Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype
Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs...
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| Veröffentlicht in: | PloS one 2014-12, Vol.9 (12), p.e113910-e113910 |
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| creator | Ohmura-Kakutani, Hitomi Akiyama, Kosuke Maishi, Nako Ohga, Noritaka Hida, Yasuhiro Kawamoto, Taisuke Iida, Junichiro Shindoh, Masanobu Tsuchiya, Kunihiko Shinohara, Nobuo Hida, Kyoko |
| description | Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis. |
| doi_str_mv | 10.1371/journal.pone.0113910 |
| format | Article |
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It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0113910</identifier><identifier>PMID: 25437864</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aldehyde dehydrogenase ; Aldehyde Dehydrogenase - analysis ; Aldehyde Dehydrogenase - genetics ; Aldehyde Dehydrogenase - metabolism ; Aldehydes ; Angiogenesis ; Animal models ; Animals ; Biology and Life Sciences ; Blood ; Blood vessels ; CD90 antigen ; Cell Line ; Comparative analysis ; Dehydrogenase ; Dermis ; Endothelial cells ; Endothelial Cells - enzymology ; Endothelial Cells - metabolism ; Endothelial Cells - pathology ; Endothelium ; Flow cytometry ; Fluorescence ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Humans ; Medicine and Health Sciences ; Melanoma ; Melanoma - enzymology ; Melanoma - genetics ; Melanoma - pathology ; Metastases ; Mice, Nude ; Multidrug resistance ; Neovascularization, Pathologic - enzymology ; Neovascularization, Pathologic - genetics ; Neovascularization, Pathologic - pathology ; Oral carcinoma ; Phenotypes ; RNA ; Stem cells ; Tubes ; Tumor Cells, Cultured ; Tumors ; Vascular endothelial growth factor ; Vascular Endothelial Growth Factor A - analysis ; Vascular Endothelial Growth Factor A - genetics ; Vascular Endothelial Growth Factor Receptor-2 - analysis ; Vascular Endothelial Growth Factor Receptor-2 - genetics ; Xenografts</subject><ispartof>PloS one, 2014-12, Vol.9 (12), p.e113910-e113910</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Ohmura-Kakutani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Ohmura-Kakutani et al 2014 Ohmura-Kakutani et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c736t-a15b7ea950343fe735857b09626d4c396cd1800d6454893a4ab7b7e3cabe9a2a3</citedby><cites>FETCH-LOGICAL-c736t-a15b7ea950343fe735857b09626d4c396cd1800d6454893a4ab7b7e3cabe9a2a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250080/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250080/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25437864$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Morishita, Ryuichi</contributor><creatorcontrib>Ohmura-Kakutani, Hitomi</creatorcontrib><creatorcontrib>Akiyama, Kosuke</creatorcontrib><creatorcontrib>Maishi, Nako</creatorcontrib><creatorcontrib>Ohga, Noritaka</creatorcontrib><creatorcontrib>Hida, Yasuhiro</creatorcontrib><creatorcontrib>Kawamoto, Taisuke</creatorcontrib><creatorcontrib>Iida, Junichiro</creatorcontrib><creatorcontrib>Shindoh, Masanobu</creatorcontrib><creatorcontrib>Tsuchiya, Kunihiko</creatorcontrib><creatorcontrib>Shinohara, Nobuo</creatorcontrib><creatorcontrib>Hida, Kyoko</creatorcontrib><title>Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.</description><subject>Aldehyde dehydrogenase</subject><subject>Aldehyde Dehydrogenase - analysis</subject><subject>Aldehyde Dehydrogenase - genetics</subject><subject>Aldehyde Dehydrogenase - metabolism</subject><subject>Aldehydes</subject><subject>Angiogenesis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biology and Life Sciences</subject><subject>Blood</subject><subject>Blood vessels</subject><subject>CD90 antigen</subject><subject>Cell Line</subject><subject>Comparative analysis</subject><subject>Dehydrogenase</subject><subject>Dermis</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - enzymology</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelial Cells - pathology</subject><subject>Endothelium</subject><subject>Flow cytometry</subject><subject>Fluorescence</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Humans</subject><subject>Medicine and Health Sciences</subject><subject>Melanoma</subject><subject>Melanoma - enzymology</subject><subject>Melanoma - genetics</subject><subject>Melanoma - pathology</subject><subject>Metastases</subject><subject>Mice, Nude</subject><subject>Multidrug resistance</subject><subject>Neovascularization, Pathologic - enzymology</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>Neovascularization, Pathologic - pathology</subject><subject>Oral carcinoma</subject><subject>Phenotypes</subject><subject>RNA</subject><subject>Stem cells</subject><subject>Tubes</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Vascular Endothelial Growth Factor A - analysis</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - analysis</subject><subject>Vascular Endothelial Growth Factor Receptor-2 - genetics</subject><subject>Xenografts</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk01r3DAQhk1padK0_6C0hkJpD7uVLFlaXwoh9GMhEOjXVYzlsa2gtTaWnHb_feVdJ6xLDsUHWdIz74xeaZLkJSVLyiT9cO2GvgO73LoOl4RSVlDyKDmlBcsWIiPs8dH_SfLM-2tCcrYS4mlykuWcyZXgp8mwrrALpjYagnFd6uo0DBvXp9hVLrRoDdhUo7U-_W1Cm7amaVOwFba7CtP90LsGO_CYgg7m1oRdCl2Vwh6146QxI2F0um2xc2G3xefJkxqsxxfTeJb8_Pzpx8XXxeXVl_XF-eVCSybCAmheSoQiJ4yzGiXLV7ksSSEyUXHNCqEruiKkEjznq4IBh1LGAKahxAIyYGfJ64Pu1jqvJse8oiIrGJNSkkisD0Tl4Fpte7OBfqccGLVfcH2joA9GW1RlLWvKRUyBkheVBFozQmrEmiGHgketj1O2odxgpaOxPdiZ6HynM61q3K3iWU7Iaizm3STQu5sBfVAb40fzoUM3HOouBM-KEX3zD_rw6SaqgXgA09Uu5tWjqDrnVAiZUzHWvXyAil-FG6Pj86pNXJ8FvJ8FRCbgn9DA4L1af__2_-zVrzn79ohtEWxovbPD-DL9HOQHUPfO-x7re5MpUWN33Lmhxu5QU3fEsFfHF3QfdNcO7C_0bwwN</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Ohmura-Kakutani, Hitomi</creator><creator>Akiyama, Kosuke</creator><creator>Maishi, Nako</creator><creator>Ohga, Noritaka</creator><creator>Hida, Yasuhiro</creator><creator>Kawamoto, Taisuke</creator><creator>Iida, Junichiro</creator><creator>Shindoh, Masanobu</creator><creator>Tsuchiya, Kunihiko</creator><creator>Shinohara, Nobuo</creator><creator>Hida, Kyoko</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20141201</creationdate><title>Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype</title><author>Ohmura-Kakutani, Hitomi ; Akiyama, Kosuke ; Maishi, Nako ; Ohga, Noritaka ; Hida, Yasuhiro ; Kawamoto, Taisuke ; Iida, Junichiro ; Shindoh, Masanobu ; Tsuchiya, Kunihiko ; Shinohara, Nobuo ; Hida, Kyoko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c736t-a15b7ea950343fe735857b09626d4c396cd1800d6454893a4ab7b7e3cabe9a2a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Aldehyde dehydrogenase</topic><topic>Aldehyde Dehydrogenase - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ohmura-Kakutani, Hitomi</au><au>Akiyama, Kosuke</au><au>Maishi, Nako</au><au>Ohga, Noritaka</au><au>Hida, Yasuhiro</au><au>Kawamoto, Taisuke</au><au>Iida, Junichiro</au><au>Shindoh, Masanobu</au><au>Tsuchiya, Kunihiko</au><au>Shinohara, Nobuo</au><au>Hida, Kyoko</au><au>Morishita, Ryuichi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>9</volume><issue>12</issue><spage>e113910</spage><epage>e113910</epage><pages>e113910-e113910</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Tumor blood vessels play an important role in tumor progression and metastasis. It has been reported that tumor endothelial cells (TECs) exhibit highly angiogenic phenotypes compared with those of normal endothelial cells (NECs). TECs show higher proliferative and migratory abilities than those NECs, together with upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2). Furthermore, compared with NECs, stem cell markers such as Sca-1, CD90, and multidrug resistance 1 are upregulated in TECs, suggesting that stem-like cells exist in tumor blood vessels. In this study, to reveal the biological role of stem-like TECs, we analyzed expression of the stem cell marker aldehyde dehydrogenase (ALDH) in TECs and characterized ALDHhigh TECs. TECs and NECs were isolated from melanoma-xenografted nude mice and normal dermis, respectively. ALDH mRNA expression and activity were higher in TECs than those in NECs. Next, ALDHhigh/low TECs were isolated by fluorescence-activated cell sorting to compare their characteristics. Compared with ALDHlow TECs, ALDHhigh TECs formed more tubes on Matrigel-coated plates and sustained the tubular networks longer. Furthermore, VEGFR2 expression was higher in ALDHhigh TECs than that in ALDHlow TECs. In addition, ALDH was expressed in the tumor blood vessels of in vivo mouse models of melanoma and oral carcinoma, but not in normal blood vessels. These findings indicate that ALDHhigh TECs exhibit an angiogenic phenotype. Stem-like TECs may have an essential role in tumor angiogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25437864</pmid><doi>10.1371/journal.pone.0113910</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-12, Vol.9 (12), p.e113910-e113910 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1629337770 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aldehyde dehydrogenase Aldehyde Dehydrogenase - analysis Aldehyde Dehydrogenase - genetics Aldehyde Dehydrogenase - metabolism Aldehydes Angiogenesis Animal models Animals Biology and Life Sciences Blood Blood vessels CD90 antigen Cell Line Comparative analysis Dehydrogenase Dermis Endothelial cells Endothelial Cells - enzymology Endothelial Cells - metabolism Endothelial Cells - pathology Endothelium Flow cytometry Fluorescence Gene expression Gene Expression Regulation, Neoplastic Genetic aspects Humans Medicine and Health Sciences Melanoma Melanoma - enzymology Melanoma - genetics Melanoma - pathology Metastases Mice, Nude Multidrug resistance Neovascularization, Pathologic - enzymology Neovascularization, Pathologic - genetics Neovascularization, Pathologic - pathology Oral carcinoma Phenotypes RNA Stem cells Tubes Tumor Cells, Cultured Tumors Vascular endothelial growth factor Vascular Endothelial Growth Factor A - analysis Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor Receptor-2 - analysis Vascular Endothelial Growth Factor Receptor-2 - genetics Xenografts |
| title | Identification of tumor endothelial cells with high aldehyde dehydrogenase activity and a highly angiogenic phenotype |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-24T14%3A24%3A47IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20tumor%20endothelial%20cells%20with%20high%20aldehyde%20dehydrogenase%20activity%20and%20a%20highly%20angiogenic%20phenotype&rft.jtitle=PloS%20one&rft.au=Ohmura-Kakutani,%20Hitomi&rft.date=2014-12-01&rft.volume=9&rft.issue=12&rft.spage=e113910&rft.epage=e113910&rft.pages=e113910-e113910&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0113910&rft_dat=%3Cgale_plos_%3EA416675164%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1629337770&rft_id=info:pmid/25437864&rft_galeid=A416675164&rft_doaj_id=oai_doaj_org_article_bf7f146b7be749d7a1f300feef3e4a94&rfr_iscdi=true |