{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:49:15Z","timestamp":1790790555548,"version":"4.1.0"},"reference-count":65,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T00:00:00Z","timestamp":1646352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["Scholarship"],"award-info":[{"award-number":["Scholarship"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["RE1631\/17-1"],"award-info":[{"award-number":["RE1631\/17-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Testicular germ cell cancer (TGCC) is the most common type of cancer in young men. Seminomas account for around half of them and are characterized by a pronounced infiltration of immune cells. So far, the impact of the tumor microenvironment (TME) on disease progression, especially the interaction of individual immune cell subtypes with the tumor cells, remains unclear. To address this question, we used an in vitro TME model involving the seminoma-derived cell line Tcam-2 and immune cell subsets purified from human peripheral blood. T cells and monocytes were strongly activated when individually cocultured with Tcam-2 cells as revealed by increased expression of activation markers and pro-inflammatory cytokines both on the mRNA and protein level. Importantly, the interaction between tumor and immune cells was mutual. Gene expression of pluripotency markers as well as markers of proliferation and cell cycle activity were upregulated in Tcam-2 cells in cocultures with T cells, whereas gene expression of SOX17, a marker for seminomas, was unaltered. Interestingly, the impact of monocytes on gene expression of Tcam-2 cells was less pronounced, indicating that the effects of individual immune cell subsets on tumor cells in the TME are highly specific. Collectively, our data indicate that seminoma cells induce immune cell activation and thereby generate a strong pro-inflammatory milieu, whereas T cells conversely increase the proliferation, metastatic potential, and stemness of tumor cells. Although the employed model does not fully mimic the physiological situation found in TGCC in vivo, it provides new insights potentially explaining the connection between inflammatory infiltrates in seminomas and their tendency to burn out and metastasize.<\/jats:p>","DOI":"10.3390\/cells11050885","type":"journal-article","created":{"date-parts":[[2022,3,6]],"date-time":"2022-03-06T20:35:50Z","timestamp":1646598950000},"page":"885","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A Coculture Model Mimicking the Tumor Microenvironment Unveils Mutual Interactions between Immune Cell Subtypes and the Human Seminoma Cell Line TCam-2"],"prefix":"10.3390","volume":"11","author":[{"given":"Fabian A.","family":"Gayer","sequence":"first","affiliation":[{"name":"Institute for Cellular and Molecular Immunology, University Medical Center G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"},{"name":"Clinic of Urology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Fichtner","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias J.","family":"Legler","sequence":"additional","affiliation":[{"name":"Department of Transfusion Medicine, University Medical Center G\u00f6ttingen, 37075 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4647-057X","authenticated-orcid":false,"given":"Holger M.","family":"Reichardt","sequence":"additional","affiliation":[{"name":"Institute for Cellular and Molecular Immunology, University Medical Center G\u00f6ttingen, 37073 G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1002\/cncr.30597","article-title":"Future of Testicular Germ Cell Tumor Incidence in the United States: Forecast through 2026","volume":"123","author":"Ghazarian","year":"2017","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4448","DOI":"10.1200\/JCO.2002.01.038","article-title":"Prognostic Factors for Relapse in Stage I Seminoma Managed by Surveillance: A Pooled Analysis","volume":"20","author":"Warde","year":"2002","journal-title":"JCO"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1007\/s00018-019-03022-7","article-title":"Testicular Germ Cell Tumor: A Comprehensive Review","volume":"76","author":"Batool","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.eururo.2016.02.029","article-title":"The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours","volume":"70","author":"Moch","year":"2016","journal-title":"Eur. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF00184714","article-title":"The Impact of the \u201cCisplatin Era\u201d Of Treatment on Survival in Testicular Cancer","volume":"9","author":"Moul","year":"1991","journal-title":"World J. Urol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e1305535","DOI":"10.1080\/2162402X.2017.1305535","article-title":"Deep Exploration of the Immune Infiltrate and Outcome Prediction in Testicular Cancer by Quantitative Multiplexed Immunohistochemistry and Gene Expression Profiling","volume":"6","author":"Siska","year":"2017","journal-title":"Oncoimmunology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jri.2013.10.005","article-title":"Phenotypic Characterisation of Immune Cell Infiltrates in Testicular Germ Cell Neoplasia","volume":"100","author":"Hvarness","year":"2013","journal-title":"J. Reprod. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/j.ucl.2015.04.001","article-title":"Epidemiology and Diagnosis of Testis Cancer","volume":"42","author":"Stevenson","year":"2015","journal-title":"Urol. Clin. N. Am."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lobo, J., Rodrigues, \u00c2., Guimar\u00e3es, R., Cantante, M., Lopes, P., Maur\u00edcio, J., Oliveira, J., Jer\u00f3nimo, C., and Henrique, R. (2019). Detailed Characterization of Immune Cell Infiltrate and Expression of Immune Checkpoint Molecules PD-L1\/CTLA-4 and MMR Proteins in Testicular Germ Cell Tumors Disclose Novel Disease Biomarkers. Cancers, 11.","DOI":"10.3390\/cancers11101535"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1016\/S0959-8049(02)00235-6","article-title":"The Prognostic Significance of the Tumour Infiltrating Lymphocyte Count in Stage I Testicular Seminoma Managed by Surveillance","volume":"38","author":"Parker","year":"2002","journal-title":"Eur. J. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1159\/000480493","article-title":"Burned-Out Testicular Cancer: Really a Different History?","volume":"10","author":"Mosillo","year":"2017","journal-title":"Case Rep. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1007\/s13193-012-0207-6","article-title":"Burned out Seminomatous Testicular Tumor with Retroperitoneal Lymph Node Metastasis: A Case Report","volume":"4","author":"Sahoo","year":"2013","journal-title":"Indian J. Surg. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2665","DOI":"10.1038\/bjc.2013.610","article-title":"Prognostic Impact of Tumour-Infiltrating Immune Cells on Biliary Tract Cancer","volume":"109","author":"Goeppert","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1586\/14737140.8.4.561","article-title":"Immune Cells in Colorectal Cancer: Prognostic Relevance and Therapeutic Strategies","volume":"8","author":"Atreya","year":"2008","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1111\/pcmr.12371","article-title":"Prognostic and Predictive Significance of Immune Cells Infiltrating Cutaneous Melanoma","volume":"28","year":"2015","journal-title":"Pigment Cell Melanoma Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Dieci, M.V., Miglietta, F., and Guarneri, V. (2021). Immune Infiltrates in Breast Cancer: Recent Updates and Clinical Implications. Cells, 10.","DOI":"10.3390\/cells10020223"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1186\/s40169-014-0041-2","article-title":"The Significance of Macrophage Phenotype in Cancer and Biomaterials","volume":"3","author":"Bygd","year":"2014","journal-title":"Clin. Transl. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"173090","DOI":"10.1016\/j.ejphar.2020.173090","article-title":"Macrophage M1\/M2 Polarization","volume":"877","author":"Yunna","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"583084","DOI":"10.3389\/fimmu.2020.583084","article-title":"Tumor-Associated Macrophages in Tumor Immunity","volume":"11","author":"Pan","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_20","first-page":"295","article-title":"Macrophages Lysing Seminoma Cells in Patients with Carcinoma-in-Situ (CIS) of the Testis","volume":"20","author":"Holstein","year":"1988","journal-title":"Andrologia"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2654","DOI":"10.1056\/NEJMoa051424","article-title":"Effector Memory T Cells, Early Metastasis, and Survival in Colorectal Cancer","volume":"353","author":"Berger","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1126\/science.1129139","article-title":"Type, Density, and Location of Immune Cells within Human Colorectal Tumors Predict Clinical Outcome","volume":"313","author":"Galon","year":"2006","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.3389\/fimmu.2017.01225","article-title":"Peripheral Leukocytosis Is Inversely Correlated with Intratumoral CD8+ T-Cell Infiltration and Associated with Worse Outcome after Chemoradiotherapy in Anal Cancer","volume":"8","author":"Martin","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/(SICI)1096-9896(199707)182:3<318::AID-PATH862>3.0.CO;2-6","article-title":"Prognostic Value of Tumour-Infiltrating Lymphocytes (TILs) in Colorectal Cancer","volume":"182","author":"Ropponen","year":"1997","journal-title":"J. Pathol."},{"key":"ref_25","first-page":"3491","article-title":"CD8+ T Cells Infiltrated within Cancer Cell Nests as a Prognostic Factor in Human Colorectal Cancer","volume":"58","author":"Naito","year":"1998","journal-title":"Cancer Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/ijc.21894","article-title":"thor Tumor Infiltrating Lymphocytes in Seminoma Lesions Comprise Clonally Expanded Cytotoxic T Cells","volume":"119","author":"Hadrup","year":"2006","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1002\/path.996","article-title":"Activated Status of Tumour-Infiltrating Lymphocytes and Apoptosis in Testicular Seminoma","volume":"196","author":"Yakirevich","year":"2002","journal-title":"J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1232","DOI":"10.1002\/eji.201646898","article-title":"Spontaneous CD4+ and CD8+ T-cell Responses Directed against Cancer Testis Antigens Are Present in the Peripheral Blood of Testicular Cancer Patients","volume":"47","author":"Pearce","year":"2017","journal-title":"Eur. J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1002\/gcc.20520","article-title":"Further Characterization of the First Seminoma Cell Line TCam-2","volume":"47","author":"Stoop","year":"2008","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Nettersheim, D., Jostes, S., Sharma, R., Schneider, S., Hofmann, A., Ferreira, H.J., Hoffmann, P., Kristiansen, G., Esteller, M.B., and Schorle, H. (2015). BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma. PLoS Genet., 11.","DOI":"10.1371\/journal.pgen.1005415"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47095","DOI":"10.18632\/oncotarget.9903","article-title":"SOX2 Is Essential for in Vivo Reprogramming of Seminoma-like TCam-2 Cells to an Embryonal Carcinoma-like Fate","volume":"7","author":"Nettersheim","year":"2016","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1093\/humrep\/dew211","article-title":"Specific Immune Cell and Cytokine Characteristics of Human Testicular Germ Cell Neoplasia","volume":"31","author":"Klein","year":"2016","journal-title":"Hum. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1111\/andr.12365","article-title":"An In Vitro Model Demonstrates the Potential of Neoplastic Human Germ Cells to Influence the Tumour Microenvironment","volume":"5","author":"Klein","year":"2017","journal-title":"Andrology"},{"key":"ref_34","first-page":"1211","article-title":"Establishment and characterization of a new human testicular germ cell tumor cell line (TCam-2)","volume":"84","author":"Mizuno","year":"1993","journal-title":"Nihon Hinyokika Gakkai Zasshi"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7845","DOI":"10.4049\/jimmunol.174.12.7845","article-title":"Sustained Pre-TCR Expression in Notch1IC-Transgenic Rats Impairs T Cell Maturation and Selection","volume":"174","author":"Kwon","year":"2005","journal-title":"J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2935","DOI":"10.1021\/acs.nanolett.9b00021","article-title":"Reprogramming Tumor Immune Microenvironment (TIME) and Metabolism via Biomimetic Targeting Codelivery of Shikonin\/JQ1","volume":"19","author":"Wang","year":"2019","journal-title":"Nano Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1016\/j.immuni.2021.01.012","article-title":"Chemokines and the Immune Response to Cancer","volume":"54","author":"Ozga","year":"2021","journal-title":"Immunity"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/s12094-015-1373-0","article-title":"Tumor-Associated Macrophages in Cancers","volume":"18","author":"Hu","year":"2016","journal-title":"Clin. Transl. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0092-8674(01)00237-9","article-title":"The TNF and TNF Receptor Superfamilies: Integrating Mammalian Biology","volume":"104","author":"Locksley","year":"2001","journal-title":"Cell"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1056\/NEJM199606273342607","article-title":"The Tumor Necrosis Factor Ligand and Receptor Families","volume":"334","author":"Bazzoni","year":"1996","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s00441-007-0527-y","article-title":"TCam-2 but Not JKT-1 Cells Resemble Seminoma in Cell Culture","volume":"331","author":"Eckert","year":"2008","journal-title":"Cell Tissue Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1111\/jcmm.13082","article-title":"The Plasticity of Germ Cell Cancers and Its Dependence on the Cellular Microenvironment","volume":"21","author":"Nettersheim","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41416-020-0891-x","article-title":"CDK4\/6 Inhibition Presents as a Therapeutic Option for Paediatric and Adult Germ Cell Tumours and Induces Cell Cycle Arrest and Apoptosis via Canonical and Non-Canonical Mechanisms","volume":"123","author":"Skowron","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1002\/gcc.21958","article-title":"Establishment of a Versatile Seminoma Model Indicates Cellular Plasticity of Germ Cell Tumor Cells","volume":"51","author":"Nettersheim","year":"2012","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and Function of Interleukin-2 in T Lymphocytes","volume":"36","author":"Ross","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_46","first-page":"111","article-title":"Cancer Stem Cell Niche and Immune-Active Tumor Microenvironment in Testicular Germ Cell Tumors","volume":"1226","author":"Kalavska","year":"2020","journal-title":"Tumor Microenviron. Organs"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1089\/ars.2007.1576","article-title":"Gating the Radical Hemoglobin to Macrophages: The Anti-Inflammatory Role of CD163, a Scavenger Receptor","volume":"9","author":"Schaer","year":"2007","journal-title":"Antioxid. Redox Signal."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1002\/jlb.67.1.97","article-title":"Regulation of Scavenger Receptor CD163 Expression in Human Monocytes and Macrophages by Pro- and Antiinflammatory Stimuli","volume":"67","author":"Buechler","year":"2000","journal-title":"J. Leukoc. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/j.1600-0765.1989.tb00864.x","article-title":"Phenotypic Dynamics of Macrophage Subpopulations during Human Experimental Gingivitis","volume":"24","author":"Topoll","year":"1989","journal-title":"J. Periodontal. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1089\/ars.2012.4834","article-title":"CD163 and Inflammation: Biological, Diagnostic, and Therapeutic Aspects","volume":"18","author":"Etzerodt","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1111\/cas.13244","article-title":"M2-like Macrophage Polarization in High Lactic Acid-Producing Head and Neck Cancer","volume":"108","author":"Ohashi","year":"2017","journal-title":"Cancer Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1210\/en.2012-1575","article-title":"Glucocorticoids Enhance CD163 Expression in Placental Hofbauer Cells","volume":"154","author":"Tang","year":"2013","journal-title":"Endocrinology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10794","DOI":"10.1158\/0008-5472.CAN-05-0623","article-title":"Interleukin-6, Secreted by Human Ovarian Carcinoma Cells, Is a Potent Proangiogenic Cytokine","volume":"65","author":"Nilsson","year":"2005","journal-title":"Cancer Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1097\/00008390-199606000-00002","article-title":"Interleukin-6 Production and Secretion in Human Melanoma Cell Lines: Regulation by Interleukin-1","volume":"6","author":"Francis","year":"1996","journal-title":"Melanoma Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12967-018-1611-7","article-title":"Unleashing Endogenous TNF-Alpha as a Cancer Immunotherapeutic","volume":"16","author":"Josephs","year":"2018","journal-title":"J. Transl. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1186\/s13046-019-1310-0","article-title":"IL-6 and IL-8 Secreted by Tumour Cells Impair the Function of NK Cells via the STAT3 Pathway in Oesophageal Squamous Cell Carcinoma","volume":"38","author":"Wu","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Nettersheim, D., Vadder, S., Jostes, S., Heimsoeth, A., and Schorle, H. (2019). TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo. Cancers, 11.","DOI":"10.3390\/cancers11050728"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s00005-008-0023-4","article-title":"Cancer Stem Cells as Targets for Cancer Therapy: Selected Cancers as Examples","volume":"56","author":"Paranjothy","year":"2008","journal-title":"Arch. Immunol. Ther. Exp. (Warsz.)"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"24731","DOI":"10.1074\/jbc.M502573200","article-title":"Transcriptional Regulation of Nanog by OCT4 and SOX2","volume":"280","author":"Rodda","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/s41379-019-0268-y","article-title":"Ki-67 Is an Independent Predictor of Prostate Cancer Death in Routine Needle Biopsy Samples: Proving Utility for Routine Assessments","volume":"32","author":"Ahmad","year":"2019","journal-title":"Mod. Pathol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"7369","DOI":"10.1158\/1078-0432.CCR-06-1472","article-title":"Ki-67 Is an Independent Predictor of Bladder Cancer Outcome in Patients Treated with Radical Cystectomy for Organ-Confined Disease","volume":"12","author":"Margulis","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.acthis.2016.05.002","article-title":"Ki67, PCNA, and MCM Proteins: Markers of Proliferation in the Diagnosis of Breast Cancer","volume":"118","author":"Danihel","year":"2016","journal-title":"Acta Histochem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1001\/archotol.134.12.1305","article-title":"Vascular Endothelial Growth Factor a and Proliferation Marker in Prediction of Lymph Node Metastasis in Oral and Pharyngeal Squamous Cell Carcinoma","volume":"134","author":"Boonkitticharoen","year":"2008","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1084\/jem.20041896","article-title":"VEGF-A Induces Tumor and Sentinel Lymph Node Lymphangiogenesis and Promotes Lymphatic Metastasis","volume":"201","author":"Hirakawa","year":"2005","journal-title":"J. Exp. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1755","DOI":"10.1002\/ijc.21899","article-title":"Tumor Lymphangiogenesis and Metastatic Spread-New Players Begin to Emerge","volume":"119","author":"Achen","year":"2006","journal-title":"Int. J. Cancer"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/5\/885\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:31:55Z","timestamp":1760135515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/5\/885"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,4]]},"references-count":65,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cells11050885"],"URL":"https:\/\/doi.org\/10.3390\/cells11050885","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,4]]}}}