doi.org/10.1021/acs.jmedchem.8b01123Guo, J., Zhang, Y., Li, H., et al. (2018) Intramembrane Ionic Protein-Lipid Interaction Regulates Integrin Structure and Function. PLoS Biology, 16, e2006525. <br>https://doi.org/10.1371/journal.pbio.2006525Zoppi, N., Chiarelli, N., Ritelli, M., et al. (2018) Multifaced Roles of the αvβ3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes’ Dermal Fibroblasts. International Journal of Molecular Sciences, 19, pii: E982.
<br>https://doi.org/10.3390/ijms19040982Sun, C.C., Qu, X.J. and Gao, Z.H. (2016) Arginine-Glycine-Aspartate-Binding Integ-rins as Therapeutic and Diagnostic Targets. American Journal of Therapeutics, 23, e198-e207. <br>https://doi.org/10.1097/MJT.0000000000000053Streuli, C.H. and Akhtar, N. (2009) Signal Co-Operation between Integ-rins and Other Receptor Systems. The Biochemical Journal, 418, 491-506. <br>https://doi.org/10.1042/BJ20081948Temming, K., Schiffelers, R.M., Molema, G., et al. (2005) RGD-Based Strategies for Selective Delivery of Therapeutics and Imaging Agents to the Tumour Vasculature. Drug Resistance Updates: Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy, 8, 381-402. <br>https://doi.org/10.1016/j.drup.2005.10.002Hsieh, M.T., Wang, L.M., Changou, C.A., et al. (2017) Crosstalk be-tween Integrin αvβ3 and ERalpha Contributes to Thyroid Hormone-Induced Proliferation of Ovarian Cancer Cells. Oncotarget, 8, 24237-24249.
<br>https://doi.org/10.18632/oncotarget.10757Cheresh, D.A. and Stupack, D.G. (2002) Integrin-Mediated Death: An Explana-tion of the Integrin-Knockout Phenotype? Nature Medicine, 8, 193-194. <br>https://doi.org/10.1038/nm0302-193Aoudjit, F. and Vuori, K. (2001) Matrix Attachment Regulates Fas-Induced Apoptosis in Endothelial Cells: A Role for c-Flip and Implications for Anoikis. The Journal of Cell Biology, 152, 633-643. <br>https://doi.org/10.1083/jcb.152.3.633Fidler, I.J. (2003) The Pathogen-esis of Cancer Metastasis: The “Seed and Soil” Hypothesis Revisited. Nature Reviews Cancer, 3, 453-458. <br>https://doi.org/10.1038/nrc1098Van Der Pluijm, G., Sijmons, B., Vloedgraven, H., et al. (2001) Uroki-nase-Receptor/Integrin Complexes Are Functionally Involved in Adhesion and Progression of Human Breast Cancer in Vivo. The American Journal of Pathology, 159, 971-982. <br>https://doi.org/10.1016/S0002-9440(10)61773-7Kubas, H., Schafer, M., Bauder-Wust, U., et al. (2010) Multivalent Cyclic RGD Ligands: Influence of Linker Lengths on Receptor Binding. Nuclear Medicine and Biology, 37, 885-891. <br>https://doi.org/10.1016/j.nucmedbio.2010.06.005Desgrosellier, J.S. and Cheresh, D.A. (2010) Integrins in Cancer: Biological Implications and Therapeutic Opportunities. Nature Reviews Cancer, 10, 9-22. <br>https://doi.org/10.1038/nrc2748Beer, A.J. and Schwaiger, M. (2011) PET Imaging of αvβ3 Expression in Cancer Patients. Methods in Molecular Biology, 680, 183-200. <br>https://doi.org/10.1007/978-1-60761-901-7_13Chen, Z., Fu, F., Li, F., et al. (2018) Comparison of [(99m)Tc]3PRGD2 Imaging and [(18)F]FDG PET/CT in Breast Cancer and Expression of Integrin αvβ3 in Breast Cancer Vascular Endothelial Cells. Molecular Imaging and Biology, 20, 846-856. <br>https://doi.org/10.1007/s11307-018-1178-yLv, N., Gao, S., Bai, L., et al. (2019) Advantages of (99m)Tc-3PRGD2 SPECT over CT in the Preoperative Assessment of Lymph Node Metastasis in Patients with Esophageal Cancer. Annals of Nuclear Medicine, 33, 39-46.
<br>https://doi.org/10.1007/s12149-018-1300-xO’connor, J.P., Jackson, A., Parker, G.J., et al. (2007) DCE-MRI Biomarkers in the Clinical Evaluation of Antiangiogenic and Vascular Disrupting Agents. British Journal of Cancer, 96, 189-195. <br>https://doi.org/10.1038/sj.bjc.6603515Hersey, P., Sosman, J., O’day, S., et al. (2010) A Randomized Phase 2 Study of Etaracizumab, a Monoclonal Antibody against Integrin alpha(v)beta(3), + or − Dacarbazine in Patients with Stage IV Metastatic Mela-noma. Cancer, 116, 1526-1534. <br>https://doi.org/10.1002/cncr.24821Borst, A.J., James, Z.M., Zagotta, W.N., et al. (2017) The Therapeutic Antibody LM609 Selectively Inhibits Ligand Binding to Human αvβ3 Integrin via Steric Hindrance. Structure, 25, 1732-9.e5.
<br>https://doi.org/10.1016/j.str.2017.09.007Gutheil, J.C., Campbell, T.N., Pierce, P.R., et al. (2000) Targeted Antiangiogenic Therapy for Cancer Using Vitaxin: A Humanized Monoclonal Antibody to the Integrin αvβ3. Clinical Cancer Research, 6, 3056-3061.Trikha, M., Zhou, Z., Timar, J., et al. (2002) Multiple Roles for Platelet GPIIb/IIIa and αvβ3 Integrins in Tumor Growth, Angiogenesis, and Metastasis. Cancer Research, 62, 2824-2833.Sheldrake, H.M. and Patterson, L.H. (2009) Function and Antagonism of beta3 Integrins in the Development of Cancer Therapy. Current Cancer Drug Targets, 9, 519-540. <br>https://doi.org/10.2174/156800909788486713Xiong, J.P., Stehle, T., Zhang, R., et al. (2002) Crystal Structure of the Ex-tracellular Segment of Integrin Alpha Vbeta3 in Complex with an Arg-Gly-Asp Ligand. Science, 296, 151-155. <br>https://doi.org/10.1126/science.1069040Zhang, L., Gulses, A., Purcz, N., et al. (2019) A Comparative Assessment of the Effects of Integrin Inhibitor Cilengitide on Primary Culture of Head and Neck Squamous Cell Carcinoma (HNSCC) and HNSCC Cell Lines. Clinical & Translational Oncology. <br>https://doi.org/10.1007/s12094-018-02025-3Kumar, C.C., Malkowski, M., Yin, Z., et al. (2001) Inhibition of Angiogenesis and Tumor Growth by SCH221153, a Dual alpha(v)beta3 and alpha(v)beta5 Integrin Re-ceptor Antagonist. Cancer Research, 61, 2232-2238.Chu, J.J. and Ng, M.L. (2004) Interaction of West Nile Virus with αvβ3 Integrin Mediates Virus Entry into Cells. The Journal of Biological Chemistry, 279, 54533-54541. <br>https://doi.org/10.1074/jbc.M410208200Hsu, A.R., Veeravagu, A., Cai, W., et al. (2007) Integrin αvβ3 Antagonists for Anti-Angiogenic Cancer Treatment. Recent Patents on Anti-Cancer Drug Discovery, 2, 143-158. <br>https://doi.org/10.2174/157489207780832469