The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer
Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic...
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| Veröffentlicht in: | PloS one 2019-11, Vol.14 (11), p.e0224727-e0224727 |
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| creator | Kuroda, Kenji Yashiro, Masakazu Sera, Tomohiro Yamamoto, Yurie Kushitani, Yukako Sugimoto, Atsushi Kushiyama, Syuhei Nishimura, Sadaaki Togano, Shingo Okuno, Tomohisa Tamura, Tatsuro Toyokawa, Takahiro Tanaka, Hiroaki Muguruma, Kazuya Ohira, Masaichi |
| description | Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC).
We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.
THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.
THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients. |
| doi_str_mv | 10.1371/journal.pone.0224727 |
| format | Article |
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We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.
THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.
THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0224727</identifier><identifier>PMID: 31703077</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Biology and Life Sciences ; Cancer ; Cancer cells ; Cancer metastasis ; Cancer-Associated Fibroblasts - metabolism ; Cancer-Associated Fibroblasts - pathology ; Carcinoma ; Cell Line, Tumor ; Cytokeratin ; Cytology ; Evaluation ; Fibroblasts ; Gastric cancer ; Gene expression ; Glycoproteins ; Humans ; Immunohistochemistry ; Keratin ; Liver cancer ; Medical prognosis ; Medicine ; Medicine and Health Sciences ; Membrane Glycoproteins - metabolism ; Metastases ; Multivariate Analysis ; Oncology ; Peritoneum ; Physical Sciences ; Prostate cancer ; Research and Analysis Methods ; Solid tumors ; Stomach cancer ; Stomach Neoplasms - metabolism ; Stomach Neoplasms - pathology ; Stromal cells ; Stromal Cells - metabolism ; Surgery ; Survival ; Survival Analysis ; Thrombospondin ; Thrombospondins - metabolism ; Tumor cell lines ; Tumor Microenvironment ; Tumors ; University graduates ; Western blotting ; Wound care ; Wound healing</subject><ispartof>PloS one, 2019-11, Vol.14 (11), p.e0224727-e0224727</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Kuroda 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>2019 Kuroda et al 2019 Kuroda et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-adb8c9162986532aa8cf867e0ea4e820db251c416ebc39b8340f5ef3b78b78da3</citedby><cites>FETCH-LOGICAL-c758t-adb8c9162986532aa8cf867e0ea4e820db251c416ebc39b8340f5ef3b78b78da3</cites><orcidid>0000-0001-5743-7228</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/PMC6839882/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839882/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31703077$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Katoh, Masaru</contributor><creatorcontrib>Kuroda, Kenji</creatorcontrib><creatorcontrib>Yashiro, Masakazu</creatorcontrib><creatorcontrib>Sera, Tomohiro</creatorcontrib><creatorcontrib>Yamamoto, Yurie</creatorcontrib><creatorcontrib>Kushitani, Yukako</creatorcontrib><creatorcontrib>Sugimoto, Atsushi</creatorcontrib><creatorcontrib>Kushiyama, Syuhei</creatorcontrib><creatorcontrib>Nishimura, Sadaaki</creatorcontrib><creatorcontrib>Togano, Shingo</creatorcontrib><creatorcontrib>Okuno, Tomohisa</creatorcontrib><creatorcontrib>Tamura, Tatsuro</creatorcontrib><creatorcontrib>Toyokawa, Takahiro</creatorcontrib><creatorcontrib>Tanaka, Hiroaki</creatorcontrib><creatorcontrib>Muguruma, Kazuya</creatorcontrib><creatorcontrib>Ohira, Masaichi</creatorcontrib><title>The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC).
We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.
THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.
THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.</description><subject>Analysis</subject><subject>Biology and Life Sciences</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer metastasis</subject><subject>Cancer-Associated Fibroblasts - metabolism</subject><subject>Cancer-Associated Fibroblasts - pathology</subject><subject>Carcinoma</subject><subject>Cell Line, Tumor</subject><subject>Cytokeratin</subject><subject>Cytology</subject><subject>Evaluation</subject><subject>Fibroblasts</subject><subject>Gastric cancer</subject><subject>Gene expression</subject><subject>Glycoproteins</subject><subject>Humans</subject><subject>Immunohistochemistry</subject><subject>Keratin</subject><subject>Liver cancer</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Metastases</subject><subject>Multivariate Analysis</subject><subject>Oncology</subject><subject>Peritoneum</subject><subject>Physical Sciences</subject><subject>Prostate cancer</subject><subject>Research and Analysis Methods</subject><subject>Solid tumors</subject><subject>Stomach cancer</subject><subject>Stomach Neoplasms - metabolism</subject><subject>Stomach Neoplasms - pathology</subject><subject>Stromal cells</subject><subject>Stromal Cells - metabolism</subject><subject>Surgery</subject><subject>Survival</subject><subject>Survival Analysis</subject><subject>Thrombospondin</subject><subject>Thrombospondins - metabolism</subject><subject>Tumor cell lines</subject><subject>Tumor Microenvironment</subject><subject>Tumors</subject><subject>University graduates</subject><subject>Western blotting</subject><subject>Wound care</subject><subject>Wound healing</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</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>eNqNk12L1DAUhoso7jr6D0QLgujFjPlo0_RGWBY_BhYWdPQ2pOlpJ0uazCbpsv57MzvdZSp7IS00pM95T86bc7LsNUYrTCv86cqN3kqz2jkLK0RIUZHqSXaKa0qWjCD69Gh9kr0I4QqhknLGnmcnFFeIoqo6zcJmC7ky2mrldjJunXG9VtLkQfdWd2lpFeSuyzdb74bGhZSu1XZZ5HC78xCCdjbXNo9JJo6D8_mglXdgb7R3dgAb98G9DNFrld-p-ZfZs06aAK-m7yL79fXL5vz78uLy2_r87GKpqpLHpWwbrmrMSM1ZSYmUXHWcVYBAFsAJahtSYlVgBo2idcNpgboSOtpUPL2tpIvs7UF3Z1wQk19BEIopYhQnXxbZ-kC0Tl6JndeD9H-Ek1rcbTjfC-mjVgYEUpzUyUHGlCw4ryVHRYFTRlXVZVlA0vo8ZRubAVqVSvfSzETnf6zeit7dCMZpzTlJAh8mAe-uRwhRDDooMEZacOPh3JThktUJffcP-nh1E9XLVIC2nUt51V5UnDFUElLxgiVq9QiVnhbSVabm6nTanwV8nAUkJsJt7OUYglj__PH_7OXvOfv-iN2CNHEbnBljarEwB4sDmBotBA_dg8kYif1s3Lsh9rMhptlIYW-OL-gh6H4Y6F-6vAqD</recordid><startdate>20191108</startdate><enddate>20191108</enddate><creator>Kuroda, Kenji</creator><creator>Yashiro, Masakazu</creator><creator>Sera, Tomohiro</creator><creator>Yamamoto, Yurie</creator><creator>Kushitani, Yukako</creator><creator>Sugimoto, Atsushi</creator><creator>Kushiyama, Syuhei</creator><creator>Nishimura, Sadaaki</creator><creator>Togano, Shingo</creator><creator>Okuno, Tomohisa</creator><creator>Tamura, Tatsuro</creator><creator>Toyokawa, Takahiro</creator><creator>Tanaka, Hiroaki</creator><creator>Muguruma, Kazuya</creator><creator>Ohira, Masaichi</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>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><orcidid>https://orcid.org/0000-0001-5743-7228</orcidid></search><sort><creationdate>20191108</creationdate><title>The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer</title><author>Kuroda, Kenji ; Yashiro, Masakazu ; Sera, Tomohiro ; Yamamoto, Yurie ; Kushitani, Yukako ; Sugimoto, Atsushi ; Kushiyama, Syuhei ; Nishimura, Sadaaki ; Togano, Shingo ; Okuno, Tomohisa ; Tamura, Tatsuro ; Toyokawa, Takahiro ; Tanaka, Hiroaki ; Muguruma, Kazuya ; Ohira, Masaichi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-adb8c9162986532aa8cf867e0ea4e820db251c416ebc39b8340f5ef3b78b78da3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Analysis</topic><topic>Biology and Life Sciences</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer metastasis</topic><topic>Cancer-Associated Fibroblasts - metabolism</topic><topic>Cancer-Associated Fibroblasts - pathology</topic><topic>Carcinoma</topic><topic>Cell Line, Tumor</topic><topic>Cytokeratin</topic><topic>Cytology</topic><topic>Evaluation</topic><topic>Fibroblasts</topic><topic>Gastric cancer</topic><topic>Gene expression</topic><topic>Glycoproteins</topic><topic>Humans</topic><topic>Immunohistochemistry</topic><topic>Keratin</topic><topic>Liver cancer</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Membrane Glycoproteins - metabolism</topic><topic>Metastases</topic><topic>Multivariate Analysis</topic><topic>Oncology</topic><topic>Peritoneum</topic><topic>Physical Sciences</topic><topic>Prostate cancer</topic><topic>Research and Analysis Methods</topic><topic>Solid tumors</topic><topic>Stomach cancer</topic><topic>Stomach Neoplasms - metabolism</topic><topic>Stomach Neoplasms - pathology</topic><topic>Stromal cells</topic><topic>Stromal Cells - metabolism</topic><topic>Surgery</topic><topic>Survival</topic><topic>Survival Analysis</topic><topic>Thrombospondin</topic><topic>Thrombospondins - 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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>Kuroda, Kenji</au><au>Yashiro, Masakazu</au><au>Sera, Tomohiro</au><au>Yamamoto, Yurie</au><au>Kushitani, Yukako</au><au>Sugimoto, Atsushi</au><au>Kushiyama, Syuhei</au><au>Nishimura, Sadaaki</au><au>Togano, Shingo</au><au>Okuno, Tomohisa</au><au>Tamura, Tatsuro</au><au>Toyokawa, Takahiro</au><au>Tanaka, Hiroaki</au><au>Muguruma, Kazuya</au><au>Ohira, Masaichi</au><au>Katoh, Masaru</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-11-08</date><risdate>2019</risdate><volume>14</volume><issue>11</issue><spage>e0224727</spage><epage>e0224727</epage><pages>e0224727-e0224727</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Thrombospondin-4 [1] is an extracellular glycoprotein involved in wound healing and tissue remodeling. Although THBS4 is reportedly frequently expressed in solid tumors, there are few reports of the clinicopathological features of carcinomas with THBS4 expression. We evaluated the clinicopathologic significance of THBS4 expression in gastric carcinoma (GC).
We retrospectively analyzed the cases of 584 GC patients. The expression of THBS4 in each tumor was evaluated by immunohistochemistry. We then divided the patients into the THBS4-high (n = 223, 38.2%) group and THBS4-low (n = 361, 61.8%) group. THBS4 expression in cancer-associated fibroblasts (CAFs), normal-associated fibroblasts (NFs) and gastric cancer cell lines was examined by western blotting.
THBS4 is expressed on stromal cells with αSMA or Podoplanin expression in the GC microenvironment, but not expressed on cancer cells with cytokeratin expression. The western blot analysis results showed that CAFs (but not NFs and cancer cells) expressed THBS4. Compared to the THBS4-low expression status, the THBS4-high expression status was correlated with higher αSMA expression, higher invasion depth, lymph-node metastasis, lymphatic invasion, peritoneal cytology, peritoneal metastasis, larger tumor size, microscopic diffuse type, and the macroscopic diffuse infiltrating type. The THBS4-high group's 5-year overall survival rate was significantly poorer than that of the THBS4-low group. A multivariate analysis revealed that THBS4 expression was an independent prognostic factor.
THBS4 is expressed on CAFs in the gastric cancer microenvironment. THBS4 from CAFs is associated with the metastasis of cancer cells, and is a useful prognostic indicator for gastric cancer patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31703077</pmid><doi>10.1371/journal.pone.0224727</doi><tpages>e0224727</tpages><orcidid>https://orcid.org/0000-0001-5743-7228</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-11, Vol.14 (11), p.e0224727-e0224727 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2313063120 |
| 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 | Analysis Biology and Life Sciences Cancer Cancer cells Cancer metastasis Cancer-Associated Fibroblasts - metabolism Cancer-Associated Fibroblasts - pathology Carcinoma Cell Line, Tumor Cytokeratin Cytology Evaluation Fibroblasts Gastric cancer Gene expression Glycoproteins Humans Immunohistochemistry Keratin Liver cancer Medical prognosis Medicine Medicine and Health Sciences Membrane Glycoproteins - metabolism Metastases Multivariate Analysis Oncology Peritoneum Physical Sciences Prostate cancer Research and Analysis Methods Solid tumors Stomach cancer Stomach Neoplasms - metabolism Stomach Neoplasms - pathology Stromal cells Stromal Cells - metabolism Surgery Survival Survival Analysis Thrombospondin Thrombospondins - metabolism Tumor cell lines Tumor Microenvironment Tumors University graduates Western blotting Wound care Wound healing |
| title | The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-23T10%3A50%3A20IST&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=The%20clinicopathological%20significance%20of%20Thrombospondin-4%20expression%20in%20the%20tumor%20microenvironment%20of%20gastric%20cancer&rft.jtitle=PloS%20one&rft.au=Kuroda,%20Kenji&rft.date=2019-11-08&rft.volume=14&rft.issue=11&rft.spage=e0224727&rft.epage=e0224727&rft.pages=e0224727-e0224727&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0224727&rft_dat=%3Cgale_plos_%3EA605227846%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=2313063120&rft_id=info:pmid/31703077&rft_galeid=A605227846&rft_doaj_id=oai_doaj_org_article_0c82900566ca4889a804410f5c79554e&rfr_iscdi=true |