{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T05:37:23Z","timestamp":1789018643161,"version":"build-2803163510"},"reference-count":52,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T00:00:00Z","timestamp":1667779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 CA080192"],"award-info":[{"award-number":["R01 CA080192"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HLA078836"],"award-info":[{"award-number":["R01 HLA078836"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50 CA83636"],"award-info":[{"award-number":["P50 CA83636"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Pacific Ovarian Cancer Research Consortium\/Specialized Program of Research Excellence in Ovarian Cancer","doi-asserted-by":"publisher","award":["R01 CA080192"],"award-info":[{"award-number":["R01 CA080192"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Pacific Ovarian Cancer Research Consortium\/Specialized Program of Research Excellence in Ovarian Cancer","doi-asserted-by":"publisher","award":["R01 HLA078836"],"award-info":[{"award-number":["R01 HLA078836"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"Pacific Ovarian Cancer Research Consortium\/Specialized Program of Research Excellence in Ovarian Cancer","doi-asserted-by":"publisher","award":["P50 CA83636"],"award-info":[{"award-number":["P50 CA83636"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Desmoglein 2 (DSG2) is overexpressed in many epithelial cancers and therefore represents a target receptor for oncolytic viruses, including Ad5\/3-based viruses. For most Ad serotypes, the receptor-binding fiber is composed of tail, shaft, and knob domains. Here, we investigated the role of the fiber shaft in Ad5\/3 tumor transduction in vitro and in human DSG2-transgenic mice carrying human DSG2high tumors. DSG2tg mice express DSG2 in a pattern similar to humans. We constructed Ad5\/3L (with the \u201clong\u201d Ad5 shaft) and Ad5\/3S (with the \u201cshort\u201d Ad3 shaft) expressing GFP or luciferase. In in vitro studies we found that coagulation factor X, which is known to mediate undesired hepatocyte transduction of Ad5, enhances the transduction of Ad5\/3(L), but not the transduction of Ad5\/3(S). We therefore hypothesized that Ad5\/3(S) would target DSG2high tumors while sparing the liver after intravenous injection. In vivo imaging studies for luciferase and analysis of luciferase activity in isolated organs, showed that Ad5\/3(L) vectors efficiently transduced DSG2high tumors and liver but not normal epithelial tissues after intravenous injection. Ad5\/3(S) showed minimal liver transduction, however it failed to transduce DSG2high tumors. Further modifications of the Ad5\/3(S) capsid are required to compensate for the lower infectivity of Ad5\/3(S) vectors.<\/jats:p>","DOI":"10.3390\/genes13112056","type":"journal-article","created":{"date-parts":[[2022,11,8]],"date-time":"2022-11-08T07:00:42Z","timestamp":1667890842000},"page":"2056","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of Fiber Shaft Length in Tumor Targeting with Ad5\/3 Vectors"],"prefix":"10.3390","volume":"13","author":[{"given":"Maximilian","family":"Richter","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongjie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Lieber","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"ref_1","unstructured":"(2022, April 11). Journal of Gene Medicine Website. Available online: www.wiley.co.uk\/genmed\/clinical\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"veab018","DOI":"10.1093\/ve\/veab018","article-title":"Emergence and characterization of a putative novel human adenovirus recombinant HAdV-C104 causing pneumonia in Southern China","volume":"7","author":"Ji","year":"2021","journal-title":"Virus Evol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/nm.2270","article-title":"Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14","volume":"17","author":"Wang","year":"2011","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1006\/excr.1994.1103","article-title":"Identification of the ubiquitous human desmoglein, Dsg2, and the expression catalogue of the desmoglein subfamily of desmosomal cadherins","volume":"211","author":"Schafer","year":"1994","journal-title":"Exp. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"148","DOI":"10.4161\/cam.3.2.7539","article-title":"Increased expression of Dsg2 in malignant skin carcinomas: A tissue-microarray based study","volume":"3","author":"Brennan","year":"2009","journal-title":"Cell Adh. Migr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"417","DOI":"10.2340\/0001555576417420","article-title":"Abnormal desmoglein expression by squamous cell carcinoma cells","volume":"76","author":"Harada","year":"1996","journal-title":"Acta Derm. Venereol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s00432-016-2250-0","article-title":"Desmoglein-2 is overexpressed in non-small cell lung cancer tissues and its knockdown suppresses NSCLC growth by regulation of p27 and CDK2","volume":"143","author":"Cai","year":"2017","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e8420","DOI":"10.7717\/peerj.8420","article-title":"Upregulation of desmoglein 2 and its clinical value in lung adenocarcinoma: A comprehensive analysis by multiple bioinformatics methods","volume":"8","author":"Sun","year":"2020","journal-title":"PeerJ."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.canlet.2020.04.001","article-title":"Desmoglein-2 Modulates Tumor Progression and Osimertinib Drug Resistance through the EGFR\/Src\/PAK1 Pathway in Lung Adenocarcinoma","volume":"483","author":"Jin","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_10","first-page":"5481","article-title":"Desmoglein-2 overexpression predicts poor prognosis in hepatocellular carcinoma patients","volume":"22","author":"Han","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1080\/15384047.2020.1843323","article-title":"Desmoglein-2 as a prognostic and biomarker in ovarian cancer","volume":"21","author":"Kim","year":"2020","journal-title":"Cancer Biol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.1821","article-title":"Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer","volume":"207","author":"Biedermann","year":"2005","journal-title":"J. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1158\/0008-5472.CAN-05-3077","article-title":"The penetration of anticancer drugs through tumor tissue as a function of cellular adhesion and packing density of tumor cells","volume":"66","author":"Grantab","year":"2006","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5115","DOI":"10.1158\/0008-5472.CAN-09-0645","article-title":"Epithelial phenotype of ovarian cancer mediates resistance to oncolytic adenoviruses","volume":"15","author":"Strauss","year":"2009","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1038\/gt.2010.17","article-title":"Prolonged systemic circulation of chimeric oncolytic adenovirus Ad5\/3-Cox2L-D24 in patients with metastatic and refractory solid tumors","volume":"17","author":"Pesonen","year":"2010","journal-title":"Gene Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1038\/mt.2010.161","article-title":"Treatment of cancer patients with a serotype 5\/3 chimeric oncolytic adenovirus expressing GMCSF","volume":"18","author":"Koski","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1158\/1078-0432.CCR-11-2852","article-title":"A phase I clinical trial of Ad5.SSTR\/TK.RGD, a novel infectivity-enhanced bicistronic adenovirus, in patients with recurrent gynecologic cancer","volume":"18","author":"Kim","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Heinio, C., Clubb, J., Kudling, T., Quixabeira, D., Cervera-Carrascon, V., Havunen, R., Gronberg-Vaha-Koskela, S., Santos, J.M., Tapper, J., and Kanerva, A. (2022). Effective Combination Immunotherapy with Oncolytic Adenovirus and Anti-PD-1 for Treatment of Human and Murine Ovarian Cancers. Diseases, 10.","DOI":"10.3390\/diseases10030052"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1038\/mt.2012.115","article-title":"Ad3-hTERT-E1A, a fully serotype 3 oncolytic adenovirus, in patients with chemotherapy refractory cancer","volume":"20","author":"Hemminki","year":"2012","journal-title":"Mol. Ther."},{"key":"ref_20","first-page":"163","article-title":"Adenovirus fiber","volume":"199","author":"Chroboczek","year":"1995","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1002\/1873-3468.13700","article-title":"Lessons learned from adenovirus (1970\u20132019)","volume":"593","author":"Nemerow","year":"2019","journal-title":"FEBS Lett."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.tim.2004.02.005","article-title":"Virus yoga: The role of flexibility in virus host cell recognition","volume":"12","author":"Wu","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7225","DOI":"10.1128\/JVI.77.13.7225-7235.2003","article-title":"Flexibility of the adenovirus fiber is required for efficient receptor interaction","volume":"77","author":"Wu","year":"2003","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00430-019-00645-2","article-title":"Human adenovirus binding to host cell receptors: A structural view","volume":"209","author":"Stasiak","year":"2020","journal-title":"Med. Microbiol. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1038\/s41467-019-09220-y","article-title":"CryoEM structure of adenovirus type 3 fibre with desmoglein 2 shows an unusual mode of receptor engagement","volume":"10","author":"Effantin","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10274","DOI":"10.1128\/JVI.74.22.10274-10286.2000","article-title":"Dependence of adenovirus infectivity on length of the fiber shaft domain","volume":"74","author":"Shayakhmetov","year":"2000","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1089\/hum.2005.16.664","article-title":"Evaluation of biodistribution and safety of adenovirus vectors containing group B fibers after intravenous injection into baboons","volume":"16","author":"Ni","year":"2005","journal-title":"Hum. Gene Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1089\/104303403765255165","article-title":"Adenovirus serotype 5 fiber shaft influences in vivo gene transfer in mice","volume":"14","author":"Smith","year":"2003","journal-title":"Hum. Gene Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12249","DOI":"10.1128\/JVI.01584-07","article-title":"Fiber shaft-chimeric adenovirus vectors lacking the KKTK motif efficiently infect liver cells in vivo","volume":"81","author":"Kalyuzhniy","year":"2007","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1038\/mt.2009.152","article-title":"Influence of coagulation factor x on in vitro and in vivo gene delivery by adenovirus (Ad) 5, Ad35, and chimeric Ad5\/Ad35 vectors","volume":"17","author":"Greig","year":"2009","journal-title":"Mol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"7478","DOI":"10.1128\/JVI.79.12.7478-7491.2005","article-title":"Adenovirus binding to blood factors results in liver cell infection and hepatotoxicity","volume":"79","author":"Shayakhmetov","year":"2005","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.cell.2008.01.016","article-title":"Adenovirus serotype 5 hexon mediates liver gene transfer","volume":"132","author":"Waddington","year":"2008","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1089\/hum.2020.222","article-title":"Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples","volume":"32","author":"Zafar","year":"2021","journal-title":"Hum. Gene Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1265717","DOI":"10.1080\/2162402X.2016.1265717","article-title":"Intravenously usable fully serotype 3 oncolytic adenovirus coding for CD40L as an enabler of dendritic cell therapy","volume":"6","author":"Zafar","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2567","DOI":"10.1128\/JVI.74.6.2567-2583.2000","article-title":"Efficient gene transfer into human CD34+ cells by a retargeted adenovirus vector","volume":"74","author":"Shayakhmetov","year":"2000","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1128\/JVI.00514-11","article-title":"Multimerization of adenovirus serotype 3 fiber knob domains is required for efficient binding of virus to desmoglein 2 and subsequent opening of epithelial junctions","volume":"85","author":"Wang","year":"2011","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"6286","DOI":"10.1128\/JVI.00205-12","article-title":"A new human DSG2-transgenic mouse model for studying the tropism and pathology of human adenoviruses","volume":"86","author":"Wang","year":"2012","journal-title":"J. Virol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/mtm.2015.5","article-title":"Preclinical safety and efficacy studies with an affinity-enhanced epithelial junction opener and PEGylated liposomal doxorubicin","volume":"2","author":"Richter","year":"2015","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1089\/hum.2016.022","article-title":"Epithelial Junction Opener Improves Oncolytic Adenovirus Therapy in Mouse Tumor Models","volume":"27","author":"Yumul","year":"2016","journal-title":"Hum. Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1038\/sj.cgt.7700981","article-title":"Evaluation of adenovirus vectors containing serotype 35 fibers for tumor targeting","volume":"13","author":"Ni","year":"2006","journal-title":"Cancer Gene Ther."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Tuve, S., Wang, H., Jacobs, J.D., Yumul, R.C., Smith, D.F., and Lieber, A. (2008). Role of cellular heparan sulfate proteoglycans in infection of human adenovirus serotype 3 and 35. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000189"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7080","DOI":"10.1158\/0008-5472.CAN-11-2009","article-title":"Epithelial junction opener JO-1 improves monoclonal antibody therapy of cancer","volume":"71","author":"Beyer","year":"2011","journal-title":"Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Koski, A., Karli, E., Kipar, A., Escutenaire, S., Kanerva, A., and Hemminki, A. (2013). Mutation of the fiber shaft heparan sulphate binding site of a 5\/3 chimeric adenovirus reduces liver tropism. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0060032"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bahlmann, N.A., Tsoukas, R.L., Erkens, S., Wang, H., Jonsson, F., Aydin, M., Naumova, E.A., Lieber, A., Ehrhardt, A., and Zhang, W. (2022). Properties of Adenovirus Vectors with Increased Affinity to DSG2 and the Potential Benefits of Oncolytic Approaches and Gene Therapy. Viruses, 14.","DOI":"10.3390\/v14081835"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S152","DOI":"10.1002\/jgm.553","article-title":"Adenovirus endocytosis","volume":"6","author":"Meier","year":"2004","journal-title":"J. Gene Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lu, Z.Z., Wang, H., Zhang, Y., Cao, H., Li, Z., Fender, P., and Lieber, A. (2013). Penton-dodecahedral particles trigger opening of intercellular junctions and facilitate viral spread during adenovirus serotype 3 infection of epithelial cells. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003718"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"S74","DOI":"10.1016\/S1525-0016(16)37634-1","article-title":"Preclinical and clinical data with a fully serotype 3 oncolytic adenovirus Ad3-hTERT-E1A in the treatment of advanced solid tumors","volume":"18","author":"Hemminki","year":"2010","journal-title":"Mol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"10567","DOI":"10.1128\/JVI.01308-08","article-title":"In vitro and in vivo properties of adenovirus vectors with increased affinity to CD46","volume":"82","author":"Wang","year":"2008","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1182\/blood-2016-04-711580","article-title":"In vivo transduction of primitive mobilized hematopoietic stem cells after intravenous injection of integrating adenovirus vectors","volume":"128","author":"Richter","year":"2016","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.omtm.2021.12.003","article-title":"Safe and efficient in vivo hematopoietic stem cell transduction in nonhuman primates using HDAd5\/35++ vectors","volume":"24","author":"Li","year":"2022","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11346","DOI":"10.1128\/JVI.01825-13","article-title":"Structural and functional studies on the interaction of adenovirus fiber knobs and desmoglein 2","volume":"87","author":"Wang","year":"2013","journal-title":"J. Virol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4360","DOI":"10.1182\/bloodadvances.2022007975","article-title":"In vivo HSC transduction in rhesus macaques with an HDAd5\/3+ vector targeting desmoglein 2 and transiently overexpressing cxcr4","volume":"6","author":"Wang","year":"2022","journal-title":"Blood Adv."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2056\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:11:45Z","timestamp":1760145105000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/11\/2056"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,7]]},"references-count":52,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11]]}},"alternative-id":["genes13112056"],"URL":"https:\/\/doi.org\/10.3390\/genes13112056","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,7]]}}}