Advances in Molecular OncologyAdvances in Molecular OncologyУспехи молекулярной онкологии2313-805X2413-3787Publishing House ABV Press17710.17650/2313-805X-2018-5-4-86-93REVIEW ARTICLESОБЗОРНЫЕ СТАТЬИThe role of integrins αv in the pathogenesis of oral squamous cell carcinomaРоль интегринов αv в патогенезе плоскоклеточного рака полости ртаhttps://orcid.org/0000-0001-7713-1891TuguzbaevaG. M.ТугузбаеваГ. М.
Russian Federation

3 Lenina St., Ufa 450008, Republic Bashkortostan

Гульнара Маратовна Тугузбаева.

Республика Башкортостан, 450008 Уфа, ул. Ленина, 3

gulnaritta@gmail.comPavlovV. N.ПавловВ. Н.
Russian Federation

3 Lenina St., Ufa 450008, Republic Bashkortostan

Республика Башкортостан, 450008 Уфа, ул. Ленина, 3

Bashkir State Medical University, Ministry of Health of RussiaФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России151220185486930301201903012019Copyright ©; 2018, Tuguzbaeva G.M., Pavlov V.N.Copyright ©; 2018, Тугузбаева Г.М., Павлов В.Н.2018Tuguzbaeva G.M., Pavlov V.N.Тугузбаева Г.М., Павлов В.Н.https://creativecommons.org/licenses/by/4.0https://umo.abvpress.ru/jour/article/view/177

The initiation of carcinoma progression is attributed to significant disorders in the synthesis of macromolecules that affect physiological processes in the epithelial cells of oral mucosa. It is known that the integrin family receptors are crucial for regenerative and reparative functions of the normal epithelium. In addition to their well-established physiological role, some types of integrins are the major determinants of malignant transformations. In particular, the results of recent studies in molecular oncology reveal the importance of αv integrins in the pathogenesis of carcinomas, including oral squamous cell carcinoma. This review aims to analyse the significance of αv integrins in the key processes of malignant growth and metastasis of oral squamous cell carcinoma. The prospects of using αv integrins as prognostic molecular markers and targets for developing novel diagnostic and therapeutic methods in the management of oral cancer are discussed.

Инициация злокачественного роста карцином связана со значительными нарушениями синтеза макромолекул, контролирующих процессы жизнедеятельности эпителиальных клеток. Известно, что семейство интегриновых рецепторов играет важную роль в обеспечении регенеративных и репаративных свойств эпителия. Помимо реализации физиологических функций некоторые типы интегринов обладают доказанным онкогенным потенциалом. В частности, результаты недавних исследований в области молекулярной онкологии показывают значимость интегриновых рецепторов типа αv в патогенезе карцином, в том числе рака полости рта. В настоящем обзоре проанализированы механизмы участия интегринов αv в ключевых процессах злокачественного роста и метастазирования плоскоклеточного рака полости рта. Продемонстрирована перспективность использования интегринов αv в качестве прогностических молекулярных маркеров и мишеней для разработки новых методов диагностики и лечения злокачественных новообразований челюстно-лицевой области.

oral squamous cell carcinomaintegrin αvmetastasiscancer invasioncancer migrationanoikisплоскоклеточный рак полости ртаинтегрины αvметастазированиеопухолевая инвазияопухолевая миграцияаноикисNguyen D.X., Bos P.D., Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9(4):274-84. DOI: 10.1038/nrc2622. PMID: 19308067.Xing Y., Zhang J., Lin H. et al. Relation between the level of lymph node metastasis and survival in locally advanced head and neck squamous cell carcinoma. Cancer 2016;122(4):534—45. DOI: 10.1002/cncr.29780. PMID: 26554754.Desgrosellier J.S., Cheresh D.A. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer 2010;10(1):9—22. DOI: 10.1038/nrc2748. PMID: 20029421.Harburger D.S., Calderwood D.A. Integ-rin signalling at a glance. J Cell Sci 2009;122(Pt 2):159—63. DOI: 10.1242/jcs.018093. PMID: 19118207.Shinohara M., Nakamura S., Sasaki M. et al. Expression of integrins in squamous cell carcinoma of the oral cavity. Correlations with tumor invasion and metastasis. Am J Clin Pathol 1999;111(1):75—88. PMID: 9894457.Wang D., Muller S., Amin A.R. et al. The pivotal role of integrin p1 in metastasis of head and neck squamous cell carcinoma. Clin Cancer Res 2012;18(17):4589—99. DOI: 10.1158/1078-0432.CCR-11-3127. PMID: 22829201.Amaral Pereira A.L., Lopes F.F., da Cruz M.C. et al. Role of integrins in the carcinogenesis of squamous cell carcinoma of the tongue and lower lip. Appl Immu-nohistochem Mol Morphol 2013;21(2):154—8. DOI: 10.1097/PAI.0b013e31825905e5. PMID: 22595951.Jones J., Watt F.M., Speight P.M. Changes in the expression of alpha v integrins in oral squamous cell carcinomas. J Oral Pathol Med 1997;26(2):63—8. PMID: 9049904.Wang W., Otsetov A.G., Wang E. et al. Integrin p6 — a potential marker for the early malignant transformation in prostate cancer. J Urol Nephrol Open Access 2016;2(1):1—7. DOI: 10.15226/2473-6430/2/1/00113.Xuan S.H., Zhou Y.G., Pan J.Q. et al. Overexpression of integrin av in the human nasopharyngeal carcinoma associated with metastasis and progression. Cancer Biomark 2013;13(5):323—8. DOI: 10.3233/CBM-130361. PMID: 24440971.Wu YJ., Pagel M.A., Muldoon L.L. et al. High av integrin level of cancer cells is associated with development of brain metastasis in athymic rats. Anticancer Res 2017;37(8):4029-40. DOI: 10.21873/anti-canres.11788. PMID: 28739685.Humphries J.D., Byron A., Humphries M.J. Integrin ligands at a glance. J Cell Sci 2006;119(19):3901—3. DOI: 10.1242/jcs.03098. PMID: 16988024.Thomas G.J., Poomsawat S., Lewis M.P. et al. avp6 Integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytes. J Invest Dermatol 2001;116(6):898—904. DOI: 10.1046/j.1523-1747.2001.01352.x. PMID: 11407978.Thomas G.J., Nystrom M.L., Marshall J.F. avp6 integrin in wound healing and cancer of the oral cavity. J Oral Pathol Med 2006;35(1):1 —10. DOI: 10.1111/j.1600-0714.2005.00374.x. PMID: 16393247.Dvorak H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 1986;315(26):1650—9. DOI: 10.1056/NEJM198612253152606. PMID: 3537791.Duperret E.K., Dahal A., Ridky T.W. Focal-adhesion-independent integrin-av regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion. J Cell Sci 2015;128(21):3997—4013. DOI: 10.1242/jcs.175539. PMID: 26359297.Savar A., Acin S., Gonzalez C.L. et al. Loss of epithelial p53 and av integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment. Oncogene 2015;34(4):516—24. DOI: 10.1038/onc.2013.585. PMID: 24469034.Jones J., Sugiyama M., Speight P.M. et al. Restoration of avp5 integrin expression in neoplastic keratinocytes results in increased capacity for terminal differentiation and suppression of anchorage-independent growth. Oncogene 1996;12(1):119—26. PMID: 8552382.Breuss J.M., Gallo J., DeLisser H.M. et al. Expression of the p6 integrin subunit in development, neoplasia and tissue repair suggests a role in epithelial remodeling. J Cell Sci 1995;108 (Pt 6):2241-51. PMID: 7673344.Jones J., Sugiyama M., Watt F.M. et al. Integrin expression in normal, hyperplastic, dysplastic, and malignant oral epithelium. J Pathol 1993;169(2):235—43. DOI: 10.1002/path.1711690210. PMID: 8445489.Nystrom M.L., McCulloch D., Weinreb P.H. et al. Cyclooxygenase-2 inhibition suppresses avp6 integrin-dependent oral squamous carcinoma invasion. Cancer Res 2006;66(22):10833—42. DOI: 10.1158/0008-5472.CAN-06-1640. PMID: 17108119.Hamidi S., Salo T., Kainulainen T. et al. Expression of avp6 integrin in oral leukoplakia. Br J Cancer 2000;82(8):1433-40. DOI: 10.1054/bjoc.1999.1130. PMID: 10780523.Xue H., Atakilit A., Zhu W. et al. Role of the avp6 integrin in human oral squamous cell carcinoma growth in vivo and in vitro. Biochem Biophys Res Commun 2001;288(3):610—8. DOI: 10.1006/bbrc.2001.5813. PMID: 11676487.Hayashido Y., Kitano H., Sakaue T. et al. Overexpression of integrin av facilitates proliferation and invasion of oral squamous cell carcinoma cells via MEK/ERK signaling pathway that is activated by interaction of integrin avp8 with type I collagen. Int J Oncol 2014;45(5):1875—82. DOI: 10.3892/ijo.2014.2642. PMID: 25190218.Janes S.M., Watt F.M. New roles of integrins in squamous-cell carcinoma. Nat Rev Cancer 2006;6(3):175-83. DOI: 10.1038/nrc1817. PMID: 16498442.Koivisto L., Grenman R., Heino J. et al. Integrins a5p1, avp1, and avp6 collaborate in squamous carcinoma cell spreading and migration on fibronectin. Exp Cell Res 2000;255(1):10—7. DOI: 10.1006/excr.1999.4769. PMID: 10666329.Ramos Gde O., Bernardi L., Lauxen I. et al. Fibronectin modulates cell adhesion and signaling to promote single cell migration of highly invasive oral squamous cell carcinoma. PLoS One 2016;11(3):e0151338. DOI: 10.1371/jour-nal.pone.0151338. PMID: 26978651.Thomas G.J., Lewis M.P., Whawell S.A. et al. Expression of the avp6 integrin promotes migration and invasion in squamous carcinoma cells. J Invest Dermatol 2001;117(1):67—73. DOI: 10.1046/j.0022-202x.2001.01379.x. PMID: 11442751.Gopal S., Veracini L., Grall D. et al. Fi-bronectin-guided migration of carcinoma collectives. Nat Commun 2017;8:14105. DOI: 10.1038/ncomms14105. PMID: 28102238.Thomas G.J., Lewis M.P., Hart I.R. et al. avp6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9. Int J Cancer 2001;92(5):641—50. PMID: 11340566.Ramos D.M., But M., Regezi J. et al. Expression of integrin p6 enhances invasive behavior in oral squamous cell carcinoma. Matrix Biol 2002;21(3):297—307. PMID: 12009335.Li H.X., Zheng J.H., Fan H.X. et al. ExE pression of avp6 integrin and collagen fibre in oral squamous cell carcinoma: association with clinical outcomes and prognostic implications. J Oral Pathol Med 2013;42(7):547—56. DOI: 10.1111/jop.12044. PMID: 23331428.Li H.X., Zheng J.H., Fan H.X. et al. ExE pression of avp6 integrin and collagen fibre in oral squamous cell carcinoma: association with clinical outcomes and prognostic implications. J Oral Pathol Med 2013;42(7):547—56. DOI: 10.1111/jop.12044. PMID: 23331428.Ylipalosaari M., Thomas G.J., Nystrom M. et al. avp6 integrin down-regulates the MMP-13 expression in oral squamous cell carcinoma cells. Exp Cell Res 2005;309(2):273—83. DOI: 10.1016/j.yex-cr.2005.06.008. PMID: 16024014.Swan E.A., Jasser S.A., Holsinger F.C. et al. Acquisition of anoikis resistance is a critical step in the progression of oral tongue cancer. Oral Oncol 2003;39(7):648—55. PMID: 12907203Guadamillas M.C., Cerezo A., Del Pozo MA. Overcoming anoikis-pathways to anchorage-independent growth in cancer. J Cell Sci 2011;124(Pt 19):3189—97. DOI: 10.1242/jcs.072165. PMID: 21940791.Zhang Y., Lu H., Dazin P. et al. Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin av mediate survival signals through focal adhesion kinase. J Biol Chem 2004;279(46):48342—9. DOI: 10.1074/jbc.M407953200. PMID: 15331608.Kamarajan P., Kapila Y.L. An altered fi-bronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK. Apoptosis 2007;12(12):2221—31. DOI: 10.1007/s10495-007-0138-9. PMID: 17879163.Janes S.M., Watt F.M. Switch from avp5 to avp6 integrin expression protects squamous cell carcinomas from anoikis. J Cell Biol 2004;166(3):419—31. DOI: 10.1083/jcb.200312074. PMID: 15289499.Seguin L., Desgrosellier J.S., Weis S.M. et al. Integrins and cancer: regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol 2015;25(4): 234-40. DOI: 10.1016/j.tcb.2014.12.006. PMID: 25572304.Nakamura T., Shinriki S., Jono H. et al. Osteopontin-integrin avp3 axis is crucial for 5-fluorouracil resistance in oral squamous cell carcinoma. FEBS Lett 2015;589(2):231 —9. DOI: 10.1016/j.febs-let.2014.12.004. PMID: 25497015.Stojanovic N., Brozovic A., Majhen D. et al. Integrin avp3 expression in tongue squamous carcinoma cells Cal27 confers anticancer drug resistance through loss of pSrc(Y418). Biochim Biophys Acta 2016;1863(8):1969—78. DOI: 10.1016/j.bbamcr.2016.04.019. PMID: 27108184.Hehlgans S., Eke I., Cordes N. Targeting FAK radiosensitizes 3-dimensional grown human HNSCC cells through reduced Akt1 and MEK1/2 signaling. Int J Radiat Oncol Biol Phys 2012;83(5):e669—76. DOI: 10.1016/j.ijrobp.2012.01.065. PMID: 22483702.Sansing H.A., Sarkeshik A., Yates J.R. et al. Integrin ap1, avp, a6p effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. Biochem Biophys Res Commun 2011;406(2):171—6. DOI: 10.1016/j.bbrc.2011.01.109. PMID: 21291860.Damiano J.S. Integrins as novel drug targets for overcoming innate drug resistance. Curr Cancer Drug Targets 2002;2(1): 37—43. PMID: 12188919.Nemeth J.A., Nakada M.T., Trikha M. et al. Alpha-v integrins as therapeutic targets in oncology. Cancer Invest 2007;25(7):632—46.Li Y., Drabsch Y., Pujuguet P. et al. Genetic depletion and pharmacological targeting of av integrin in breast cancer cells impairs metastasis in zebrafish and mouse xenograft models. Breast Cancer Res 2015;17:28. DOI: 10.1186/s13058-015-0537-8. PMID: 25849225.van der Horst G., van den Hoogen C., Buijs J.T. et al. Targeting of av-integrins in stem/progenitor cells and supportive microenvironment impairs bone metastasis in human prostate cancer. Neoplasia 2011;13(6):516—25. DOI: 10.1593/neo.11122. PMID: 21677875van der Horst G., Bos L., van der Mark M. et al. Targeting of alpha-v integrins reduces malignancy of bladder carcinoma. PLoS One 2014;9(9):e108464. DOI: 10.1371/journal.pone.0108464. PMID: 25247809.Keereweer S., Mol I.M., Kerrebijn J.D. et al. Targeting integrins and enhanced permeability and retention (EPR) effect for optical imaging of oral cancer. J Surg Oncol 2012 Jun;105(7):714—8. DOI: 10.1002/jso.22102. PMID: 21952950.Bunschoten A., Buckle T., Visser N.L. et al. Multimodal interventional molecular imaging of tumor margins and distant me-tastases by targeting avp3 integrin. Chem-biochem 2012;13(7):1039—45. DOI: 10.1002/cbic.201200034. PMID: 22505018.Huang H., Bai Y.L., Yang K. et al. Optical imaging of head and neck squamous cell carcinoma in vivo using arginine-glycine-aspartic acid peptide conjugated near-infrared quantum dots. Onco Targets Ther 2013;6:1779—87. DOI: 10.2147/OTT.S53901. PMID: 24324343.Li H., Huang D., Gao Z. et al. Scutellarin inhibits the growth and invasion of human tongue squamous carcinoma through the inhibition of matrix metalloproteinase-2 and -9 and avp6 integrin. Int J Oncol 2013;42(5):1674—81. DOI: 10.3892/ijo.2013.1873. PMID: 23546449.Hatley R.J.D., Macdonald S.J.F., Slack R.J. et al. An av-RGD integrin inhibitor toolbox: drug discovery insight, challenges and opportunities. Angew Chem Int Ed Engl 2018;57(13):3298—321. DOI: 10.1002/anie.201707948. PMID: 28944552.Nothelfer E.M., Zitzmann-Kolbe S., Gar-cia-Boy R. et al. Identification and characterization of a peptide with affinity to head and neck cancer. J Nucl Med 2009;50(3):426—34. DOI: 10.2967/jnumed.108.058123. PMID: 19223422.Hsiao J.R., Chang Y., Chen Y.L. et al. Cyclic avp6-targeting peptide selected from biopanning with clinical potential for head and neck squamous cell carcinoma. Head Neck 2010;32(2):160—72. DOI: 10.1002/hed.21166. PMID: 19572290.Samsonov R.B., Radzhabova Z.A., Cheburkin Yu.V et al. Epigenetic regulation of gene expression in head and neck squamous cell carcinoma: therapeutic perspectives. Opukholi go-lovy i shei = Head and Neck Tumors 2016;6(4):35—44 (In Russ.).Самсонов Р.Б., Раджабова З.А., Чебур-кин Ю.В. и др. Эпигенетические механизм^! регуляции генной экспрессии в развитии плоскоклеточного рака головы и шеи: терапевтические перспективы. Опухоли головы и шеи 2016;6(4):35—44. DOI: 10.17650/2222-1468-2016-6-4-35-44.Cai Q.Q., Dong Y.W., Wang R. et al. MiR-124 inhibits the migration and invasion of human hepatocellular carcinoma cells by suppressing integrin aV expression. Sci Rep 2017;7:40733. DOI: 10.1038/srep40733. PMID: 28094803.Yu S., Li L., Tian W. et al. PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial mesenchymal transition. Br J Pharmacol 2018;175(11):3111—30. DOI: 10.1111/bph.14352. PMID: 29722931.Beer A.J., Grosu A.L., Carlsen J. et al. [18F]galacto-RGD positron emission tomography for imaging of avp3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 2007;13(22 Pt 1): 6610—6. DOI: 10.1158/1078-0432.CCR-07-0528. PMID: 18006761.