{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T07:59:07Z","timestamp":1790668747378,"version":"4.1.0"},"reference-count":71,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T00:00:00Z","timestamp":1615420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["OTKA-PD111656"],"award-info":[{"award-number":["OTKA-PD111656"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["OTKA 132225 ANN"],"award-info":[{"award-number":["OTKA 132225 ANN"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012550","name":"Nemzeti Kutat\u00e1si, Fejleszt\u00e9si \u00e9s Innovaci\u00f3s Alap","doi-asserted-by":"publisher","award":["OTKA-KH130356"],"award-info":[{"award-number":["OTKA-KH130356"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"name":"J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences"},{"name":"The Mats Paulsson Trust"},{"name":"The Stefan Paulsson Trust"},{"DOI":"10.13039\/501100004635","name":"Fru Berta Kamprads Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004635","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF I3977"],"award-info":[{"award-number":["FWF I3977"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["FWF I3522"],"award-info":[{"award-number":["FWF I3522"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"\u00daNKP-19-4 New National Excellence Program of the Ministry for Innovation and Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Apelin, a ligand of the APJ receptor, is overexpressed in several human cancers and plays an important role in tumor angiogenesis and growth in various experimental systems. We investigated the role of apelin signaling in the malignant behavior of cutaneous melanoma. Murine B16 and human A375 melanoma cell lines were stably transfected with apelin encoding or control vectors. Apelin overexpression significantly increased melanoma cell migration and invasion in vitro, but it had no impact on its proliferation. In our in vivo experiments, apelin significantly increased the number and size of lung metastases of murine melanoma cells. Melanoma cell proliferation rates and lymph and blood microvessel densities were significantly higher in the apelin-overexpressing pulmonary metastases. APJ inhibition by the competitive APJ antagonist MM54 significantly attenuated the in vivo pro-tumorigenic effects of apelin. Additionally, we detected significantly elevated circulating apelin and VEGF levels in patients with melanoma compared to healthy controls. Our results show that apelin promotes blood and lymphatic vascularization and the growth of pulmonary metastases of skin melanoma. Further studies are warranted to validate apelin signaling as a new potential therapeutic target in this malignancy.<\/jats:p>","DOI":"10.1038\/s41598-021-85162-0","type":"journal-article","created":{"date-parts":[[2021,3,11]],"date-time":"2021-03-11T11:03:49Z","timestamp":1615460629000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Apelin promotes blood and lymph vessel formation and the growth of melanoma lung metastasis"],"prefix":"10.1038","volume":"11","author":[{"given":"Judit","family":"Berta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szilvia","family":"T\u00f6r\u00f6k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia","family":"T\u00e1rnoki-Z\u00e1ch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orsolya","family":"Drozdovszky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f3zsef","family":"T\u00f3v\u00e1ri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e1ndor","family":"Paku","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ildik\u00f3","family":"Kov\u00e1cs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e1s","family":"Czir\u00f3k","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernard","family":"Masri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zsolt","family":"Megyesfalvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henriett","family":"Oskol\u00e1s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Malm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ingvar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gy\u00f6rgy","family":"Mark\u00f3-Varga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bal\u00e1zs","family":"D\u00f6me","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikt\u00f3ria","family":"L\u00e1szl\u00f3","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,11]]},"reference":[{"key":"85162_CR1","first-page":"852","volume":"1","author":"MS Emmett","year":"2011","unstructured":"Emmett, M. S., Dewing, D. & Pritchard-Jones, R. O. Angiogenesis and melanoma\u2014from basic science to clinical trials. Am. J. Cancer Res.  1, 852\u2013868 (2011).","journal-title":"Am. J. Cancer Res."},{"key":"85162_CR2","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/1741-7015-10-23","volume":"10","author":"L Finn","year":"2012","unstructured":"Finn, L., Markovic, S. N. & Joseph, R. W. Therapy for metastatic melanoma: the past, present, and future. BMC Med. 10, 23. https:\/\/doi.org\/10.1186\/1741-7015-10-23 (2012).","journal-title":"BMC Med."},{"key":"85162_CR3","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1023\/A:1013123532723","volume":"20","author":"D Grossman","year":"2001","unstructured":"Grossman, D. & Altieri, D. C. Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev. 20, 3\u201311 (2001).","journal-title":"Cancer Metastasis Rev."},{"key":"85162_CR4","doi-asserted-by":"publisher","first-page":"2507","DOI":"10.1056\/NEJMoa1103782","volume":"364","author":"PB Chapman","year":"2011","unstructured":"Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 364, 2507\u20132516. https:\/\/doi.org\/10.1056\/NEJMoa1103782 (2011).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR5","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1056\/NEJMoa1412082","volume":"372","author":"C Robert","year":"2015","unstructured":"Robert, C. et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 372, 320\u2013330. https:\/\/doi.org\/10.1056\/NEJMoa1412082 (2015).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR6","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1056\/NEJMoa1904059","volume":"381","author":"C Robert","year":"2019","unstructured":"Robert, C. et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. N. Engl. J. Med. 381, 626\u2013636. https:\/\/doi.org\/10.1056\/NEJMoa1904059 (2019).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR7","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1056\/NEJMoa1412690","volume":"372","author":"C Robert","year":"2015","unstructured":"Robert, C. et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 372, 30\u201339. https:\/\/doi.org\/10.1056\/NEJMoa1412690 (2015).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR8","doi-asserted-by":"publisher","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","volume":"372","author":"C Robert","year":"2015","unstructured":"Robert, C. et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N. Engl. J. Med. 372, 2521\u20132532. https:\/\/doi.org\/10.1056\/NEJMoa1503093 (2015).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR9","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1056\/NEJMoa1104621","volume":"364","author":"C Robert","year":"2011","unstructured":"Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517\u20132526. https:\/\/doi.org\/10.1056\/NEJMoa1104621 (2011).","journal-title":"N. Engl. J. Med."},{"key":"85162_CR10","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","volume":"251","author":"K Tatemoto","year":"1998","unstructured":"Tatemoto, K. et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251, 471\u2013476. https:\/\/doi.org\/10.1006\/bbrc.1998.9489 (1998).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"85162_CR11","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.pharmthera.2005.04.001","volume":"107","author":"MJ Kleinz","year":"2005","unstructured":"Kleinz, M. J. & Davenport, A. P. Emerging roles of apelin in biology and medicine. Pharmacol. Ther. 107, 198\u2013211. https:\/\/doi.org\/10.1016\/j.pharmthera.2005.04.001 (2005).","journal-title":"Pharmacol. Ther."},{"key":"85162_CR12","first-page":"112","volume":"12","author":"J Beltowski","year":"2006","unstructured":"Beltowski, J. Apelin and visfatin: unique \u201cbeneficial\u201d adipokines upregulated in obesity?. Med. Sci. Monit. 12, 112\u2013119 (2006).","journal-title":"Med. Sci. Monit."},{"key":"85162_CR13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1080\/14728222.2019.1561871","volume":"23","author":"I Castan-Laurell","year":"2019","unstructured":"Castan-Laurell, I., Masri, B. & Valet, P. The apelin\/APJ system as a therapeutic target in metabolic diseases. Expert Opin. Ther. Targets 23, 215\u2013225. https:\/\/doi.org\/10.1080\/14728222.2019.1561871 (2019).","journal-title":"Expert Opin. Ther. Targets"},{"key":"85162_CR14","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1139\/bcb-2014-0072","volume":"92","author":"NA Chapman","year":"2014","unstructured":"Chapman, N. A., Dupre, D. J. & Rainey, J. K. The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR. Biochem. Cell Biol. 92, 431\u2013440. https:\/\/doi.org\/10.1139\/bcb-2014-0072 (2014).","journal-title":"Biochem. Cell Biol."},{"key":"85162_CR15","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1161\/CIRCRESAHA.108.179333","volume":"103","author":"M Eyries","year":"2008","unstructured":"Eyries, M. et al. Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circ. Res. 103, 432\u2013440. https:\/\/doi.org\/10.1161\/CIRCRESAHA.108.179333 (2008).","journal-title":"Circ. Res."},{"key":"85162_CR16","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.bbrc.2004.10.042","volume":"325","author":"A Kasai","year":"2004","unstructured":"Kasai, A. et al. Apelin is a novel angiogenic factor in retinal endothelial cells. Biochem. Biophys. Res. Commun. 325, 395\u2013400. https:\/\/doi.org\/10.1016\/j.bbrc.2004.10.042 (2004).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"85162_CR17","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.ydbio.2006.04.452","volume":"296","author":"CM Cox","year":"2006","unstructured":"Cox, C. M., D\u2019Agostino, S. L., Miller, M. K., Heimark, R. L. & Krieg, P. A. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev. Biol. 296, 177\u2013189. https:\/\/doi.org\/10.1016\/j.ydbio.2006.04.452 (2006).","journal-title":"Dev. Biol."},{"key":"85162_CR18","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.regpep.2003.11.002","volume":"118","author":"MJ Kleinz","year":"2004","unstructured":"Kleinz, M. J. & Davenport, A. P. Immunocytochemical localization of the endogenous vasoactive peptide apelin to human vascular and endocardial endothelial cells. Regul. Pept. 118, 119\u2013125. https:\/\/doi.org\/10.1016\/j.regpep.2003.11.002 (2004).","journal-title":"Regul. Pept."},{"key":"85162_CR19","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.ydbio.2007.03.004","volume":"305","author":"RE Kalin","year":"2007","unstructured":"Kalin, R. E. et al. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev. Biol. 305, 599\u2013614. https:\/\/doi.org\/10.1016\/j.ydbio.2007.03.004 (2007).","journal-title":"Dev. Biol."},{"key":"85162_CR20","doi-asserted-by":"publisher","first-page":"7692","DOI":"10.1038\/sj.onc.1210573","volume":"26","author":"SC Sorli","year":"2007","unstructured":"Sorli, S. C., Le Gonidec, S., Knibiehler, B. & Audigier, Y. Apelin is a potent activator of tumour neoangiogenesis. Oncogene 26, 7692\u20137699. https:\/\/doi.org\/10.1038\/sj.onc.1210573 (2007).","journal-title":"Oncogene"},{"key":"85162_CR21","doi-asserted-by":"publisher","first-page":"1120","DOI":"10.1097\/JTO.0b013e3181e2c1ff","volume":"5","author":"J Berta","year":"2010","unstructured":"Berta, J. et al. Apelin expression in human non-small cell lung cancer: role in angiogenesis and prognosis. J. Thorac. Oncol. 5, 1120\u20131129. https:\/\/doi.org\/10.1097\/JTO.0b013e3181e2c1ff (2010).","journal-title":"J. Thorac. Oncol."},{"key":"85162_CR22","doi-asserted-by":"publisher","first-page":"3254","DOI":"10.1038\/onc.2011.489","volume":"31","author":"H Kidoya","year":"2012","unstructured":"Kidoya, H. et al. The apelin\/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. Oncogene 31, 3254\u20133264. https:\/\/doi.org\/10.1038\/onc.2011.489 (2012).","journal-title":"Oncogene"},{"key":"85162_CR23","doi-asserted-by":"publisher","first-page":"e9266","DOI":"10.15252\/emmm.201809266","volume":"11","author":"I Uribesalgo","year":"2019","unstructured":"Uribesalgo, I. et al. Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO Mol. Med. 11, e9266. https:\/\/doi.org\/10.15252\/emmm.201809266 (2019).","journal-title":"EMBO Mol. Med."},{"key":"85162_CR24","doi-asserted-by":"publisher","first-page":"4426","DOI":"10.18632\/oncotarget.2032","volume":"5","author":"J Berta","year":"2014","unstructured":"Berta, J. et al. Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget 5, 4426\u20134437. https:\/\/doi.org\/10.18632\/oncotarget.2032 (2014).","journal-title":"Oncotarget"},{"key":"85162_CR25","doi-asserted-by":"publisher","first-page":"619649","DOI":"10.1155\/2014\/619649","volume":"2014","author":"D Diakowska","year":"2014","unstructured":"Diakowska, D., Markocka-Maczka, K., Szelachowski, P. & Grabowski, K. Serum levels of resistin, adiponectin, and apelin in gastroesophageal cancer patients. Dis. Markers. 2014, 619649. https:\/\/doi.org\/10.1155\/2014\/619649 (2014).","journal-title":"Dis. Markers."},{"key":"85162_CR26","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1186\/s12885-016-2815-y","volume":"16","author":"M Feng","year":"2016","unstructured":"Feng, M., Yao, G., Yu, H., Qing, Y. & Wang, K. Tumor apelin, not serum apelin, is associated with the clinical features and prognosis of gastric cancer. BMC Cancer 16, 794. https:\/\/doi.org\/10.1186\/s12885-016-2815-y (2016).","journal-title":"BMC Cancer"},{"key":"85162_CR27","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.oraloncology.2011.12.015","volume":"48","author":"K Heo","year":"2012","unstructured":"Heo, K. et al. Hypoxia-induced up-regulation of apelin is associated with a poor prognosis in oral squamous cell carcinoma patients. Oral Oncol. 48, 500\u2013506. https:\/\/doi.org\/10.1016\/j.oraloncology.2011.12.015 (2012).","journal-title":"Oral Oncol."},{"key":"85162_CR28","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1007\/s10238-014-0272-y","volume":"15","author":"A Lacquaniti","year":"2015","unstructured":"Lacquaniti, A. et al. Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation. Clin. Exp. Med. 15, 97\u2013105. https:\/\/doi.org\/10.1007\/s10238-014-0272-y (2015).","journal-title":"Clin. Exp. Med."},{"issue":"5","key":"85162_CR29","first-page":"5559","volume":"10","author":"Y Ni","year":"2017","unstructured":"Ni, Y. et al. Apelin is a novel circulating biomarker for the diagnosis of lung cancer. Int. J. Clin. Exp. Pathol. 10(5), 5559\u20135565 (2017).","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"85162_CR30","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.humpath.2014.10.027","volume":"46","author":"Y Wan","year":"2015","unstructured":"Wan, Y. et al. Dysregulated microRNA-224\/apelin axis associated with aggressive progression and poor prognosis in patients with prostate cancer. Hum. Pathol. 46, 295\u2013303. https:\/\/doi.org\/10.1016\/j.humpath.2014.10.027 (2015).","journal-title":"Hum. Pathol."},{"key":"85162_CR31","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.cca.2016.04.001","volume":"457","author":"Y Yang","year":"2016","unstructured":"Yang, Y., Lv, S. Y., Ye, W. & Zhang, L. Apelin\/APJ system and cancer. Clin. Chim. Acta Int. J. Clin. Chem. 457, 112\u2013116. https:\/\/doi.org\/10.1016\/j.cca.2016.04.001 (2016).","journal-title":"Clin. Chim. Acta Int. J. Clin. Chem."},{"key":"85162_CR32","doi-asserted-by":"publisher","first-page":"4586405","DOI":"10.1155\/2019\/4586405","volume":"2019","author":"L Yang","year":"2019","unstructured":"Yang, L., Li, Y. L., Li, X. Q. & Zhang, Z. High Apelin level indicates a poor prognostic factor in muscle-invasive bladder cancer. Dis. Markers 2019, 4586405. https:\/\/doi.org\/10.1155\/2019\/4586405 (2019).","journal-title":"Dis. Markers"},{"key":"85162_CR33","doi-asserted-by":"publisher","first-page":"5246","DOI":"10.7150\/thno.34713","volume":"9","author":"H Chen","year":"2019","unstructured":"Chen, H. et al. APLN promotes hepatocellular carcinoma through activating PI3K\/Akt pathway and is a druggable target. Theranostics 9, 5246\u20135260. https:\/\/doi.org\/10.7150\/thno.34713 (2019).","journal-title":"Theranostics"},{"key":"85162_CR34","first-page":"5313","volume":"34","author":"J Muto","year":"2014","unstructured":"Muto, J. et al. The apelin-APJ system induces tumor arteriogenesis in hepatocellular carcinoma. Anticancer Res. 34, 5313\u20135320 (2014).","journal-title":"Anticancer Res."},{"key":"85162_CR35","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.29560","author":"M Vachher","year":"2019","unstructured":"Vachher, M., Arora, K., Burman, A. & Kumar, B. NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas. J. Cell Biochem. https:\/\/doi.org\/10.1002\/jcb.29560 (2019).","journal-title":"J. Cell Biochem."},{"key":"85162_CR36","doi-asserted-by":"publisher","first-page":"57","DOI":"10.5152\/eurasianjmed.2018.18411","volume":"51","author":"M Aktan","year":"2019","unstructured":"Aktan, M. & Ozmen, H. K. A preliminary study of serum apelin levels in patients with head and neck cancer. Eurasian J. Med. 51, 57\u201359. https:\/\/doi.org\/10.5152\/eurasianjmed.2018.18411 (2019).","journal-title":"Eurasian J. Med."},{"key":"85162_CR37","first-page":"1419","volume":"21","author":"T Salman","year":"2016","unstructured":"Salman, T. et al. Serum apelin levels and body composition changes in breast cancer patients treated with an aromatase inhibitor. J BUON 21, 1419\u20131424 (2016).","journal-title":"J BUON"},{"key":"85162_CR38","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8101513","author":"M Podgorska","year":"2019","unstructured":"Podgorska, M., Diakowska, D., Pietraszek-Gremplewicz, K., Nienartowicz, M. & Nowak, D. Evaluation of apelin and apelin receptor level in the primary tumor and serum of colorectal cancer patients. J. Clin. Med. https:\/\/doi.org\/10.3390\/jcm8101513 (2019).","journal-title":"J. Clin. Med."},{"key":"85162_CR39","doi-asserted-by":"publisher","first-page":"1378","DOI":"10.1158\/1541-7786.MCR-18-0989","volume":"17","author":"D Neelakantan","year":"2019","unstructured":"Neelakantan, D. et al. Multifunctional APJ pathway promotes ovarian cancer progression and metastasis. Mol. Cancer Res. 17, 1378\u20131390. https:\/\/doi.org\/10.1158\/1541-7786.MCR-18-0989 (2019).","journal-title":"Mol. Cancer Res."},{"key":"85162_CR40","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1054\/bjoc.2000.1335","volume":"83","author":"F Leo","year":"2000","unstructured":"Leo, F. et al. Lung metastases from melanoma: when is surgical treatment warranted?. Br. J. Cancer 83, 569\u2013572. https:\/\/doi.org\/10.1054\/bjoc.2000.1335 (2000).","journal-title":"Br. J. Cancer"},{"issue":"Suppl 3","key":"85162_CR41","doi-asserted-by":"publisher","first-page":"S274","DOI":"10.3978\/j.issn.2072-1439.2013.08.42","volume":"5","author":"PP Velu","year":"2013","unstructured":"Velu, P. P., Cao, C. & Yan, T. D. Current surgical management of melanoma metastases to the lung. J. Thorac. Dis. 5(Suppl 3), S274-276. https:\/\/doi.org\/10.3978\/j.issn.2072-1439.2013.08.42 (2013).","journal-title":"J. Thorac. Dis."},{"key":"85162_CR42","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1038\/s41416-019-0396-7","volume":"120","author":"Y Tolkach","year":"2019","unstructured":"Tolkach, Y. et al. Apelin and apelin receptor expression in renal cell carcinoma. Br. J. Cancer 120, 633\u2013639. https:\/\/doi.org\/10.1038\/s41416-019-0396-7 (2019).","journal-title":"Br. J. Cancer"},{"key":"85162_CR43","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1038\/nature23477","volume":"548","author":"SJ Patel","year":"2017","unstructured":"Patel, S. J. et al. Identification of essential genes for cancer immunotherapy. Nature 548, 537\u2013542. https:\/\/doi.org\/10.1038\/nature23477 (2017).","journal-title":"Nature"},{"key":"85162_CR44","doi-asserted-by":"publisher","first-page":"19379","DOI":"10.1038\/srep19379","volume":"6","author":"M Samura","year":"2016","unstructured":"Samura, M. et al. Combinatorial treatment with apelin-13 enhances the therapeutic efficacy of a preconditioned cell-based therapy for peripheral ischemia. Sci. Rep. 6, 19379. https:\/\/doi.org\/10.1038\/srep19379 (2016).","journal-title":"Sci. Rep."},{"key":"85162_CR45","first-page":"2227","volume":"19","author":"D Qin","year":"2013","unstructured":"Qin, D., Zheng, X. X. & Jiang, Y. R. Apelin-13 induces proliferation, migration, and collagen I mRNA expression in human RPE cells via PI3K\/Akt and MEK\/Erk signaling pathways. Mol. Vis. 19, 2227\u20132236 (2013).","journal-title":"Mol. Vis."},{"key":"85162_CR46","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1387\/ijdb.092948ow","volume":"54","author":"O De Wever","year":"2010","unstructured":"De Wever, O. et al. Modeling and quantification of cancer cell invasion through collagen type I matrices. Int. J. Dev. Biol. 54, 887\u2013896. https:\/\/doi.org\/10.1387\/ijdb.092948ow (2010).","journal-title":"Int. J. Dev. Biol."},{"key":"85162_CR47","doi-asserted-by":"publisher","DOI":"10.3791\/52686","author":"M Vinci","year":"2015","unstructured":"Vinci, M., Box, C. & Eccles, S. A. Three-dimensional (3D) tumor spheroid invasion assay. J. Vis. Exp.: JoVE https:\/\/doi.org\/10.3791\/52686 (2015).","journal-title":"J. Vis. Exp.: JoVE"},{"key":"85162_CR48","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1093\/abbs\/gmt140","volume":"46","author":"L Yang","year":"2014","unstructured":"Yang, L. et al. ERK1\/2 mediates lung adenocarcinoma cell proliferation and autophagy induced by apelin-13. Acta Biochim. Biophys. Sin. 46, 100\u2013111. https:\/\/doi.org\/10.1093\/abbs\/gmt140 (2014).","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"85162_CR49","doi-asserted-by":"publisher","DOI":"10.1042\/BSR20180905","author":"G Jin","year":"2018","unstructured":"Jin, G. et al. Association of brain natriuretic peptide gene polymorphisms with chronic obstructive pulmonary disease complicated with pulmonary hypertension and its mechanism. Biosci. Rep. https:\/\/doi.org\/10.1042\/BSR20180905 (2018)."},{"key":"85162_CR50","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1093\/abbs\/gmt040","volume":"45","author":"D Lv","year":"2013","unstructured":"Lv, D., Li, H. & Chen, L. Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis. Acta Biochim. Biophys. Sin. 45, 527\u2013533. https:\/\/doi.org\/10.1093\/abbs\/gmt040 (2013).","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"85162_CR51","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/j.rmed.2012.10.026","volume":"107","author":"E Machura","year":"2013","unstructured":"Machura, E. et al. Serum apelin-12 level is elevated in schoolchildren with atopic asthma. Respir. Med. 107, 196\u2013201. https:\/\/doi.org\/10.1016\/j.rmed.2012.10.026 (2013).","journal-title":"Respir. Med."},{"key":"85162_CR52","doi-asserted-by":"publisher","first-page":"557","DOI":"10.3389\/fphys.2018.00557","volume":"9","author":"MB Wysocka","year":"2018","unstructured":"Wysocka, M. B., Pietraszek-Gremplewicz, K. & Nowak, D. The role of apelin in cardiovascular diseases, obesity and cancer.  Front. Physiol. 9, 557. https:\/\/doi.org\/10.3389\/fphys.2018.00557 (2018).","journal-title":"Front. Physiol."},{"key":"85162_CR53","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1016\/j.bbadis.2016.11.007","volume":"1942\u20131950","author":"JC Zhong","year":"1863","unstructured":"Zhong, J. C. et al. Targeting the apelin pathway as a novel therapeutic approach for cardiovascular diseases. Biochim Biophys. Acta Mol. Basis Dis. 1942\u20131950, 2017. https:\/\/doi.org\/10.1016\/j.bbadis.2016.11.007 (1863).","journal-title":"Biochim Biophys. Acta Mol. Basis Dis."},{"key":"85162_CR54","doi-asserted-by":"publisher","first-page":"W556","DOI":"10.1093\/nar\/gkz430","volume":"47","author":"Z Tang","year":"2019","unstructured":"Tang, Z., Kang, B., Li, C., Chen, T. & Zhang, Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 47, W556\u2013W560. https:\/\/doi.org\/10.1093\/nar\/gkz430 (2019).","journal-title":"Nucleic Acids Res."},{"key":"85162_CR55","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1755-8794-2-18","volume":"2","author":"H Mizuno","year":"2009","unstructured":"Mizuno, H., Kitada, K., Nakai, K. & Sarai, A. PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med. Genomics 2, 18. https:\/\/doi.org\/10.1186\/1755-8794-2-18 (2009).","journal-title":"BMC Med. Genomics"},{"key":"85162_CR56","doi-asserted-by":"publisher","first-page":"W509","DOI":"10.1093\/nar\/gkaa407","volume":"48","author":"T Li","year":"2020","unstructured":"Li, T. et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 48, W509\u2013W514. https:\/\/doi.org\/10.1093\/nar\/gkaa407 (2020).","journal-title":"Nucleic Acids Res."},{"key":"85162_CR57","doi-asserted-by":"publisher","DOI":"10.1126\/science.aan2507","author":"M Uhlen","year":"2017","unstructured":"Uhlen, M. et al. A pathology atlas of the human cancer transcriptome. Science https:\/\/doi.org\/10.1126\/science.aan2507 (2017).","journal-title":"Science"},{"key":"85162_CR58","doi-asserted-by":"publisher","first-page":"522","DOI":"10.1038\/sj.emboj.7601982","volume":"27","author":"H Kidoya","year":"2008","unstructured":"Kidoya, H. et al. Spatial and temporal role of the apelin\/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J. 27, 522\u2013534. https:\/\/doi.org\/10.1038\/sj.emboj.7601982 (2008).","journal-title":"EMBO J."},{"key":"85162_CR59","doi-asserted-by":"publisher","first-page":"733","DOI":"10.3892\/ijmm.2015.2265","volume":"36","author":"X Peng","year":"2015","unstructured":"Peng, X. et al. Apelin-13 induces MCF-7 cell proliferation and invasion via phosphorylation of ERK1\/2. Int. J. Mol. Med. 36, 733\u2013738. https:\/\/doi.org\/10.3892\/ijmm.2015.2265 (2015).","journal-title":"Int. J. Mol. Med."},{"key":"85162_CR60","doi-asserted-by":"publisher","DOI":"10.3390\/cells7080113","author":"M Podgorska","year":"2018","unstructured":"Podgorska, M., Pietraszek-Gremplewicz, K. & Nowak, D. Apelin effects migration and invasion abilities of colon cancer cells. Cells https:\/\/doi.org\/10.3390\/cells7080113 (2018).","journal-title":"Cells"},{"key":"85162_CR61","doi-asserted-by":"publisher","first-page":"946","DOI":"10.1002\/ijc.10283","volume":"98","author":"MM Mattila","year":"2002","unstructured":"Mattila, M. M. et al. VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int. J. Cancer 98, 946\u2013951. https:\/\/doi.org\/10.1002\/ijc.10283 (2002).","journal-title":"Int. J. Cancer"},{"key":"85162_CR62","doi-asserted-by":"publisher","first-page":"2939","DOI":"10.1093\/brain\/awx253","volume":"140","author":"E Harford-Wright","year":"2017","unstructured":"Harford-Wright, E. et al. Pharmacological targeting of apelin impairs glioblastoma growth. Brain 140, 2939\u20132954. https:\/\/doi.org\/10.1093\/brain\/awx253 (2017).","journal-title":"Brain"},{"key":"85162_CR63","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1016\/j.drudis.2006.10.011","volume":"11","author":"SC Sorli","year":"2006","unstructured":"Sorli, S. C., van den Berghe, L., Masri, B., Knibiehler, B. & Audigier, Y. Therapeutic potential of interfering with apelin signalling. Drug Discov. Today 11, 1100\u20131106. https:\/\/doi.org\/10.1016\/j.drudis.2006.10.011 (2006).","journal-title":"Drug Discov. Today"},{"key":"85162_CR64","doi-asserted-by":"publisher","first-page":"e0203203","DOI":"10.1371\/journal.pone.0203203","volume":"13","author":"M Gulyas","year":"2018","unstructured":"Gulyas, M., Csiszer, M., Mehes, E. & Czirok, A. Software tools for cell culture-related 3D printed structures. PLoS ONE 13, e0203203. https:\/\/doi.org\/10.1371\/journal.pone.0203203 (2018).","journal-title":"PLoS ONE"},{"key":"85162_CR65","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1007\/s10439-005-3037-7","volume":"33","author":"EA Zamir","year":"2005","unstructured":"Zamir, E. A., Czirok, A., Rongish, B. J. & Little, C. D. A digital image-based method for computational tissue fate mapping during early avian morphogenesis. Ann. Biomed. Eng. 33, 854\u2013865 (2005).","journal-title":"Ann. Biomed. Eng."},{"key":"85162_CR66","doi-asserted-by":"publisher","first-page":"10404","DOI":"10.1038\/s41598-017-10094-7","volume":"7","author":"A Czirok","year":"2017","unstructured":"Czirok, A. et al. Optical-flow based non-invasive analysis of cardiomyocyte contractility. Sci. Rep. 7, 10404. https:\/\/doi.org\/10.1038\/s41598-017-10094-7 (2017).","journal-title":"Sci. Rep."},{"key":"85162_CR67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1109\/10.362924","volume":"42","author":"K Wu","year":"1995","unstructured":"Wu, K., Gauthier, D. & Levine, M. D. Live cell image segmentation. IEEE Trans. Biomed. Eng. 42, 1\u201312 (1995).","journal-title":"IEEE Trans. Biomed. Eng."},{"key":"85162_CR68","doi-asserted-by":"publisher","first-page":"e1005818","DOI":"10.1371\/journal.pcbi.1005818","volume":"13","author":"Z Neufeld","year":"2017","unstructured":"Neufeld, Z. et al. The role of Allee effect in modelling post resection recurrence of glioblastoma. PLoS Comput. Biol. 13, e1005818. https:\/\/doi.org\/10.1371\/journal.pcbi.1005818 (2017).","journal-title":"PLoS Comput. Biol."},{"key":"85162_CR69","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/1471-2342-8-16","volume":"8","author":"MM Jensen","year":"2008","unstructured":"Jensen, M. M., Jorgensen, J. T., Binderup, T. & Kjaer, A. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. BMC Med. Imaging 8, 16. https:\/\/doi.org\/10.1186\/1471-2342-8-16 (2008).","journal-title":"BMC Med. Imaging"},{"key":"85162_CR70","doi-asserted-by":"publisher","DOI":"10.1186\/s40169-016-0086-5","author":"M Truedsson","year":"2016","unstructured":"Truedsson, M. et al. Biomarkers of early chronic obstructive pulmonary disease (COPD) in smokers and former smokers. Protocol of a longitudinal study. Clin. Transl. Med. https:\/\/doi.org\/10.1186\/s40169-016-0086-5 (2016).","journal-title":"Clin. Transl. Med."},{"key":"85162_CR71","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s12953-017-0116-2","volume":"15","author":"J Eriksson","year":"2016","unstructured":"Eriksson, J. et al. Merging clinical chemistry biomarker data with a COPD database\u2014building a clinical infrastructure for proteomic studies. Proteome Sci. 15, 8. https:\/\/doi.org\/10.1186\/s12953-017-0116-2 (2016).","journal-title":"Proteome Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85162-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85162-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85162-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T05:05:36Z","timestamp":1670043936000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-85162-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,11]]},"references-count":71,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["85162"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-85162-0","relation":{"references":[{"id-type":"uri","id":"","asserted-by":"subject"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,11]]},"assertion":[{"value":"28 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5798"}}