{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:29:09Z","timestamp":1773070149414,"version":"3.50.1"},"reference-count":78,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T00:00:00Z","timestamp":1617667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2008\/57887-9"],"award-info":[{"award-number":["2008\/57887-9"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2013\/03667-6"],"award-info":[{"award-number":["2013\/03667-6"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2015\/25373-0"],"award-info":[{"award-number":["2015\/25373-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["573589\/08-9"],"award-info":[{"award-number":["573589\/08-9"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Science and Technology in Oncogenomics","award":["FAPESP #2008\/57887-9 and CNPq #573589\/08-9"],"award-info":[{"award-number":["FAPESP #2008\/57887-9 and CNPq #573589\/08-9"]}]},{"name":"Research Council of Lillebaelt Hospital, Denmark","award":["no nr."],"award-info":[{"award-number":["no nr."]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K\/AKT\/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease.<\/jats:p>","DOI":"10.3390\/cells10040814","type":"journal-article","created":{"date-parts":[[2021,4,6]],"date-time":"2021-04-06T10:34:12Z","timestamp":1617705252000},"page":"814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies"],"prefix":"10.3390","volume":"10","author":[{"given":"Hellen","family":"Kuasne","sequence":"first","affiliation":[{"name":"Department of Clinical Genetics, University Hospital of Southern Denmark-Vejle, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark"},{"name":"International Research Center\u2014A.C.Camargo Cancer Center, S\u00e3o Paulo 01508-010, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9095-9431","authenticated-orcid":false,"given":"Luisa Matos do","family":"Canto","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital of Southern Denmark-Vejle, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4742-7047","authenticated-orcid":false,"given":"Mads Malik","family":"Aagaard","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital of Southern Denmark-Vejle, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1547-6357","authenticated-orcid":false,"given":"Juan Jose Moyano","family":"Mu\u00f1oz","sequence":"additional","affiliation":[{"name":"International Research Center\u2014A.C.Camargo Cancer Center, S\u00e3o Paulo 01508-010, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille De","family":"Jamblinne","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer and D\u00e9partement de Pathologie et de Biologie Cellulaire, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5815-8423","authenticated-orcid":false,"given":"Fabio Albuquerque","family":"Marchi","sequence":"additional","affiliation":[{"name":"International Research Center\u2014A.C.Camargo Cancer Center, S\u00e3o Paulo 01508-010, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristovam","family":"Scapulatempo-Neto","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil"},{"name":"Diagn\u00f3sticos da Am\u00e9rica\u2014DASA, Barueri, S\u00e3o Paulo 06455-010, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eliney Ferreira","family":"Faria","sequence":"additional","affiliation":[{"name":"Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, Brazil"},{"name":"Uro-oncology and Robotic Surgery, Hospital Felicio Rocho, Belo Horizonte 30110-934, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ademar","family":"Lopes","sequence":"additional","affiliation":[{"name":"Pelvic Surgery Department, A.C.Camargo Cancer Center, S\u00e3o Paulo 01508-010, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00e9bastien","family":"Carr\u00e9no","sequence":"additional","affiliation":[{"name":"Institute for Research in Immunology and Cancer and D\u00e9partement de Pathologie et de Biologie Cellulaire, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, QC H3C 3J7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-5687","authenticated-orcid":false,"given":"Silvia Regina","family":"Rogatto","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, University Hospital of Southern Denmark-Vejle, Institute of Regional Health Research, University of Southern Denmark, 7100 Vejle, Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.currproblcancer.2015.03.010","article-title":"Epidemiology of penile cancer","volume":"39","author":"Christodoulidou","year":"2015","journal-title":"Curr. Probl. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"785","DOI":"10.21037\/tau.2017.05.19","article-title":"Updates on the epidemiology and risk factors for penile cancer","volume":"6","author":"Douglawi","year":"2017","journal-title":"Transl. Androl. Urol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1414","DOI":"10.1016\/j.ejca.2012.10.029","article-title":"Population-based survival of penile cancer patients in Europe and the United States of America: No improvement since 1990","volume":"49","author":"Verhoeven","year":"2013","journal-title":"Eur. J. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1016\/j.ejca.2015.07.027","article-title":"Survival of male genital cancers (prostate, testis and penis) in Europe 1999\u20132007: Results from the EUROCARE-5 study","volume":"51","author":"Trama","year":"2015","journal-title":"Eur. J. Cancer"},{"key":"ref_5","first-page":"1","article-title":"Penile cancer","volume":"7","author":"Thomas","year":"2021","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"10791","DOI":"10.3390\/ijms140610791","article-title":"Epigenetic Mechanisms in Penile Carcinoma","volume":"14","author":"Kuasne","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1097\/MOU.0000000000000712","article-title":"Risk factors and molecular characterization of penile cancer","volume":"30","author":"Thomas","year":"2020","journal-title":"Curr. Opin. Urol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1158\/1940-6207.CAPR-14-0284","article-title":"Genomic Profiling of Human Penile Carcinoma Predicts Worse Prognosis and Survival","volume":"8","author":"Marchi","year":"2015","journal-title":"Cancer Prev. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15294","DOI":"10.18632\/oncotarget.14783","article-title":"Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact","volume":"8","author":"Kuasne","year":"2017","journal-title":"Oncotarget"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11375","DOI":"10.1007\/s13277-016-4951-z","article-title":"A comprehensive characterization of cell cultures and xenografts derived from a human verrucous penile carcinoma","volume":"37","author":"Drigo","year":"2016","journal-title":"Tumor Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.juro.2014.11.097","article-title":"Down-Regulation of SLC8A1 as a Putative Apoptosis Evasion Mechanism by Modulation of Calcium Levels in Penile Carcinoma","volume":"194","author":"Drigo","year":"2015","journal-title":"J. Urol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Medeiros-Fonseca, B., Cubilla, A., Brito, H., Martins, T., Medeiros, R., Oliveira, P., and Gil da Costa, R. (2021). Experimental Models for Studying HPV-Positive and HPV-Negative Penile Cancer: New Tools for An Old Disease. Cancers, 13.","DOI":"10.3390\/cancers13030460"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1620\/tjem.88.9","article-title":"Establishment of a Cell Line in vitro from the Lesion of a Clinical Case of Penis Cancroid","volume":"88","author":"Yamane","year":"1966","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_14","first-page":"373","article-title":"Establishment of a cell line (TSUS-1) derived from a human squamous cell carcinoma of the penis","volume":"29","author":"Ishikawa","year":"1983","journal-title":"Hinyokika kiyo. Acta Urol. Jpn."},{"key":"ref_15","first-page":"164","article-title":"Cytogenetic study of a cell line of human penile cancer","volume":"30","author":"Gentile","year":"1987","journal-title":"Ann. de G\u00e9n\u00e9tique"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"277","DOI":"10.2302\/kjm.38.277","article-title":"Establishment and characterization of a cell line (KU-8) from squamous cell carcinoma of the penis","volume":"38","author":"Tsukamoto","year":"1989","journal-title":"Keio J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1016\/j.juro.2012.01.035","article-title":"Establishment and Characterization of Primary Cell Lines of Squamous Cell Carcinoma of the Penis and its Metastasis","volume":"187","author":"Naumann","year":"2012","journal-title":"J. Urol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"51687","DOI":"10.18632\/oncotarget.10098","article-title":"Establishment and characterization of a penile cancer cell line, penl1, with a deleterious TP53 mutation as a paradigm of HPV-negative penile carcinogenesis","volume":"7","author":"Chen","year":"2016","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-018-0736-1","article-title":"Molecular characterization and integrative genomic analysis of a panel of newly established penile cancer cell lines","volume":"9","author":"Zhou","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.euf.2017.02.009","article-title":"E2F1 Signalling is Predictive of Chemoresistance and Lymphogenic Metastasis in Penile Cancer: A Pilot Functional Study Reveals New Prognostic Biomarkers","volume":"4","author":"Fenner","year":"2018","journal-title":"Eur. Urol. Focus"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3503","DOI":"10.1038\/s41467-018-05992-x","article-title":"EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-019-5353-6","article-title":"Cancer-associated fibroblasts induce epithelial\u2013mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling","volume":"19","author":"Goulet","year":"2019","journal-title":"BMC Cancer"},{"key":"ref_23","first-page":"1","article-title":"The androgen receptor\/filamin a complex as a target in prostate cancer microenvironment","volume":"12","author":"Zamagni","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"srep41677","DOI":"10.1038\/srep41677","article-title":"Germline large genomic alterations on 7q in patients with multiple primary cancers","volume":"7","author":"Villacis","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"395","DOI":"10.3389\/fonc.2019.00395","article-title":"Increased Levels of Genomic Instability and Mutations in Homologous Recombination Genes in Locally Advanced Rectal Carcinomas","volume":"9","author":"Canto","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"36158","DOI":"10.1038\/srep36158","article-title":"Rawcopy: Improved copy number analysis with Affymetrix arrays","volume":"6","author":"Mayrhofer","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1002\/humu.23220","article-title":"Exomic variants of an elderly cohort of Brazilians in the ABraOM database","volume":"38","author":"Naslavsky","year":"2017","journal-title":"Hum. Mutat."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"10860","DOI":"10.1074\/jbc.M113.461970","article-title":"IMPACT Is a Developmentally Regulated Protein in Neurons That Opposes the Eukaryotic Initiation Factor 2\u03b1 Kinase GCN2 in the modulation of Neurite Outgrowth*","volume":"288","author":"Hajj","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13045-019-0770-1","article-title":"Cancer-associated fibroblasts: An emerging target of anti-cancer immunotherapy","volume":"12","author":"Liu","year":"2019","journal-title":"J. Hematol. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/nrc1877","article-title":"Fibroblasts in cancer","volume":"6","author":"Kalluri","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1002\/ijc.32193","article-title":"In search of definitions: Cancer-associated fibroblasts and their markers","volume":"146","author":"Nurmik","year":"2020","journal-title":"Int. J. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.biosystems.2014.06.009","article-title":"RPPApipe: A pipeline for the analysis of reverse-phase protein array data","volume":"122","author":"Eichner","year":"2014","journal-title":"Biosystems"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13148-015-0082-4","article-title":"Genome-wide methylation and transcriptome analysis in penile carcinoma: Uncovering new molecular markers","volume":"7","author":"Kuasne","year":"2015","journal-title":"Clin. Epigenetics"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Stankiewicz, E., Prowse, D.M., Ng, M., Cuzick, J., Mesher, D., Hiscock, F., Lu, Y.-J., Watkin, N., Corbishley, C., and Lam, W. (2011). Alternative HER\/PTEN\/Akt Pathway Activation in HPV Positive and Negative Penile Carcinomas. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017517"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1111\/his.12338","article-title":"Immunohistochemical expression of the mammalian target of rapamycin pathway in penile squamous cell carcinomas: A tissue microarray study of 112 cases","volume":"64","author":"Chaux","year":"2014","journal-title":"Histopathology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e80","DOI":"10.1016\/j.clgc.2018.09.012","article-title":"Impact of PI3K-AKT-mTOR Signaling Pathway Up-regulation on Prognosis of Penile Squamous-Cell Carcinoma: Results From a Tissue Microarray Study and Review of the Literature","volume":"17","author":"Azizi","year":"2019","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.humpath.2015.01.018","article-title":"Immunohistochemical expression of ARID1A in penile squamous cell carcinomas: A tissue microarray study of 112 cases","volume":"46","author":"Faraj","year":"2015","journal-title":"Hum. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/j.prp.2013.02.002","article-title":"C-MET is expressed in the majority of penile squamous cell carcinomas and correlates with polysomy-7 but is not associated with MET oncogene amplification, pertinent histopathologic parameters, or with cancer-specific survival","volume":"209","author":"Gunia","year":"2013","journal-title":"Pathol.-Res. Pract."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Arya, M., Thrasivoulou, C., Henrique, R., Millar, M., Hamblin, R., Davda, R., Aare, K., Masters, J.R., Thomson, C., and Muneer, A. (2015). Targets of Wnt\/\u00df-Catenin Transcription in Penile Carcinoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124395"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.humpath.2016.07.041","article-title":"Epidermal growth factor receptor as an adverse survival predictor in squamous cell carcinoma of the penis","volume":"61","author":"Amancio","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.clgc.2016.01.013","article-title":"Epidermal Growth Factor Receptor, Excision-Repair Cross-Complementation Group 1 Protein, and Thymidylate Synthase Expression in Penile Cancer","volume":"14","author":"Dorff","year":"2016","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1016\/j.juro.2013.06.015","article-title":"mTOR Signaling Pathway in Penile Squamous Cell Carcinoma: pmTOR and peIF4E Over Expression Correlate with Aggressive Tumor Behavior","volume":"190","author":"Masferrer","year":"2013","journal-title":"J. Urol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Steinestel, J., Al Ghazal, A., Arndt, A., Schnoeller, T.J., Schrader, A.J., Moeller, P., and Steinestel, K. (2015). The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1268-z"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1097\/PAS.0b013e318203cdba","article-title":"Value of p16INK4a in the Pathology of Invasive Penile Squamous Cell Carcinomas","volume":"35","author":"Cubilla","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.juro.2014.08.120","article-title":"Lack of P16 ink4a Over Expression in Penile Squamous Cell Carcinoma is Associated with Recurrence after Lymph Node Dissection","volume":"193","author":"Tang","year":"2015","journal-title":"J. Urol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jaad.2012.12.973","article-title":"Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression","volume":"69","author":"Mannweiler","year":"2013","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1136\/jclinpath-2011-200429","article-title":"Expression of p53, p21 and cyclin D1 in penile cancer: p53 predicts poor prognosis","volume":"65","author":"Gunia","year":"2011","journal-title":"J. Clin. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.humpath.2011.06.013","article-title":"A clinical, pathologic, and molecular study of p53 and murine double minute 2 in penile carcinogenesis and its relation to prognosis","volume":"43","author":"Rocha","year":"2012","journal-title":"Hum. Pathol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e1269047","DOI":"10.1080\/2162402X.2016.1269047","article-title":"Tumor PD-L1 expression is correlated with increased TILs and poor prognosis in penile squamous cell carcinoma","volume":"6","author":"Deng","year":"2017","journal-title":"OncoImmunology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1093\/annonc\/mdw216","article-title":"Frequent PD-L1 expression in primary and metastatic penile squamous cell carcinoma: Potential opportunities for immunotherapeutic approaches","volume":"27","author":"Udager","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.humpath.2016.09.003","article-title":"Immune-checkpoint status in penile squamous cell carcinoma: A North American cohort","volume":"59","author":"Cocks","year":"2017","journal-title":"Hum. Pathol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.juro.2016.09.088","article-title":"Expression of Programmed Death Ligand 1 in Penile Cancer is of Prognostic Value and Associated with HPV Status","volume":"197","author":"Ottenhof","year":"2017","journal-title":"J. Urol."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Termini, L., Fregnani, J.H., Boccardo, E., Da Costa, W.H., Longatto-Filho, A., Andreoli, M.A., Costa, M.C., Lopes, A., Da Cunha, I.W., and Soares, F.A. (2015). SOD2 immunoexpression predicts lymph node metastasis in penile cancer. BMC Clin. Pathol., 15.","DOI":"10.1186\/s12907-015-0003-7"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"245","DOI":"10.7150\/ijms.8.245","article-title":"Current Status of Methods to Assess Cancer Drug Resistance","volume":"8","author":"Lippert","year":"2011","journal-title":"Int. J. Med Sci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.gde.2013.12.002","article-title":"The evolving role of cancer cell line-based screens to define the impact of cancer genomes on drug response","volume":"24","author":"Garnett","year":"2014","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s12935-014-0103-y","article-title":"Establishment and characterization of a novel primary hepatocellular carcinoma cell line with metastatic ability in vivo","volume":"14","author":"Cheung","year":"2014","journal-title":"Cancer Cell Int."},{"key":"ref_59","first-page":"188292","article-title":"Corrigendum to Preclinical models for precision oncology. BBACAN 1870\/2 (2018) 239\u2013246","volume":"1872","author":"Cervantes","year":"2019","journal-title":"Biochim. et Biophys. Acta (BBA)-Bioenerg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/978-3-030-37184-5_2","article-title":"Fibroblasts in the Tumor Microenvironment","volume":"1234","author":"Truffi","year":"2020","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1111\/cas.14346","article-title":"Cancer-associated fibroblasts that restrain cancer progression: Hypotheses and perspectives","volume":"111","author":"Miyai","year":"2020","journal-title":"Cancer Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/CMR.16.1.1-17.2003","article-title":"Human Papillomavirus and Cervical Cancer","volume":"16","author":"Burd","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.juro.2009.04.028","article-title":"Penile Squamous Cell Carcinoma Clinicopathological Features, Nodal Metastasis and Outcome in 333 Cases","volume":"182","author":"Cunha","year":"2009","journal-title":"J. Urol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1053\/j.semdp.2014.12.017","article-title":"Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC)","volume":"32","author":"Sanchez","year":"2015","journal-title":"Semin. Diagn. Pathol."},{"key":"ref_65","first-page":"22","article-title":"Translatome profiling: Methods for genome-scale analysis of mRNA translation","volume":"15","author":"King","year":"2014","journal-title":"Briefings Funct. Genom."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2690","DOI":"10.1016\/j.humpath.2013.07.012","article-title":"The epidermal growth factor receptor is frequently overexpressed in penile squamous cell carcinomas: A tissue microarray and digital image analysis study of 112 cases","volume":"44","author":"Chaux","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_67","first-page":"473","article-title":"The epidermal growth factor receptors as biological targets in penile cancer","volume":"15","author":"Buonerba","year":"2014","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.ucl.2016.06.009","article-title":"Emerging Systemic Therapies for the Management of Penile Cancer","volume":"43","author":"Gupta","year":"2016","journal-title":"Urol. Clin. N. Am."},{"key":"ref_69","first-page":"71","article-title":"EGFR mono-antibody salvage therapy for locally advanced and distant metastatic penile cancer: Clinical outcomes and genetic analysis","volume":"37","author":"Huang","year":"2019","journal-title":"Urol. Oncol. Semin. Orig. Investig."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1111\/bju.14013","article-title":"First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: Results of an open-label, single-arm, single-centre, phase 2 study","volume":"121","author":"Necchi","year":"2017","journal-title":"BJU Int."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"6899","DOI":"10.1158\/1078-0432.CCR-19-0823","article-title":"Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies","volume":"25","author":"Parseghian","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1007\/s00428-018-2404-3","article-title":"Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: Role as a driver event and as a prognosis factor","volume":"473","author":"Kuasne","year":"2018","journal-title":"Virchows Archiv f\u00fcr Pathol. Anat. und Physiol. und f\u00fcr Klin. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.juro.2018.09.056","article-title":"Comparative Genomic Profiling of Refractory and Metastatic Penile and Nonpenile Cutaneous Squamous Cell Carcinoma: Implications for Selection of Systemic Therapy","volume":"201","author":"Jacob","year":"2019","journal-title":"J. Urol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1097\/MOU.0000000000000640","article-title":"Genetics and penile cancer","volume":"29","author":"Chahoud","year":"2019","journal-title":"Curr. Opin. Urol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1038\/s41585-018-0083-0","article-title":"Immunotherapy for advanced penile cancer\u2014Rationale and potential","volume":"15","author":"McGregor","year":"2018","journal-title":"Nat. Rev. Urol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1016\/j.cell.2017.07.029","article-title":"The PI3K Pathway in Human Disease","volume":"170","author":"Fruman","year":"2017","journal-title":"Cell"},{"key":"ref_77","first-page":"1889","article-title":"Therapeutic targeting of the crosstalk between cancer-associated fibroblasts and cancer stem cells","volume":"9","author":"Huang","year":"2019","journal-title":"Am. J. Cancer Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8","DOI":"10.17305\/bjbms.2018.2756","article-title":"The role of the Hedgehog signaling pathway in cancer: A comprehensive review","volume":"18","author":"Skoda","year":"2018","journal-title":"Bosn. J. Basic Med. Sci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/814\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:34:03Z","timestamp":1760362443000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/4\/814"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,6]]},"references-count":78,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["cells10040814"],"URL":"https:\/\/doi.org\/10.3390\/cells10040814","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,6]]}}}