{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:37:11Z","timestamp":1787027831878,"version":"build-2736575974"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,5]],"date-time":"2020-04-05T00:00:00Z","timestamp":1586044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K10697 and 16H01747"],"award-info":[{"award-number":["16K10697 and 16H01747"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Occupational and Environmental Health, Japan","award":["the Promotion of Occupational Health for the Post Graduate Student"],"award-info":[{"award-number":["the Promotion of Occupational Health for the Post Graduate Student"]}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["JP19am0101078"],"award-info":[{"award-number":["JP19am0101078"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel microfluidic system (CTC-chip) in which any antibody to capture CTCs is easily conjugated. In previous studies, we employed an antibody (clone E-1) against podoplanin that was strongly expressed on mesothelioma cells. The CTC-chip coated by the E-1 antibody (E1-chip) provided a modest sensitivity in detection of CTCs in malignant pleural mesothelioma (MPM). Here, to achieve a higher sensitivity, we employed a novel anti-podoplanin antibody (clone NZ-1.2). In an experimental model, MPM cells with high podoplanin expression were effectively captured with the CTC-chip coated by the NZ-1.2 antibody (NZ1.2-chip). Next, we evaluated CTCs in the peripheral blood sampled from 22 MPM patients using the NZ1.2-chip and the E1-chip. One or more CTCs were detected in 15 patients (68.2%) with the NZ1.2-chip, whereas only in 10 patients (45.5%) with the E1-chip. Of noted, in most (92.3%, 12\/13) patients with epithelioid MPM subtype, CTCs were positive with the NZ1.2-chip. The CTC-count detected with the NZ1.2-chip was significantly higher than that with the E1-chip (p = 0.034). The clinical implications of CTCs detected with the NZ1.2-chip will be examined in a future study.<\/jats:p>","DOI":"10.3390\/cells9040888","type":"journal-article","created":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T03:58:39Z","timestamp":1586231919000},"page":"888","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Detection of Circulating Tumor Cells (CTCs) in Malignant Pleural Mesothelioma (MPM) with the \u201cUniversal\u201d CTC-Chip and An Anti-Podoplanin Antibody NZ-1.2"],"prefix":"10.3390","volume":"9","author":[{"given":"Taiji","family":"Kuwata","sequence":"first","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazue","family":"Yoneda","sequence":"additional","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masataka","family":"Mori","sequence":"additional","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Kanayama","sequence":"additional","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Kuroda","sequence":"additional","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mika K.","family":"Kaneko","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5385-8201","authenticated-orcid":false,"given":"Yukinari","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"},{"name":"New Industry Creation Hatchery Center, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiro","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Second Department of Surgery (Chest Surgery), University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, Fukuoka 807-8555, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/S1470-2045(14)70069-5","article-title":"Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data","volume":"15","author":"Bidard","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3213","DOI":"10.1200\/JCO.2007.15.8923","article-title":"Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer","volume":"26","author":"Cohen","year":"2008","journal-title":"J. Clin. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"6302","DOI":"10.1158\/1078-0432.CCR-08-0872","article-title":"Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer","volume":"14","author":"Scher","year":"2008","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"5701","DOI":"10.1158\/1078-0432.CCR-12-1587","article-title":"Meta-analysis of the prognostic value of circulating tumor cells in breast cancer","volume":"18","author":"Zhang","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.1073\/pnas.0813188106","article-title":"Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device","volume":"106","author":"Talasaz","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Kirby, B.J., Jodari, M., Loftus, M.S., Gakhar, G., Pratt, E.D., Chanel-Vos, C., Gleghorn, J.P., Santana, S.M., Liu, H., and Smith, J.P. (2012). Functional characterization of circulating tumor cells with a prostate-cancer-specific microfluidic device. PLoS ONE, 7.","DOI":"10.1371\/annotation\/9d3d22ed-dc5a-4484-9254-1584864f4aac"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/978-3-642-59349-9_13","article-title":"Detection of circulating tumor cells in blood using an optimized density gradient centrifugation","volume":"162","author":"Gertler","year":"2003","journal-title":"Recent Results Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1158\/1078-0432.CCR-10-0445","article-title":"Preoperative circulating tumor cell detection using the isolation by size of epithelial tumor cell method for patients with lung cancer is a new prognosis biomarker","volume":"17","author":"Hofman","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1039\/b506803g","article-title":"An efficient cell separation system using 3D-asymmetric microelectrodes","volume":"5","author":"Park","year":"2005","journal-title":"Lab. Chip."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6897","DOI":"10.1158\/1078-0432.CCR-04-0378","article-title":"Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases","volume":"10","author":"Allard","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yoneda, K., Tanaka, F., Kondo, N., Hashimoto, M., Takuwa, T., Matsumoto, S., Okumura, Y., Tsubota, N., Sato, A., and Tsujimura, T. (2014). Circulating tumor cells (CTCs) in malignant pleural mesothelioma (MPM). Ann. Surg. Oncol., S472\u2013S480.","DOI":"10.1245\/s10434-013-3399-2"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s10544-013-9775-7","article-title":"Polymeric microfluidic devises exhibiting sufficient capture of cancer cell line for isolation of circulating tumor cells","volume":"15","author":"Ohnaga","year":"2013","journal-title":"Biomed. Microdevices"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"12005","DOI":"10.1038\/s41598-018-30511-9","article-title":"Highly efficient capture of cancer cells expressing EGFR by microfluidic methods based on antigen-antibody association","volume":"8","author":"Ohnaga","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"77","DOI":"10.3892\/or.2016.5235","article-title":"Capture of mesothelioma cells with a \u201cUniversal CTC-chip\u201d","volume":"37","author":"Chikaishi","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_15","first-page":"2635","article-title":"Capture of mesothelioma cells with \u2018universal\u2019 CTC-chip","volume":"15","author":"Yoneda","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1111\/cas.13895","article-title":"Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma","volume":"110","author":"Yoneda","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3546","DOI":"10.1093\/emboj\/cdg342","article-title":"T1alpha\/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema","volume":"22","author":"Schacht","year":"2003","journal-title":"EMBO J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/S0012-1606(02)00098-2","article-title":"T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth","volume":"256","author":"Ramirez","year":"2003","journal-title":"Dev. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"51599","DOI":"10.1074\/jbc.M309935200","article-title":"Molecular identification of Aggrus\/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors","volume":"278","author":"Kato","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1007\/s00401-006-0063-y","article-title":"Increased expression of podoplanin in malignant astrocytic tumors as a novel molecular marker of malignant progression","volume":"111","author":"Mishima","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8552","DOI":"10.1038\/sj.onc.1207869","article-title":"Aggrus: A diagnostic marker that distinguishes seminoma from embryonal carcinoma in testicular germ cell tumors","volume":"23","author":"Kato","year":"2004","journal-title":"Oncogene"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1159\/000086952","article-title":"Enhanced expression of Aggrus (T1alpha\/podoplanin), a platelet-aggregation-inducing factor in lung squamous cell carcinoma","volume":"26","author":"Kato","year":"2005","journal-title":"Tumour Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.nucmedbio.2010.03.010","article-title":"Evaluation of anti-podoplanin rat monocle antibody NZ-1 for targeting malignant gliomas","volume":"37","author":"Kato","year":"2010","journal-title":"Nucl. Med. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1111\/j.1440-1827.2005.01791.x","article-title":"Podoplanin as a marker for mesothelioma","volume":"55","author":"Kimura","year":"2005","journal-title":"Pathol. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6239","DOI":"10.4049\/jimmunol.1300448","article-title":"A novel targeting therapy of malignant mesothelioma using anti-podoplanin antibody","volume":"190","author":"Abe","year":"2013","journal-title":"J. Immunol."},{"key":"ref_26","first-page":"5437","article-title":"Characterization of metastatic clones derived from a metastatic variant of mouse colon adenocarcinoma 26","volume":"43","author":"Tsuruo","year":"1983","journal-title":"Cancer Res."},{"key":"ref_27","first-page":"921","article-title":"Suppression of experimental lung colonization of a metastatic variant of murine colon adenocarcinoma 26 by a monoclonal antibody 8F11 inhibiting tumor cell-induced platelet aggregation","volume":"51","author":"Sugimoto","year":"1991","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.ccr.2006.03.010","article-title":"Tumor invasion in the absence of epithelial-mesenchymal transition: Podplanin-mediated remodeling of the actin cytoskeleton","volume":"9","author":"Wicki","year":"2006","journal-title":"Cancer Cell."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4541","DOI":"10.1242\/jcs.03218","article-title":"Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymeal transition","volume":"119","author":"Megias","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/j.bbrc.2006.08.171","article-title":"Inhibition of tumor cell-induced platelet aggregation using a novel anti-podoplanin antibody reacting with its platelet- aggregation-stimulating domain","volume":"349","author":"Kato","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"89","DOI":"10.5858\/arpa.2017-0124-RA","article-title":"Guidelines for Pathologic Diagnosis of Malignant Mesothelioma 2017 Update of the Consensus Statement From the International Mesothelioma Interest Group","volume":"142","author":"Husain","year":"2018","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.humpath.2005.01.019","article-title":"D2-40 and podoplanin are highly specific and sensitive immunohistochemical markers of epithelioid malignant mesothelioma","volume":"36","year":"2005","journal-title":"Hum. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/modpathol.3800736","article-title":"D2-40 and calretinin\u2014A tissue microarray analysis of 341 malignant mesotheliomas with emphasis on sarcomatoid differentiation","volume":"20","author":"Hinterberger","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1097\/PAS.0b013e31814faacf","article-title":"Podoplanin is a better immunohistochemical marker for sarcomatoid mesothelioma than calretinin","volume":"32","author":"Padgett","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151","DOI":"10.3233\/CBM-140448","article-title":"Detection of circulating tumour cells in peripheral blood of patients with malignant pleural mesothelioma","volume":"15","author":"Raphael","year":"2015","journal-title":"Cancer Biomark."},{"key":"ref_36","first-page":"2565","article-title":"Detection and cultivation of circulating tumor cells in malignant pleural mesothelioma","volume":"34","author":"Bobek","year":"2014","journal-title":"Anticancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1080\/17425247.2019.1598374","article-title":"Epidermal growth factor receptor (EGFR)-targeted therapies in mesothelioma","volume":"16","author":"Chia","year":"2019","journal-title":"Exp. Opin. Drug Deliv."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.lungcan.2005.10.016","article-title":"EGFR overexpression in malignant pleural mesothelioma. An immunohistochemical and molecular study with clinico-pathological correlations","volume":"51","author":"Destro","year":"2006","journal-title":"Lung Cancer."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3322\/caac.21572","article-title":"Mesothelioma: Scientific clues for prevention, diagnosis, and therapy","volume":"69","author":"Carbone","year":"2019","journal-title":"CA Cancer J. Clin."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/888\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:15:45Z","timestamp":1760174145000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/4\/888"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,5]]},"references-count":39,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["cells9040888"],"URL":"https:\/\/doi.org\/10.3390\/cells9040888","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,5]]}}}