Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer
When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cance...
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| Veröffentlicht in: | Cancer gene therapy 2016-10, Vol.23 (10), p.355-364 |
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| creator | Wong, C M Nash, L A Del Papa, J Poulin, K L Falls, T Bell, J C Parks, R J |
| description | When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cancer cell death directly, and enhance the release of exosome-like particles containing tumor-associated antigens, which boosts the anti-tumor immune response. In this study, we have examined whether delivery of an early region 1 (E1)-deleted, replication-defective Ad vector encoding the reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein can provide therapeutic efficacy in an immunocompetent mouse tumor model. A high multiplicity of infection of AdFAST is required to induce cell fusion in mouse mammary carcinoma 4T1 cells
in vitro
, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect. |
| doi_str_mv | 10.1038/cgt.2016.41 |
| format | Article |
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in vitro
, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect.</description><identifier>ISSN: 0929-1903</identifier><identifier>EISSN: 1476-5500</identifier><identifier>DOI: 10.1038/cgt.2016.41</identifier><identifier>PMID: 27740615</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>13 ; 13/1 ; 13/106 ; 13/2 ; 13/44 ; 14/63 ; 631/337 ; 631/67/1059/602 ; 64/60 ; 82/29 ; 82/80 ; A549 Cells ; Adenoviridae ; Adenoviridae - genetics ; Animals ; Apoptosis ; Biomedical and Life Sciences ; Biomedicine ; Cancer ; Cell Fusion ; Cell Line, Tumor ; Disease Models, Animal ; Gene Expression ; Gene Therapy ; Genetic aspects ; Genetic Vectors ; Humans ; Male ; Melanoma, Experimental ; Membrane proteins ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred BALB C ; Microscopy, Fluorescence ; Neoplasms - genetics ; Neoplasms - immunology ; Original ; original-article ; Physiological aspects ; Reoviridae ; Viral Fusion Proteins - genetics ; Viral Proteins - metabolism</subject><ispartof>Cancer gene therapy, 2016-10, Vol.23 (10), p.355-364</ispartof><rights>The Author(s) 2016</rights><rights>COPYRIGHT 2016 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2016</rights><rights>Copyright © 2016 The Author(s) 2016 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c577t-e627fc0206b8be218600bf78a5cdb8525a36abaac529889cd21aa0103fd615bf3</citedby><cites>FETCH-LOGICAL-c577t-e627fc0206b8be218600bf78a5cdb8525a36abaac529889cd21aa0103fd615bf3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/cgt.2016.41$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/cgt.2016.41$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,778,782,883,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27740615$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wong, C M</creatorcontrib><creatorcontrib>Nash, L A</creatorcontrib><creatorcontrib>Del Papa, J</creatorcontrib><creatorcontrib>Poulin, K L</creatorcontrib><creatorcontrib>Falls, T</creatorcontrib><creatorcontrib>Bell, J C</creatorcontrib><creatorcontrib>Parks, R J</creatorcontrib><title>Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer</title><title>Cancer gene therapy</title><addtitle>Cancer Gene Ther</addtitle><addtitle>Cancer Gene Ther</addtitle><description>When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cancer cell death directly, and enhance the release of exosome-like particles containing tumor-associated antigens, which boosts the anti-tumor immune response. In this study, we have examined whether delivery of an early region 1 (E1)-deleted, replication-defective Ad vector encoding the reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein can provide therapeutic efficacy in an immunocompetent mouse tumor model. A high multiplicity of infection of AdFAST is required to induce cell fusion in mouse mammary carcinoma 4T1 cells
in vitro
, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/2</subject><subject>13/44</subject><subject>14/63</subject><subject>631/337</subject><subject>631/67/1059/602</subject><subject>64/60</subject><subject>82/29</subject><subject>82/80</subject><subject>A549 Cells</subject><subject>Adenoviridae</subject><subject>Adenoviridae - genetics</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer</subject><subject>Cell Fusion</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Gene Expression</subject><subject>Gene Therapy</subject><subject>Genetic aspects</subject><subject>Genetic Vectors</subject><subject>Humans</subject><subject>Male</subject><subject>Melanoma, Experimental</subject><subject>Membrane proteins</subject><subject>Membrane Proteins - 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genetics</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer</topic><topic>Cell Fusion</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Gene Expression</topic><topic>Gene Therapy</topic><topic>Genetic aspects</topic><topic>Genetic Vectors</topic><topic>Humans</topic><topic>Male</topic><topic>Melanoma, Experimental</topic><topic>Membrane proteins</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Microscopy, Fluorescence</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - immunology</topic><topic>Original</topic><topic>original-article</topic><topic>Physiological aspects</topic><topic>Reoviridae</topic><topic>Viral Fusion Proteins - genetics</topic><topic>Viral Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wong, C M</creatorcontrib><creatorcontrib>Nash, L A</creatorcontrib><creatorcontrib>Del Papa, J</creatorcontrib><creatorcontrib>Poulin, K L</creatorcontrib><creatorcontrib>Falls, T</creatorcontrib><creatorcontrib>Bell, J C</creatorcontrib><creatorcontrib>Parks, R J</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wong, C M</au><au>Nash, L A</au><au>Del Papa, J</au><au>Poulin, K L</au><au>Falls, T</au><au>Bell, J C</au><au>Parks, R J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer</atitle><jtitle>Cancer gene therapy</jtitle><stitle>Cancer Gene Ther</stitle><addtitle>Cancer Gene Ther</addtitle><date>2016-10-01</date><risdate>2016</risdate><volume>23</volume><issue>10</issue><spage>355</spage><epage>364</epage><pages>355-364</pages><issn>0929-1903</issn><eissn>1476-5500</eissn><abstract>When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cancer cell death directly, and enhance the release of exosome-like particles containing tumor-associated antigens, which boosts the anti-tumor immune response. In this study, we have examined whether delivery of an early region 1 (E1)-deleted, replication-defective Ad vector encoding the reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein can provide therapeutic efficacy in an immunocompetent mouse tumor model. A high multiplicity of infection of AdFAST is required to induce cell fusion in mouse mammary carcinoma 4T1 cells
in vitro
, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>27740615</pmid><doi>10.1038/cgt.2016.41</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/1 13/106 13/2 13/44 14/63 631/337 631/67/1059/602 64/60 82/29 82/80 A549 Cells Adenoviridae Adenoviridae - genetics Animals Apoptosis Biomedical and Life Sciences Biomedicine Cancer Cell Fusion Cell Line, Tumor Disease Models, Animal Gene Expression Gene Therapy Genetic aspects Genetic Vectors Humans Male Melanoma, Experimental Membrane proteins Membrane Proteins - metabolism Mice Mice, Inbred BALB C Microscopy, Fluorescence Neoplasms - genetics Neoplasms - immunology Original original-article Physiological aspects Reoviridae Viral Fusion Proteins - genetics Viral Proteins - metabolism |
| title | Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer |
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