{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T22:44:46Z","timestamp":1761864286929,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["CAN 2018\/613"],"award-info":[{"award-number":["CAN 2018\/613"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish National Health Services (ALF)","award":["40615"],"award-info":[{"award-number":["40615"]}]},{"DOI":"10.13039\/501100004635","name":"Fru Berta Kamprads Stiftelse","doi-asserted-by":"publisher","award":["2019-43 and 2019-28"],"award-info":[{"award-number":["2019-43 and 2019-28"]}],"id":[{"id":"10.13039\/501100004635","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007230","name":"Stiftelsen Konung Gustaf V:s Jubileumsfond","doi-asserted-by":"publisher","award":["187011"],"award-info":[{"award-number":["187011"]}],"id":[{"id":"10.13039\/501100007230","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016290","name":"Insamlingsstiftelsen Cancer- och Allergifonden","doi-asserted-by":"publisher","award":["211"],"award-info":[{"award-number":["211"]}],"id":[{"id":"10.13039\/100016290","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011077","name":"Sk\u00e5nes universitetssjukhus","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100011077","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003461","name":"Gunnar Nilssons Cancerstiftelse","doi-asserted-by":"publisher","award":["2018-16-119 and 2019-8-154"],"award-info":[{"award-number":["2018-16-119 and 2019-8-154"]}],"id":[{"id":"10.13039\/501100003461","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Overexpression of the receptor tyrosine kinase MET has been linked to poor survival in several cancer types, and MET has been suggested to interact with stem cell networks. In vitro studies have further suggested a possible benefit of a combined treatment using PARP and MET inhibitors. We used a tissue microarray (TMA) with 130 samples of advanced-stage high-grade serous fallopian tube\/ovarian cancer (HGSC) to investigate the prognostic value of MET protein expression alone and in combination with the stem cell factor SOX2. The possible synergistic effects of a PARP and MET inhibitor treatment were evaluated in two cell lines with BRCA1 or BRCA2 deficiency and in their BRCA1\/2-proficient counterparts. Patients with tumors positive for MET had worse overall survival (log-rank test, p = 0.015) compared to patients with MET-negative tumors. The prognostic role of MET was even more prominent in the subgroup of patients with SOX2-negative tumors (p = 0.0081). No synergistic effects of the combined treatment with PARP and MET inhibitors were found in the cell lines examined. We conclude that MET expression could be used as a marker for OS in HGSC and that stemness should be taken into consideration when evaluating the mechanisms of this effect.<\/jats:p>","DOI":"10.3390\/genes12050742","type":"journal-article","created":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T10:54:22Z","timestamp":1620989662000},"page":"742","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["MET Expression and Cancer Stem Cell Networks Impact Outcome in High-Grade Serous Ovarian Cancer"],"prefix":"10.3390","volume":"12","author":[{"given":"Maria","family":"B\u00e5\u00e5th","sequence":"first","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-7813","authenticated-orcid":false,"given":"Jenny-Maria","family":"J\u00f6nsson","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sofia","family":"Westbom Fremer","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"},{"name":"Department of Surgical Pathology, Division of Laboratory Medicine, Sk\u00e5ne University Hospital, 222 42 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Mart\u00edn de la Fuente","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lena","family":"Tran","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susanne","family":"Malander","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"P\u00e4ivi","family":"Kannisto","sequence":"additional","affiliation":[{"name":"Division of Obstetrics and Gynaecology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 222 42 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1948-4298","authenticated-orcid":false,"given":"Anna","family":"M\u00e5sb\u00e4ck","sequence":"additional","affiliation":[{"name":"Department of Surgical Pathology, Division of Laboratory Medicine, Sk\u00e5ne University Hospital, 222 42 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Honeth","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6840-3397","authenticated-orcid":false,"given":"Ingrid","family":"Hedenfalk","sequence":"additional","affiliation":[{"name":"Division of Oncology, Department of Clinical Sciences Lund, Lund University and Sk\u00e5ne University Hospital, 223 81 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLO-BOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lisio, M.-A., Fu, L., Goyeneche, A., Gao, Z.-H., and Telleria, C. (2019). High-Grade Serous Ovarian Cancer: Basic Sciences, Clinical and Therapeutic Standpoints. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040952"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2495","DOI":"10.1056\/NEJMoa1810858","article-title":"Maintenance Olaparib in Pa-tients with Newly Diagnosed Advanced Ovarian Cancer","volume":"379","author":"Moore","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1016\/S1470-2045(17)30469-2","article-title":"Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1\/2 mutation (SOLO2\/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial","volume":"18","author":"Ledermann","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1056\/NEJMoa1611310","article-title":"Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer","volume":"375","author":"Mirza","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(17)32440-6","article-title":"Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): A randomised, double-blind, placebo-controlled, phase 3 trial","volume":"390","author":"Coleman","year":"2017","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/s41416-018-0271-y","article-title":"Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy","volume":"119","author":"Friedlander","year":"2018","journal-title":"Br. J. 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Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1038\/sj.bjc.6601718","article-title":"The tumour-stromal in-teraction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients","volume":"90","author":"Masuya","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1038\/nm.4032","article-title":"Block-ing c-Met-mediated PARP1 phosphorylation enhances anti-tumor effects of PARP inhibitors","volume":"22","author":"Du","year":"2016","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"198","DOI":"10.7150\/ijbs.17240","article-title":"Reverse the Resistance to PARP Inhibitors","volume":"13","author":"Kim","year":"2017","journal-title":"Int. J. Biol. Sci."},{"key":"ref_15","first-page":"608","article-title":"Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells","volume":"9","author":"Han","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6981","DOI":"10.18632\/oncotarget.27363","article-title":"Crizotinib and PARP inhibitors act synergistically by triggering apoptosis in high-grade serous ovarian cancer","volume":"10","author":"Sahin","year":"2019","journal-title":"Oncotarget"},{"key":"ref_17","first-page":"1667","article-title":"Crizotinib synergizes with cisplatin in preclinical models of ovarian cancer","volume":"9","author":"Huang","year":"2017","journal-title":"Am. J. Transl. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4922","DOI":"10.1158\/0008-5472.CAN-14-1022","article-title":"Epigenetic Targeting of Ovarian Cancer Stem Cells","volume":"74","author":"Wang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1158\/1078-0432.CCR-11-2188","article-title":"Stem Cell Pathways Contribute to Clinical Chemoresistance in Ovarian Cancer","volume":"18","author":"Steg","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1805094","DOI":"10.1080\/23723556.2020.1805094","article-title":"SOX2 is a promising predictor of relapse and death in advanced stage high-grade serous ovarian cancer pa-tients with residual disease after debulking surgery","volume":"7","author":"Ebbesson","year":"2020","journal-title":"Mol. Cell. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3349\/ymj.2018.59.1.35","article-title":"Correlation of Cancer Stem-Cell Markers OCT4, SOX2, and NANOG with Clinicopathological Features and Prognosis in Operative Patients with Rectal Cancer","volume":"59","author":"You","year":"2018","journal-title":"Yonsei Med. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s12032-014-0433-6","article-title":"Prognostic evaluation of Nanog, Oct4, Sox2, PCNA, Ki67 and E-cadherin expression in gastric cancer","volume":"32","author":"Li","year":"2015","journal-title":"Med. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"628","DOI":"10.18632\/genesandcancer.148","article-title":"Correlation between c-Met and ALDH1 contributes to the survival and tumor-sphere formation of ALDH1 positive breast cancer stem cells and predicts poor clinical outcome in breast cancer","volume":"8","author":"Nozaki","year":"2017","journal-title":"Genes Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1158\/1541-7786.MCR-18-0594","article-title":"PARP Inhibition Induces Enrichment of DNA Repair\u2013Proficient CD133 and CD117 Positive Ovarian Cancer Stem Cells","volume":"17","author":"Bellio","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"9951","DOI":"10.1073\/pnas.1016912108","article-title":"c-Met sig-naling induces a reprogramming network and supports the glioblastoma stem-like phenotype","volume":"108","author":"Li","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","unstructured":"Kurman, R.J., Carcangiu, M.L., Herrington, C.S., and Young, R.H. (2014). WHO Classification of Tumours of Female Reproductive Organs, International Agency for Research on Cancer."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijgo.2013.10.001","article-title":"Staging classification for cancer of the ovary, fallopian tube, and peritoneum","volume":"124","author":"Prat","year":"2014","journal-title":"Int. J. Gynecol. Obstet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00428-020-02751-6","article-title":"PD-1\/PD-L1 expression and tumor-infiltrating lymphocytes are prognostically favorable in advanced high-grade serous ovarian carcinoma","volume":"477","author":"Arildsen","year":"2020","journal-title":"Virchows Archiv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/nature10166","article-title":"Integrated genomic analyses of ovarian carcinoma","volume":"474","author":"Bell","year":"2011","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"16910","DOI":"10.1073\/pnas.1009843107","article-title":"ASCAT: Allele-Specific Copy Number Analysis of Tumours. (2018)","volume":"107","author":"Nordgard","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3764","DOI":"10.1158\/1078-0432.CCR-15-2477","article-title":"Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer","volume":"22","author":"Telli","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-017-00921-w","article-title":"Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes","volume":"8","author":"Riaz","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6381","DOI":"10.1158\/0008-5472.CAN-09-1178","article-title":"Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carci-noma","volume":"69","author":"Sakai","year":"2009","journal-title":"Cancer Res."},{"key":"ref_34","unstructured":"R Core Team (2021). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4731","DOI":"10.1073\/pnas.91.11.4731","article-title":"Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor\/scatter factor autocrine stimulation","volume":"91","author":"Rong","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/ncb2048","article-title":"Wnt activity defines colon cancer stem cells and is regulated by the microenvironment","volume":"12","author":"Vermeulen","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yesudhas, D., Batool, M., Anwar, M.A., Panneerselvam, S., and Choi, S. (2017). Proteins Recognizing DNA: Structural Uniqueness and Versatility of DNA-Binding Domains in Stem Cell Transcription Factors. Genes, 8.","DOI":"10.3390\/genes8080192"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3828","DOI":"10.1158\/0008-5472.CAN-11-3760","article-title":"MET sig-naling regulates glioblastoma stem cells","volume":"72","author":"Joo","year":"2012","journal-title":"Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Robinson, M., Gilbert, S.F., Waters, J.A., Lujano-Olazaba, O., Lara, J., Alexander, L.J., Green, S.E., Burkeen, G.A., Patrus, O., and Sarwar, Z. (2020). Characterization of SOX2, OCT4 and NANOG in Ovarian Cancer Tumor-Initiating Cells. bioRxiv.","DOI":"10.1101\/2020.09.08.288381"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-59671-3","article-title":"Homologous recombination deficiency status-based clas-sification of high-grade serous ovarian carcinoma","volume":"10","author":"Takaya","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3389\/fonc.2018.00016","article-title":"Role of BRCA Mutations in the Modulation of Response to Platinum Therapy","volume":"8","author":"Mylavarapu","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4905","DOI":"10.1038\/onc.2010.245","article-title":"Ge-nomic analysis of genetic heterogeneity and evolution in high-grade serous ovarian carcinoma","volume":"29","author":"Cooke","year":"2010","journal-title":"Oncogene"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"120066","DOI":"10.1098\/rsob.120066","article-title":"Cancer drug pan-resistance: Pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what?","volume":"2","author":"Borst","year":"2012","journal-title":"Open Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2512","DOI":"10.1200\/JCO.2009.26.9589","article-title":"Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval","volume":"28","author":"Fong","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1056\/NEJMoa1910962","article-title":"Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer","volume":"381","author":"Pothuri","year":"2019","journal-title":"N. Engl. J. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/742\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:00:57Z","timestamp":1760162457000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/5\/742"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,14]]},"references-count":45,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["genes12050742"],"URL":"https:\/\/doi.org\/10.3390\/genes12050742","relation":{},"ISSN":["2073-4425"],"issn-type":[{"type":"electronic","value":"2073-4425"}],"subject":[],"published":{"date-parts":[[2021,5,14]]}}}