{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T03:42:23Z","timestamp":1769053343098,"version":"3.49.0"},"reference-count":53,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP17lm0203039"],"award-info":[{"award-number":["JP17lm0203039"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["15H04310"],"award-info":[{"award-number":["15H04310"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Engineered vaccinia virus serves as an oncolytic virus for cancer virotherapy. We evaluated the oncolytic characteristics of VGF- and O1-deleted recombinant mitogen-activated protein kinase (MAPK)-dependent vaccinia virus (MDRVV). We found that compared with viruses with the deletion of either gene alone, MDRVV is more attenuated in normal cells and can replicate in cancer cells that exhibit constitutive ERK1\/2 activation in the MAPK pathway. We armed MDRVV with a bifunctional fusion gene encoding cytosine deaminase and uracil phosphoribosyltransferase (CD\/UPRT), which converts 5-fluorocytosine (5-FC) into chemotherapeutic agents, and evaluated its oncolytic activity alone or in combination with 5-FC in human pancreatic cancer cell lines, tumor mouse models of peritoneal dissemination and liver metastasis, and ex vivo-infected live pancreatic cancer patient-derived tissues. CD\/UPRT-armed MDRVV alone could efficiently eliminate pancreatic cancers, and its antitumor effects were partially enhanced in combination with 5-FC in vitro and in vivo. Moreover, the replication of MDRVV was detected in tumor cells of patient-derived, surgically resected tissues, which showed enlarged nuclei and high expression of pERK1\/2 and Ki-67, and not in stromal cells. Our findings suggest that systemic injections of CD\/UPRT-armed MDRVV alone or in combination with 5-FC are promising therapeutic strategies for pancreatic ductal adenocarcinoma.<\/jats:p>","DOI":"10.3390\/cells10050985","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T12:08:30Z","timestamp":1619179710000},"page":"985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Anti-Tumor Effects of MAPK-Dependent Tumor-Selective Oncolytic Vaccinia Virus Armed with CD\/UPRT against Pancreatic Ductal Adenocarcinoma in Mice"],"prefix":"10.3390","volume":"10","author":[{"given":"Hajime","family":"Kurosaki","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motomu","family":"Nakatake","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teruhisa","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nozomi","family":"Kuwano","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Yamane","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenta","family":"Ishii","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshiyuki","family":"Fujiwara","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Nakamura","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Department of Genomic Medicine and Regenerative Therapy, Faculty of Medicine, Tottori University, Yonago 683-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s12275-015-5041-4","article-title":"Replicating Poxviruses for Human Cancer Therapy","volume":"53","author":"Kim","year":"2015","journal-title":"J. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s40425-018-0495-7","article-title":"Vaccinia Virus-mediated Cancer Immunotherapy: Cancer Vaccines and Oncolytics","volume":"7","author":"Guo","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/j.ymthe.2006.05.008","article-title":"Systemic Armed Oncolytic and Immunologic Therapy for Cancer With JX-594, a Targeted Poxvirus Expressing GM-CSF","volume":"14","author":"Kim","year":"2006","journal-title":"Mol. Ther."},{"key":"ref_4","first-page":"8751","article-title":"Systemic Cancer Therapy with a Tumor-Selective Vaccinia Virus Mutant Lacking Thymidine Kinase and Vaccinia Growth Factor Genes","volume":"61","author":"McCart","year":"2001","journal-title":"Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5300","DOI":"10.1073\/pnas.82.16.5300","article-title":"Vaccinia Virus-infected Cells Release a Novel Polypeptide Functionally Related to Transforming and Epidermal Growth Factors","volume":"82","author":"Twardzik","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/313491a0","article-title":"Vaccinia Virus Encodes a Polypeptide Homologous to Epidermal Growth Factor and Transforming Growth Factor","volume":"313","author":"Brown","year":"1985","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1128\/jvi.62.3.866-874.1988","article-title":"Deletion of the Vaccinia Virus Growth Factor Gene Reduces Virus Virulence","volume":"62","author":"Buller","year":"1988","journal-title":"J. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1042\/BJ20031375","article-title":"The Vaccinia Virus-stimulated Mitogen-activated Protein Kinase (MAPK) Pathway is Required for Virus Multiplication","volume":"381","author":"Andrade","year":"2004","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/0042-6822(88)90635-6","article-title":"Cell Proliferative Response to Vaccinia Virus is Mediated by VGF","volume":"164","author":"Buller","year":"1988","journal-title":"Virology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.1093\/emboj\/17.20.5948","article-title":"Pathogenic Poxviruses Reveal Viral Strategies to Exploit the ErbB Signaling Network","volume":"17","author":"Tzahar","year":"1998","journal-title":"EMBO J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1128\/JVI.06166-11","article-title":"The Vaccinia Virus O1 Protein is Required for Sustained Activation of Extracellular Signal-regulated Kinase 1\/2 and Promotes Viral Virulence","volume":"86","author":"Schweneker","year":"2012","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer Statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1126\/science.1164368","article-title":"Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses","volume":"321","author":"Jones","year":"2008","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/nrc.2016.66","article-title":"Pancreatic Cancer Biology and Genetics from an Evolutionary Perspective","volume":"16","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e173420","DOI":"10.1001\/jamaoncol.2017.3420","article-title":"Association of Alterations in Main Driver Genes with Outcomes of Patients with Resected Pancreatic Ductal Adenocarcinoma","volume":"4","author":"Qian","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nrd4389","article-title":"Drugging the Undruggable RAS: Mission Possible?","volume":"13","author":"Cox","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1053\/j.gastro.2015.08.056","article-title":"Genetic Diversity of Pancreatic Ductal Adenocarcinoma and Opportunities for Precision Medicine","volume":"150","author":"Knudsen","year":"2016","journal-title":"Gastroenterology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1038\/s41568-018-0076-6","article-title":"A Model for RAS Mutation Patterns in Cancers: Finding the Sweet Spot","volume":"18","author":"Li","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.ccr.2012.07.024","article-title":"EGF Receptor is Required for KRAS-induced Pancreatic Tumorigenesis","volume":"22","author":"Ardito","year":"2012","journal-title":"Cancer Cell."},{"key":"ref_20","first-page":"524","article-title":"Pancreatic Cancer: EGFR Inhibition is Effective against KRAS-wild-type Disease","volume":"14","author":"Sidaway","year":"2017","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1889","DOI":"10.1016\/j.celrep.2018.01.051","article-title":"Differential Effector Engagement by Oncogenic KRAS","volume":"22","author":"Yuan","year":"2018","journal-title":"Cell Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1007\/s00280-017-3375-9","article-title":"A Phase II Trial of Erlotinib Monotherapy in Advanced Pancreatic Cancer as a First- Or Second-line Agent","volume":"80","author":"Fountzilas","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1007\/s10637-011-9687-4","article-title":"A Phase II Open-label Randomized Study to Assess the Efficacy and Safety of Selumetinib (AZD6244 [ARRY-142886]) Versus Capecitabine in Patients with Advanced or Metastatic Pancreatic Cancer Who Have Failed First-line Gemcitabine Therapy","volume":"30","author":"Bodoky","year":"2012","journal-title":"Investig. New Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"a031492","DOI":"10.1101\/cshperspect.a031492","article-title":"Targeting the MAPK Pathway in RAS Mutant Cancers","volume":"8","author":"Hymowitz","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"114371","DOI":"10.18632\/oncotarget.22825","article-title":"Genomic Alterations of ERBB Receptors in Cancer: Clinical Implications","volume":"8","author":"Mishra","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wee, P., and Wang, Z. (2017). Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers, 9.","DOI":"10.3390\/cancers9050052"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1007\/s10529-008-9787-1","article-title":"Implication of Functional Activity for Determining Therapeutic Efficacy of Suicide Genes In Vitro","volume":"30","author":"Gopinath","year":"2008","journal-title":"Biotechnol. Lett."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/sj.cgt.7701110","article-title":"Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene","volume":"15","author":"Chalikonda","year":"2008","journal-title":"Cancer Gene Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1001\/jamaoncol.2020.3161","article-title":"Effect of Vocimagene Amiretrorepvec in Combination with Flucytosine vs Standard of Care on Survival Following Tumor Resection in Patients with Recurrent High-Grade Glioma: A Randomized Clinical Trial","volume":"6","author":"Cloughesy","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1038\/cgt.2011.75","article-title":"Chemovirotherapy for head and neck squamous cell carcinoma with EGFR-targeted and CD\/UPRT-armed oncolytic measles virus","volume":"19","author":"Zaoui","year":"2012","journal-title":"Cancer Gene Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.omto.2019.03.005","article-title":"The Enhanced Tumor Specificity of TG6002, an Armed Oncolytic Vaccinia Virus Deleted in Two Genes Involved in Nucleotide Metabolism","volume":"14","author":"Foloppe","year":"2019","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Franck, C., M\u00fcller, C., Rosania, R., Croner, R.S., Pech, M., and Venerito, M. (2020). Advanced Pancreatic Ductal Adenocarcinoma: Moving Forward. Cancers, 12.","DOI":"10.3390\/cancers12071955"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.yexmp.2014.12.001","article-title":"Pancreatic Cancer Cells Express CD44 Variant 9 and Multidrug Resistance Protein 1 During Mitosis","volume":"98","author":"Kiuchi","year":"2015","journal-title":"Exp. Mol. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6170","DOI":"10.1158\/1078-0432.CCR-06-0992","article-title":"The use of a tropism-modified measles virus in folate receptor-targeted virotherapy of ovarian cancer","volume":"12","author":"Hasegawa","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/mt.2011.36","article-title":"MicroRNA Regulation of Glycoprotein B5R in Oncolytic Vaccinia Virus Reduces Viral Pathogenicity without Impairing Its Antitumor Efficacy","volume":"19","author":"Hikichi","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_36","unstructured":"Nakamura, T. (2021, January 27). National Center for Biotechnology Information. \u201cPubChem Patent Summary for US-9809803-B2\u201d. Available online: https:\/\/pubchem.ncbi.nlm.nih.gov\/patent\/US-9809803-B2."},{"key":"ref_37","unstructured":"Nakamura, T., Nakatake, M., Kurosaki, H., and Horita, K. (2019). Method for Producing Vaccinia Virus Expressing Foreign Gene. (16\/317,198), U.S. Patent."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.omto.2019.03.003","article-title":"lncRNA UCA1-Mediated Cdc42 Signaling Promotes Oncolytic Vaccinia Virus Cell-to-Cell Spread in Ovarian Cancer","volume":"13","author":"Horita","year":"2019","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/S0166-0934(97)00045-1","article-title":"A Synthetic Vaccinia Virus Promoter with Enhanced Early and Late Activity","volume":"66","author":"Hammond","year":"1997","journal-title":"J. Virol. Methods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7009","DOI":"10.1016\/j.vaccine.2006.03.087","article-title":"LC16m8: An Attenuated Smallpox Vaccine","volume":"24","author":"Kenner","year":"2006","journal-title":"Vaccine"},{"key":"ref_41","unstructured":"Hashizume, K., Yoshizawa, H., Morita, M., and Suzuki, K (1985). Properties of Attenuated Mutant of Vaccinia Virus, LC16m8, Derived from Lister Strain, Elsevier Science Publishing Co. Inc."},{"key":"ref_42","unstructured":"(1993). Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of vaccines and immune globulins for persons with altered immunocompetence. MMWR Recomm Rep., 42, 1\u201318."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2777","DOI":"10.1158\/1078-0432.CCR-08-2342","article-title":"Efficacy of Systemically Administered Oncolytic Vaccinia Virotherapy for Malignant Gliomas is Enhanced by Combination Therapy with Rapamycin or Cyclophosphamide","volume":"15","author":"Lun","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/11320","article-title":"Oncolytic Virus Therapy of Multiple Tumors in The Brain Requires Suppression of Innate and Elicited Antiviral Responses","volume":"5","author":"Ikeda","year":"1999","journal-title":"Nat. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1097\/MPA.0b013e3181c15963","article-title":"Phenotype and Genotype of Pancreatic Cancer Cell Lines","volume":"39","author":"Deer","year":"2010","journal-title":"Pancreas"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"69927","DOI":"10.18632\/oncotarget.12068","article-title":"SMAD4 Loss Enables EGF, TGF\u03b21 and S100A8\/A9 Induced Activation of Critical Pathways to Invasion in Human Pancreatic Adenocarcinoma Cells","volume":"7","author":"Moz","year":"2016","journal-title":"Oncotarget"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1007\/s10585-005-2891-x","article-title":"Restoration of Smad4 in BxPC3 Pancreatic Cancer Cells Attenuates Proliferation Without Altering Angiogenesis","volume":"22","author":"Yasutome","year":"2005","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.omto.2019.05.003","article-title":"Partial Deletion of Glycoprotein B5R Enhances Vaccinia Virus Neutralization Escape while Preserving Oncolytic Function","volume":"14","author":"Nakatake","year":"2019","journal-title":"Mol. Ther. Oncolytics"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s40164-020-00192-0","article-title":"CD44 as a Tumor Biomarker and Therapeutic Target","volume":"9","author":"Xu","year":"2020","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6163","DOI":"10.21873\/anticanres.12969","article-title":"Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression","volume":"38","author":"Miyoshi","year":"2018","journal-title":"Anticancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"eaax7992","DOI":"10.1126\/scitranslmed.aax7992","article-title":"Intratumoral Expression of IL-7 and IL-12 using an Oncolytic Virus Increases Systemic Sensitivity to Immune Checkpoint Blockade","volume":"12","author":"Nakao","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Nakatake, M., Kuwano, N., Kaitsurumaru, E., Kurosaki, H., and Nakamura, T. (2020). Fusogenic Oncolytic Vaccinia Virus Enhances Systemic Antitumor Immune Response by Modulating the Tumor Microenvironment. Mol. Ther.","DOI":"10.1016\/j.ymthe.2020.12.024"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.ymthe.2020.02.017","article-title":"Transient Inhibition of PI3Kdelta Enhances the Therapeutic Effect of Intravenous Delivery of Oncolytic Vaccinia Virus","volume":"28","author":"Ferguson","year":"2020","journal-title":"Mol. Ther."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/985\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:39Z","timestamp":1760161899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/985"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":53,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10050985"],"URL":"https:\/\/doi.org\/10.3390\/cells10050985","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]}}}