Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma
Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived gr...
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| Veröffentlicht in: | Cancer science 2018-05, Vol.109 (5), p.1513-1523 |
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| creator | Sumiyoshi, Keisuke Koso, Hideto Watanabe, Sumiko |
| description | Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
A single transposon vector efficiently induced malignant glioma. Co‐transduction of two transposon vectors spontaneously generated intratumoral heterogeneity. |
| doi_str_mv | 10.1111/cas.13579 |
| format | Article |
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A single transposon vector efficiently induced malignant glioma. Co‐transduction of two transposon vectors spontaneously generated intratumoral heterogeneity.</description><identifier>ISSN: 1347-9032</identifier><identifier>EISSN: 1349-7006</identifier><identifier>DOI: 10.1111/cas.13579</identifier><identifier>PMID: 29575648</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Animals ; Biotechnology ; Brain cancer ; Brain Neoplasms - etiology ; Brain Neoplasms - genetics ; Brain Neoplasms - pathology ; Brain tumors ; Cell Hypoxia ; Cell Proliferation ; Cooperation ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; DNA Transposable Elements - genetics ; Experiments ; Genetic engineering ; Glial stem cells ; Glioma ; Glioma - etiology ; Glioma - genetics ; Glioma - pathology ; Hypoxia ; Medical prognosis ; Mice ; Mice, Inbred ICR ; mouse model ; Mutation ; Neonates ; Neurofibromin 1 - genetics ; NIH 3T3 Cells ; Original ; Platelet-Derived Growth Factor - genetics ; Platelet-Derived Growth Factor - physiology ; platelet‐derived growth factor subunit A ; Signal Transduction ; Spatial distribution ; Stem cell transplantation ; Stem cells ; Subventricular zone ; transposon ; Transposons ; Tumor cells ; tumor heterogeneity ; Tumor Suppressor Protein p53 - genetics</subject><ispartof>Cancer science, 2018-05, Vol.109 (5), p.1513-1523</ispartof><rights>2018 The Authors. published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by-nc/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5339-f130350732dd4085bac1ce718e83b4eb3b99589f96aab0ab27fb251c457362103</citedby><cites>FETCH-LOGICAL-c5339-f130350732dd4085bac1ce718e83b4eb3b99589f96aab0ab27fb251c457362103</cites><orcidid>0000-0002-8986-7617</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980157/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5980157/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1411,11541,27901,27902,45550,45551,46027,46451,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29575648$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sumiyoshi, Keisuke</creatorcontrib><creatorcontrib>Koso, Hideto</creatorcontrib><creatorcontrib>Watanabe, Sumiko</creatorcontrib><title>Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma</title><title>Cancer science</title><addtitle>Cancer Sci</addtitle><description>Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
A single transposon vector efficiently induced malignant glioma. Co‐transduction of two transposon vectors spontaneously generated intratumoral heterogeneity.</description><subject>Animals</subject><subject>Biotechnology</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - etiology</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain tumors</subject><subject>Cell Hypoxia</subject><subject>Cell Proliferation</subject><subject>Cooperation</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA Transposable Elements - genetics</subject><subject>Experiments</subject><subject>Genetic engineering</subject><subject>Glial stem cells</subject><subject>Glioma</subject><subject>Glioma - etiology</subject><subject>Glioma - genetics</subject><subject>Glioma - pathology</subject><subject>Hypoxia</subject><subject>Medical prognosis</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>mouse model</subject><subject>Mutation</subject><subject>Neonates</subject><subject>Neurofibromin 1 - genetics</subject><subject>NIH 3T3 Cells</subject><subject>Original</subject><subject>Platelet-Derived Growth Factor - genetics</subject><subject>Platelet-Derived Growth Factor - physiology</subject><subject>platelet‐derived growth factor subunit A</subject><subject>Signal Transduction</subject><subject>Spatial distribution</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Subventricular zone</subject><subject>transposon</subject><subject>Transposons</subject><subject>Tumor cells</subject><subject>tumor heterogeneity</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><issn>1347-9032</issn><issn>1349-7006</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kc9qFTEUh4NYbHt14QvIgBu7mDZ_JjPJRigXq0LBRXUdMpkztymZZExmKnfnI_iMPkkznVqqYBZJ4Hx8nHN-CL0m-JTkc2Z0OiWMN_IZOiKskmWDcf38_t-UEjN6iI5TusGY1ZWsXqBDKnnD60ocIbgag5-0hzCnooNbcGEcwE9F6Avrp6ineQhRu-IaJohhBx7stM-lQhe56tMYUvC_f_6yvpsNdMWQRZDvDtzi2DkbBv0SHfTaJXj18G7Qt4sPX7efyssvHz9vzy9LwxmTZU8YZhw3jHZdhQVvtSEGGiJAsLaClrVSciF7WWvdYt3Spm8pJ6biDaspwWyD3q_ecW4H6AwsEzg1RjvouFdBW_V3xdtrtQu3ikuBSbZs0LsHQQzfZ0iTGmwy4Ny6IUUxEXVdY7ygb_9Bb8IcfR5P0Uosi6ZCZupkpUwMKUXoH5shWC3hqRyeug8vs2-edv9I_kkrA2cr8MM62P_fpLbnV6vyDvuwpqY</recordid><startdate>201805</startdate><enddate>201805</enddate><creator>Sumiyoshi, Keisuke</creator><creator>Koso, Hideto</creator><creator>Watanabe, Sumiko</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8FE</scope><scope>8FH</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8986-7617</orcidid></search><sort><creationdate>201805</creationdate><title>Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma</title><author>Sumiyoshi, Keisuke ; Koso, Hideto ; Watanabe, Sumiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5339-f130350732dd4085bac1ce718e83b4eb3b99589f96aab0ab27fb251c457362103</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Animals</topic><topic>Biotechnology</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - etiology</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain tumors</topic><topic>Cell Hypoxia</topic><topic>Cell Proliferation</topic><topic>Cooperation</topic><topic>Deoxyribonucleic acid</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>DNA Transposable Elements - genetics</topic><topic>Experiments</topic><topic>Genetic engineering</topic><topic>Glial stem cells</topic><topic>Glioma</topic><topic>Glioma - etiology</topic><topic>Glioma - genetics</topic><topic>Glioma - pathology</topic><topic>Hypoxia</topic><topic>Medical prognosis</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>mouse model</topic><topic>Mutation</topic><topic>Neonates</topic><topic>Neurofibromin 1 - genetics</topic><topic>NIH 3T3 Cells</topic><topic>Original</topic><topic>Platelet-Derived Growth Factor - genetics</topic><topic>Platelet-Derived Growth Factor - physiology</topic><topic>platelet‐derived growth factor subunit A</topic><topic>Signal Transduction</topic><topic>Spatial distribution</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Subventricular zone</topic><topic>transposon</topic><topic>Transposons</topic><topic>Tumor cells</topic><topic>tumor heterogeneity</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sumiyoshi, Keisuke</creatorcontrib><creatorcontrib>Koso, Hideto</creatorcontrib><creatorcontrib>Watanabe, Sumiko</creatorcontrib><collection>Wiley Online Library Open Access</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 SciTech Collection</collection><collection>ProQuest Natural Science Collection</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>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer science</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sumiyoshi, Keisuke</au><au>Koso, Hideto</au><au>Watanabe, Sumiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma</atitle><jtitle>Cancer science</jtitle><addtitle>Cancer Sci</addtitle><date>2018-05</date><risdate>2018</risdate><volume>109</volume><issue>5</issue><spage>1513</spage><epage>1523</epage><pages>1513-1523</pages><issn>1347-9032</issn><eissn>1349-7006</eissn><abstract>Glioma is the most common form of malignant brain cancer in adults. The Sleeping Beauty (SB) transposon‐based glioma mouse model allows for effective in vivo analysis of candidate genes. In the present study, we developed a transposon vector that encodes the triple combination of platelet‐derived growth factor subunit A (PDGFA), and shRNAs against Nf1 and Trp53 (shNf1/shp53). Initiation and progression of glioma in the brain were monitored by expression of a fluorescent protein. Transduction of the vector into neural progenitor and stem cells (NPC) in the subventricular zone (SVZ) of the neonatal brain induced proliferation of oligodendrocyte precursor cells, and promoted formation of highly penetrant malignant gliomas within 2‐4 months. Cells isolated from the tumors were capable of forming secondary tumors. Two transposon vectors, encoding either PDGFA or shNf1/shp53 were co‐electroporated into NPC. Cells expressing PDGFA or shNf1/shp53 were labeled with unique fluorescent proteins allowing visualization of the spatial distribution of cells with different genetic alterations within the same tumor. Tumor cells located at the center of tumors expressed PDGFA at higher levels than those located at the periphery, indicating that intratumoral heterogeneity in PDGFA expression levels spontaneously developed within the same tumor. Tumor cells comprising the palisading necrosis strongly expressed PDGFA, suggesting that PDGFA signaling is involved in hypoxic responses in glioma. The transposon vectors developed are compatible with any genetically engineered mouse model, providing a useful tool for the functional analysis of candidate genes in glioma.
A single transposon vector efficiently induced malignant glioma. Co‐transduction of two transposon vectors spontaneously generated intratumoral heterogeneity.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>29575648</pmid><doi>10.1111/cas.13579</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-8986-7617</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Biotechnology Brain cancer Brain Neoplasms - etiology Brain Neoplasms - genetics Brain Neoplasms - pathology Brain tumors Cell Hypoxia Cell Proliferation Cooperation Deoxyribonucleic acid Disease Models, Animal DNA DNA Transposable Elements - genetics Experiments Genetic engineering Glial stem cells Glioma Glioma - etiology Glioma - genetics Glioma - pathology Hypoxia Medical prognosis Mice Mice, Inbred ICR mouse model Mutation Neonates Neurofibromin 1 - genetics NIH 3T3 Cells Original Platelet-Derived Growth Factor - genetics Platelet-Derived Growth Factor - physiology platelet‐derived growth factor subunit A Signal Transduction Spatial distribution Stem cell transplantation Stem cells Subventricular zone transposon Transposons Tumor cells tumor heterogeneity Tumor Suppressor Protein p53 - genetics |
| title | Spontaneous development of intratumoral heterogeneity in a transposon‐induced mouse model of glioma |
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