{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T18:24:41Z","timestamp":1788114281309,"version":"build-2803163510"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,1,27]],"date-time":"2014-01-27T00:00:00Z","timestamp":1390780800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS\u2010R, from SAS cells. SAS\u2010R cells continue to proliferate when exposed to fractionated radiation (FR) of 2\u00a0Gy\/day for more than 30\u00a0days in vitro. A xenograft tumor model of SAS\u2010R was also resistant to 2\u00a0Gy\/day of X\u2010rays for 30\u00a0days. The density of blood vessels in SAS\u2010R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS\u2010R cells in vitro. Everolimus with FR markedly reduced SAS and SAS\u2010R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS\u2010R tumor tissues when both Everolimus and radiation were administered. Both CD34\u2010positive and tomato lectin\u2010positive blood vessel densities in SAS\u2010R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus\u2010induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs.<\/jats:p>","DOI":"10.1002\/cam4.185","type":"journal-article","created":{"date-parts":[[2014,1,27]],"date-time":"2014-01-27T06:46:51Z","timestamp":1390805211000},"page":"310-321","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Targeting of tumor endothelial cells combining 2\u00a0Gy\/day of X\u2010ray with Everolimus is the effective modality for overcoming clinically relevant radioresistant tumors"],"prefix":"10.1002","volume":"3","author":[{"given":"Yoshikazu","family":"Kuwahara","sequence":"first","affiliation":[{"name":"Department of Pathology Institute of Development, Aging and Cancer Tohoku University Sendai Miyagi 980\u20108575 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Dentistry and Oral surgery National Hospital Tokyo Medical Center Tokyo 152\u20108902 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Kitahara","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology Tokyo Women's Medical University Tokyo 162\u20108666 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoi","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Department of Pathology Institute of Development, Aging and Cancer Tohoku University Sendai Miyagi 980\u20108575 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Ezaki","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Developmental Biology Tokyo Women's Medical University Tokyo 162\u20108666 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiro","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Tohoku University Hospital Sendai Miyagi 980\u20108575 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seishi","family":"Echigo","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine and Surgery Graduate School of Dentistry Tohoku University Sendai Miyagi 980\u20108575 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhito","family":"Ohkubo","sequence":"additional","affiliation":[{"name":"Department of Radiopharmacy Tohoku Pharmaceutical University Sendai Miyagi 981\u20108558 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Fukumoto","sequence":"additional","affiliation":[{"name":"Department of Pathology Institute of Development, Aging and Cancer Tohoku University Sendai Miyagi 980\u20108575 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,1,27]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.40"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1650"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1148\/48.4.398"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.238"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.2307\/3579812"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1082504"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/35025220"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semradonc.2004.04.008"},{"key":"e_1_2_7_10_1","first-page":"3374","article-title":"Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation","volume":"59","author":"Gorski D. 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