Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin
Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and t...
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| creator | Saito, Keita Matsumoto, Shingo Yasui, Hironobu Devasahayam, Nallathamby Subramanian, Sankaran Munasinghe, Jeeva P Patel, Vyomesh Gutkind, J Silvio Mitchell, James B Krishna, Murali C |
| description | Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2) |
| doi_str_mv | 10.1371/journal.pone.0049456 |
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Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0049456</identifier><identifier>PMID: 23185335</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aberration ; Allosteric properties ; Angiogenesis ; Angiogenesis Inhibitors - therapeutic use ; Animals ; Biology ; Biomarkers - metabolism ; Blood ; Blood volume ; Cancer therapies ; Carcinoma, Squamous Cell - metabolism ; Density ; Diagnostic imaging ; Diagnostic Imaging - methods ; Electron paramagnetic resonance ; Electron Spin Resonance Spectroscopy - methods ; Fourier transforms ; Hypoxia ; Immunohistochemistry - methods ; Implantation ; Inhibitors ; Kinases ; Laboratory animals ; Magnetic resonance ; Magnetic resonance imaging ; Magnetic Resonance Imaging - methods ; Medical research ; Medicine ; Mercury ; Metabolism ; Mice ; Mice, Inbred C3H ; Microcirculation ; Neovascularization, Pathologic - drug therapy ; NMR ; Nuclear magnetic resonance ; Oxygen - chemistry ; Oxygen - metabolism ; Oxygenation ; Radiation therapy ; Radiotherapy ; Rapamycin ; Resonance ; Sirolimus - pharmacology ; Solid tumors ; Squamous cell carcinoma ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Tumor Microenvironment ; Tumors ; Vascular endothelial growth factor ; Veterinary medicine</subject><ispartof>PloS one, 2012-11, Vol.7 (11), p.e49456-e49456</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012. This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3f69090c24b3ac2b8ffc0b440e419383eb927badf326191e84fa019625b3e1593</citedby><cites>FETCH-LOGICAL-c692t-3f69090c24b3ac2b8ffc0b440e419383eb927badf326191e84fa019625b3e1593</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/PMC3502528/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3502528/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,2098,2917,23849,27907,27908,53774,53776,79351,79352</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23185335$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Man, Kwan</contributor><creatorcontrib>Saito, Keita</creatorcontrib><creatorcontrib>Matsumoto, Shingo</creatorcontrib><creatorcontrib>Yasui, Hironobu</creatorcontrib><creatorcontrib>Devasahayam, Nallathamby</creatorcontrib><creatorcontrib>Subramanian, Sankaran</creatorcontrib><creatorcontrib>Munasinghe, Jeeva P</creatorcontrib><creatorcontrib>Patel, Vyomesh</creatorcontrib><creatorcontrib>Gutkind, J Silvio</creatorcontrib><creatorcontrib>Mitchell, James B</creatorcontrib><creatorcontrib>Krishna, Murali C</creatorcontrib><title>Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Rapamycin is an allosteric inhibitor of mammalian target of rapamycin, and inhibits tumor growth and angiogenesis. Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.</description><subject>Aberration</subject><subject>Allosteric properties</subject><subject>Angiogenesis</subject><subject>Angiogenesis Inhibitors - therapeutic use</subject><subject>Animals</subject><subject>Biology</subject><subject>Biomarkers - metabolism</subject><subject>Blood</subject><subject>Blood volume</subject><subject>Cancer therapies</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Density</subject><subject>Diagnostic imaging</subject><subject>Diagnostic Imaging - methods</subject><subject>Electron paramagnetic resonance</subject><subject>Electron Spin Resonance Spectroscopy - methods</subject><subject>Fourier transforms</subject><subject>Hypoxia</subject><subject>Immunohistochemistry - methods</subject><subject>Implantation</subject><subject>Inhibitors</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Magnetic resonance</subject><subject>Magnetic resonance imaging</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Mercury</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C3H</subject><subject>Microcirculation</subject><subject>Neovascularization, Pathologic - drug therapy</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Oxygen - chemistry</subject><subject>Oxygen - metabolism</subject><subject>Oxygenation</subject><subject>Radiation therapy</subject><subject>Radiotherapy</subject><subject>Rapamycin</subject><subject>Resonance</subject><subject>Sirolimus - pharmacology</subject><subject>Solid tumors</subject><subject>Squamous cell carcinoma</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><subject>Vascular endothelial growth factor</subject><subject>Veterinary medicine</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</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>eNqNk11rFDEUhgdRbK3-A9EBQfRi13zOx41Qih8LCwu1ehsy2ZOZlJlkTTLV_nuz7rTsSC8kFwknz_sm5yQny15itMS0xB-u3eit7Jc7Z2GJEKsZLx5lp7imZFEQRB8frU-yZyFcI8RpVRRPsxNCccUp5adZt3a2NXHcmuSVm0G2xrZ52Acg5E7ncRyczwejvAN7Y7yzA9iYG7uPQR49yAjb_JeJXR47yIerzWXa7UxjYhJ6uZPDrTL2efZEyz7Ai2k-y75__nR18XWx3nxZXZyvF6qoSVxQXdSoRoqwhkpFmkprhRrGELCUTUWhqUnZyK2mpMA1hoppiXBdEN5QwLymZ9nrg--ud0FMRQoCJ75kpEAsEasDsXXyWux8StrfCieN-BtwvhXSR6N6EAxkRZGUQLliqOIN1xqpSqlGVhUuUfL6OJ02NgNsVSqNl_3MdL5jTSdadyMoR4STKhm8mwy8-zlCiGIwQUHfSwtuTPcmBPESI4QT-uYf9OHsJqqVKQFjtUvnqr2pOGdliXjB6yJRyweoNLaQnjX9KG1SfCZ4PxMkJsLv2MoxBLH6dvn_7ObHnH17xHYg-9gF14_ROBvmIDuA6SOG4EHfFxkjsW-Iu2qIfUOIqSGS7NXxA92L7jqA_gEIIQaV</recordid><startdate>20121120</startdate><enddate>20121120</enddate><creator>Saito, Keita</creator><creator>Matsumoto, Shingo</creator><creator>Yasui, Hironobu</creator><creator>Devasahayam, Nallathamby</creator><creator>Subramanian, Sankaran</creator><creator>Munasinghe, Jeeva P</creator><creator>Patel, Vyomesh</creator><creator>Gutkind, J Silvio</creator><creator>Mitchell, James B</creator><creator>Krishna, Murali C</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>20121120</creationdate><title>Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin</title><author>Saito, Keita ; Matsumoto, Shingo ; Yasui, Hironobu ; Devasahayam, Nallathamby ; Subramanian, Sankaran ; Munasinghe, Jeeva P ; Patel, Vyomesh ; Gutkind, J Silvio ; Mitchell, James B ; Krishna, Murali C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-3f69090c24b3ac2b8ffc0b440e419383eb927badf326191e84fa019625b3e1593</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aberration</topic><topic>Allosteric properties</topic><topic>Angiogenesis</topic><topic>Angiogenesis Inhibitors - 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Recent studies suggested a possibility that rapamycin renormalizes aberrant tumor vasculature and improves tumor oxygenation. The longitudinal effects of rapamycin on angiogenesis and tumor oxygenation were evaluated in murine squamous cell carcinoma (SCCVII) by electron paramagnetic resonance imaging (EPRI) and magnetic resonance imaging (MRI) to identify an optimal time after rapamycin treatment for enhanced tumor radioresponse. Rapamycin treatment was initiated on SCCVII solid tumors 8 days after implantation (500-750 mm(3)) and measurements of tumor pO(2) and blood volume were conducted from day 8 to 14 by EPRI/MRI. Microvessel density was evaluated over the same time period by immunohistochemical analysis. Tumor blood volume as measured by MRI significantly decreased 2 days after rapamycin treatment. Tumor pO(2) levels modestly but significantly increased 2 days after rapamycin treatment; whereas, it decreased in non-treated control tumors. Furthermore, the fraction of hypoxic area (pixels with pO(2)<10 mm Hg) in the tumor region decreased 2 days after rapamycin treatments. Immunohistochemical analysis of tumor microvessel density and pericyte coverage revealed that microvessel density decreased 2 days after rapamycin treatment, but pericyte coverage did not change, similar to what was seen with anti-angiogenic agents such as sunitinib which cause vascular renormalization. Collectively, EPRI/MRI co-imaging can provide non-invasive evidence of rapamycin-induced vascular renormalization and resultant transient increase in tumor oxygenation. Improved oxygenation by rapamycin treatment provides a temporal window for anti-cancer therapies to realize enhanced response to radiotherapy.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23185335</pmid><doi>10.1371/journal.pone.0049456</doi><tpages>e49456</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1326742604 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Aberration Allosteric properties Angiogenesis Angiogenesis Inhibitors - therapeutic use Animals Biology Biomarkers - metabolism Blood Blood volume Cancer therapies Carcinoma, Squamous Cell - metabolism Density Diagnostic imaging Diagnostic Imaging - methods Electron paramagnetic resonance Electron Spin Resonance Spectroscopy - methods Fourier transforms Hypoxia Immunohistochemistry - methods Implantation Inhibitors Kinases Laboratory animals Magnetic resonance Magnetic resonance imaging Magnetic Resonance Imaging - methods Medical research Medicine Mercury Metabolism Mice Mice, Inbred C3H Microcirculation Neovascularization, Pathologic - drug therapy NMR Nuclear magnetic resonance Oxygen - chemistry Oxygen - metabolism Oxygenation Radiation therapy Radiotherapy Rapamycin Resonance Sirolimus - pharmacology Solid tumors Squamous cell carcinoma TOR protein TOR Serine-Threonine Kinases - metabolism Tumor Microenvironment Tumors Vascular endothelial growth factor Veterinary medicine |
| title | Longitudinal imaging studies of tumor microenvironment in mice treated with the mTOR inhibitor rapamycin |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-16T18%3A29%3A58IST&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=Longitudinal%20imaging%20studies%20of%20tumor%20microenvironment%20in%20mice%20treated%20with%20the%20mTOR%20inhibitor%20rapamycin&rft.jtitle=PloS%20one&rft.au=Saito,%20Keita&rft.date=2012-11-20&rft.volume=7&rft.issue=11&rft.spage=e49456&rft.epage=e49456&rft.pages=e49456-e49456&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0049456&rft_dat=%3Cgale_plos_%3EA477056596%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=1326742604&rft_id=info:pmid/23185335&rft_galeid=A477056596&rft_doaj_id=oai_doaj_org_article_4ea830aae35c4085b5ff0c8ccba88170&rfr_iscdi=true |