{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T10:48:13Z","timestamp":1784026093490,"version":"3.55.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T00:00:00Z","timestamp":1671667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010877","name":"Science, Technology and Innovation Commission of Shenzhen Municipality","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100010877","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Tumor hypoxia is frequently observed in primary solid malignancies, but the hypoxic status of tumor cells floating in body cavity effusions is largely unknown, especially in patients. This study was to observe the hypoxia and proliferation status of cancer cells floating in effusions in mice and patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The distribution of hypoxia in cancer cells floating in ascites was first studied in nude mice. Hypoxia was detected by immunofluorescent visualization of pimonidazole and GLUT-1. For cancer patients, we retrospectively collected 21 ascites and 7 pleural effusion sample blocks of cancer patients, which were confirmed to contain tumor cells. Immunohistochemistry was performed to detect the expression of endogenous hypoxic markers HIF-1\u03b1 and GLUT-1, proliferation index Ki-67. <jats:sup>18<\/jats:sup>F-FDG PET\/CT was performed to detect the glucose metabolism status of tumor cells in effusions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The tumor cells collected from ascites were positive for pimonidazole and GLUT-1, which suggesting that the cancer cells floating in ascites were hypoxic. Patterns of tumor hypoxia in human patients are similar to those observed in animal. HIF-1\u03b1 and GLUT-1 were expressed by tumor cells in nearly all 28 cytological cases. For Ki-67 index, ascites tumor cells had a relatively low expression level compared with their corresponding primary or its metastatic lesions. Tumor cells in effusions showed high <jats:sup>18<\/jats:sup>F-FDG uptake indicated the enhanced activity of glucose metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Tumor cells in body cavity effusions, as a unique subgroup of tumor, are in a state of hypoxia and low proliferation, which would be one of the driven causes of chemo-radiotherapy resistance. Novel therapeutic interventions are urgently needed to overcome tumor hypoxia.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2022.1019360","type":"journal-article","created":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T14:26:26Z","timestamp":1671719186000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Visualization of hypoxia in cancer cells from effusions in animals and cancer patients"],"prefix":"10.3389","volume":"12","author":[{"given":"Yue","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Long","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"331","DOI":"10.1186\/s12957-020-02097-y","article-title":"Quality assessment of the guidelines for the management of malignant pleural effusions and ascites","volume":"18","author":"Li","year":"2020","journal-title":"World J Surg Oncol"},{"key":"B2","first-page":"67","article-title":"Expert consensus on the clinical application of rmhTNF in the treatment of malignant pleural effusion and malignant ascites","volume":"23","author":"Qin","year":"2008","journal-title":"Chin Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.2560","article-title":"Ovarian cancer: Current status and strategies for improving therapeutic outcomes","volume":"8","author":"Chandra","year":"2019","journal-title":"Cancer Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.32544","article-title":"New strategies in ovarian cancer treatment","author":"Lee","year":"2019","journal-title":"Cancer"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx443","article-title":"Real-world evidence in the treatment of ovarian cancer","volume":"28","author":"Eisenhauer","year":"2017","journal-title":"Ann Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1708618","article-title":"Hyperthermic intraperitoneal chemotherapy in ovarian cancer","volume":"378","author":"van Driel","year":"2018","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s13048-019-0509-1","article-title":"The prognosis impact of hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery (CRS) in advanced ovarian cancer: the meta-analysis","volume":"12","author":"Zhang","year":"2019","journal-title":"J Ovarian Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ygyno.2018.09.007","article-title":"It's time to warm up to hyperthermic intraperitoneal chemotherapy for patients with ovarian cancer","volume":"151","author":"Zivanovic","year":"2018","journal-title":"Gynecol Oncol"},{"key":"B9","article-title":"New developments in molecular targeted therapy of ovarian cancer","volume":"26","author":"Guan","year":"2018","journal-title":"Discov Med"},{"key":"B10","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/s13148-018-0602-0","article-title":"Epigenetic therapy for ovarian cancer: promise and progress","volume":"11","author":"Moufarrij","year":"2019","journal-title":"Clin Epigenetics"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx444","article-title":"Immunotherapy in ovarian cancer","volume":"28","author":"Odunsi","year":"2017","journal-title":"Ann Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3322\/canjclin.45.1.8","article-title":"Cancer statistics, 1995","volume":"45","author":"Wingo","year":"1995","journal-title":"CA Cancer J Clin"},{"key":"B13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijrobp.2006.01.007","article-title":"Hypoxia in human colorectal adenocarcinoma: comparison between extrinsic and potential intrinsic hypoxia markers","volume":"65","author":"Goethals","year":"2006","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1177\/15330338211036304","article-title":"Hypoxia and the tumor microenvironment","volume":"20","author":"Li","year":"2021","journal-title":"Technol Cancer Res Treat"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-4353","article-title":"Visualization of hypoxia in microscopic tumors by immunofluorescent microscopy","volume":"67","author":"Li","year":"2007","journal-title":"Cancer Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.109.071233","article-title":"High 18F-FDG uptake in microscopic peritoneal tumors requires physiologic hypoxia","volume":"51","author":"Li","year":"2010","journal-title":"J Nucl Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-009-1310-y","article-title":"Detection of hypoxia in microscopic tumors using 131I-labeled iodo-azomycin galactopyranoside (131I-IAZGP) digital autoradiography","volume":"37","author":"Li","year":"2010","journal-title":"Eur J Nucl Med Mol Imaging."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.111.098087","article-title":"Tumor microenvironment-dependent 18F-FDG, 18F-fluorothymidine, and 18F-misonidazole uptake: a pilot study in mouse models of human non-small cell lung cancer","volume":"53","author":"Huang","year":"2012","journal-title":"J Nucl Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2014.02.010","article-title":"(18)F-fluorodeoxyglucose uptake and tumor hypoxia: revisit (18)f-fluorodeoxyglucose in oncology application","volume":"7","author":"Li","year":"2014","journal-title":"Transl Oncol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1080\/07357907.2016.1245317","article-title":"Hypoxia: A double-edged sword in cancer therapy","volume":"34","author":"Manoochehri Khoshinani","year":"2016","journal-title":"Cancer Invest"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S140462","article-title":"Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment","volume":"13","author":"Graham","year":"2018","journal-title":"Int J Nanomedicine"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-3-030-12734-3_1","article-title":"Hypoxia mediates tumor malignancy and therapy resistance","volume":"1136","author":"Luo","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18091854","article-title":"Targeting tumor adaption to chronic hypoxia: Implications for drug resistance, and how it can be overcome","volume":"18","author":"Kim","year":"2017","journal-title":"Int J Mol Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1093\/jrr\/rrw007","article-title":"The impact of hypoxia and its modification of the outcome of radiotherapy","author":"Horsman","year":"2016","journal-title":"J Radiat Res"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emm.2004.1","article-title":"Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions","volume":"36","author":"Lee","year":"2004","journal-title":"Exp Mol Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1124\/mol.106.027029","article-title":"Hypoxia-inducible factor-1 (HIF-1)","volume":"70","author":"Ke","year":"2006","journal-title":"Mol Pharmacol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.cca.2019.01.011","article-title":"Ki-67 protein as a tumour proliferation marker","volume":"491","author":"Menon","year":"2019","journal-title":"Clin Chim Acta"},{"key":"B29","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1006\/gyno.2002.6800","article-title":"Ascites as a predictor of ovarian malignancy","volume":"87","author":"Shen-Gunther","year":"2002","journal-title":"Gynecol Oncol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/367103","article-title":"Molecular profiling and clinical outcome of high-grade serous ovarian cancer presenting with low- versus high-volume ascites","volume":"2014","author":"Feigenberg","year":"2014","journal-title":"BioMed Res Int"},{"key":"B31","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/S0142-9612(98)00112-4","article-title":"F-18-FDG PET and PET\/CT in the evaluation of cancer treatment response","volume":"50","author":"Ben-Haim","year":"2009","journal-title":"J Nucl Med"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-008-0758-5","article-title":"FDG uptake, a surrogate of tumour hypoxia","volume":"35","author":"Dierckx","year":"2008","journal-title":"Eur J Nucl Med Mol Imag"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1187","article-title":"Targeting HIF-1 for cancer therapy","volume":"3","author":"Semenza","year":"2003","journal-title":"Nat Rev Cancer."},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djj068","article-title":"A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype","volume":"98","author":"Naumov","year":"2006","journal-title":"J Natl Cancer Inst"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-0813com","article-title":"Persistence of microscopic human cancers in mice: alterations in the angiogenic balance accompanies loss of tumor dormancy","volume":"16","author":"Udagawa","year":"2002","journal-title":"FASEB J"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201600644","article-title":"Engineered breast cancer cell spheroids reproduce biologic properties of solid tumors","volume":"5","author":"Ham","year":"2016","journal-title":"Adv Healthc Mater"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181340","article-title":"Development and characterization of a human three-dimensional chondrosarcoma culture for in vitro drug testing","volume":"12","author":"Voissiere","year":"2017","journal-title":"PLoS One"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.700407","article-title":"Targeting hypoxia: Hypoxia-activated prodrugs in cancer therapy","volume":"11","author":"Li","year":"2021","journal-title":"Front Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.636892","article-title":"The hypoxia-activated prodrug TH-302: Exploiting hypoxia in cancer therapy","volume":"12","author":"Li","year":"2021","journal-title":"Front Pharmacol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1019360\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,22]],"date-time":"2022-12-22T14:26:30Z","timestamp":1671719190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2022.1019360\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,22]]},"references-count":39,"alternative-id":["10.3389\/fonc.2022.1019360"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2022.1019360","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,22]]},"article-number":"1019360"}}