{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T18:12:32Z","timestamp":1790446352930,"version":"4.1.0"},"reference-count":106,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Polyploid giant cancer cells (PGCCs) are characterized by abnormal enlargement and considerable polyploidy. Though the presence of giant cancer cells has been documented for decades, they remain not fully understood, especially in clinical practice, due to diagnostic challenges, and confusion regarding synonyms for PGCCs still exists. Thus, understanding PGCCs may be a key clue to overcoming them. This review offers a comprehensive overview of PGCCs, integrating insights from basic research and clinical studies to enhance understanding of their complex biology and clinical implications. In basic research, PGCCs are known to emerge under various stressors, including chemotherapy exposure, radiation, viral infection, and hypoxic environments. These cells play crucial roles in tumor progression through multiple mechanisms: enhancing genetic diversity, and facilitating metastatic spread via asymmetrical cell division and genomic instability. In clinical studies, PGCC-containing tumors have been shown to exhibit marked treatment resistance and are associated with a poor prognosis across multiple solid tumor types, including prostate, lung, and pancreatic cancers. Despite these therapeutic challenges, taxane-based chemotherapy has shown promising results in PGCC-containing tumors, such as pleomorphic carcinoma and undifferentiated carcinoma. Furthermore, emerging targeted therapies directed at specific pathways in PGCCs, particularly those involving TP53, represent potential strategies to improve clinical outcomes of patients with PGCC-containing tumors.<\/jats:p>","DOI":"10.3390\/cancers18111818","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:19:42Z","timestamp":1780316382000},"page":"1818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical Implications of Polyploid Giant Cancer Cells in Solid Tumors: Biology, Diagnosis, and Therapeutic Considerations"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0584-0095","authenticated-orcid":false,"given":"Hiroshi","family":"Imaoka","sequence":"first","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4050-2086","authenticated-orcid":false,"given":"Masafumi","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Wakabayashi","sequence":"additional","affiliation":[{"name":"Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa 277-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kumiko","family":"Umemoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki 216-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyuki","family":"Satake","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary and 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241-8515, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1158\/1535-7163.MCT-23-0578","article-title":"Polyploidy in Cancer: Causal Mechanisms, Cancer-Specific Consequences, and Emerging Treatments","volume":"23","author":"Conway","year":"2024","journal-title":"Mol. Cancer Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/j.canlet.2013.01.037","article-title":"Generation of erythroid cells from fibroblasts and cancer cells in vitro and in vivo","volume":"333","author":"Zhang","year":"2013","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/onc.2013.96","article-title":"Generation of cancer stem-like cells through the formation of polyploid giant cancer cells","volume":"33","author":"Zhang","year":"2014","journal-title":"Oncogene"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1007\/s12032-019-1303-z","article-title":"EMT-related protein expression in polyploid giant cancer cells and their daughter cells with different passages after triptolide treatment","volume":"36","author":"Wang","year":"2019","journal-title":"Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/35102167","article-title":"Stem cells, cancer, and cancer stem cells","volume":"414","author":"Reya","year":"2001","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.semcancer.2021.10.005","article-title":"The life cycle of polyploid giant cancer cells and dormancy in cancer: Opportunities for novel therapeutic interventions","volume":"81","author":"Liu","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.semcancer.2021.04.005","article-title":"Human cell polyploidization: The good and the evil","volume":"81","author":"Zhang","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Coward, J., and Harding, A. (2014). Size Does Matter: Why Polyploid Tumor Cells are Critical Drug Targets in the War on Cancer. Front. Oncol., 4.","DOI":"10.3389\/fonc.2014.00123"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/j.ccr.2008.11.011","article-title":"The aneuploidy paradox in cell growth and tumorigenesis","volume":"14","author":"Weaver","year":"2008","journal-title":"Cancer Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.leukres.2016.11.016","article-title":"Tetraploidy\/near-tetraploidy acute myeloid leukemia","volume":"53","author":"Huang","year":"2017","journal-title":"Leuk. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Shimono, J., Miyoshi, H., Kiyasu, J., Kamimura, T., Eto, T., Miyagishima, T., Nagafuji, K., Seto, M., Teshima, T., and Ohshima, K. (2018). Clinicopathological analysis of polyploid diffuse large B-cell lymphoma. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0194525"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2020838118","DOI":"10.1073\/pnas.2020838118","article-title":"Cancer recurrence and lethality are enabled by enhanced survival and reversible cell cycle arrest of polyaneuploid cells","volume":"118","author":"Pienta","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Virchow, R. (1860). Cellular Pathology as Based upon Physiological and Pathological Histology: Twenty Lectures Delivered in the Pathological Institute of Berlin During the Months of February, March, and April, 1858, J.B. Lippincott.","DOI":"10.5962\/bhl.title.110759"},{"key":"ref_14","unstructured":"WHO Classification of Tumours Editorial Board (2021). WHO Classification of Thoracic Tumours, International Agency for Research on Cancer (IARC). [5th ed.]."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1093\/jjco\/hyad062","article-title":"Comprehensive review of undifferentiated carcinoma of the pancreas: From epidemiology to treatment","volume":"53","author":"Imaoka","year":"2023","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.surg.2010.04.026","article-title":"Anaplastic pancreatic cancer: Presentation, surgical management, and outcome","volume":"149","author":"Strobel","year":"2011","journal-title":"Surgery"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1097\/PAS.0000000000000689","article-title":"Undifferentiated Carcinoma with Osteoclastic Giant Cells of the Pancreas: Clinicopathologic Analysis of 38 Cases Highlights a More Protracted Clinical Course Than Currently Appreciated","volume":"40","author":"Muraki","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1073\/pnas.1320198111","article-title":"Circulating giant macrophages as a potential biomarker of solid tumors","volume":"111","author":"Adams","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100275","DOI":"10.1016\/j.jlb.2024.100275","article-title":"Cancer-associated macrophage-like cells as a prognostic biomarker in solid tumors","volume":"6","author":"Pirrello","year":"2024","journal-title":"J. Liq. Biopsy"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108600","DOI":"10.1016\/j.clim.2020.108600","article-title":"A study of multinucleated giant cells in esophageal cancer","volume":"222","author":"Wang","year":"2021","journal-title":"Clin. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ahmadzadeh, K., Vanoppen, M., Rose, C.D., Matthys, P., and Wouters, C.H. (2022). Multinucleated Giant Cells: Current Insights in Phenotype, Biological Activities, and Mechanism of Formation. Front. Cell Dev. Biol., 10.","DOI":"10.3389\/fcell.2022.873226"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2316436","DOI":"10.1155\/2019\/2316436","article-title":"Formation of Polyploid Giant Cancer Cells Involves in the Prognostic Value of Neoadjuvant Chemoradiation in Locally Advanced Rectal Cancer","volume":"2019","author":"Fei","year":"2019","journal-title":"J. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1002\/1878-0261.12913","article-title":"Irradiation-induced polyploid giant cancer cells are involved in tumor cell repopulation via neosis","volume":"15","author":"Zhang","year":"2021","journal-title":"Mol. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Lopez-S\u00e1nchez, L.M., Jimenez, C., Valverde, A., Hernandez, V., Pe\u00f1arando, J., Martinez, A., Lopez-Pedrera, C., Mu\u00f1oz-Casta\u00f1eda, J.R., De la Haba-Rodr\u00edguez, J.R., and Aranda, E. (2014). CoCl2, a mimic of hypoxia, induces formation of polyploid giant cells with stem characteristics in colon cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0099143"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/s41588-018-0165-1","article-title":"Genome doubling shapes the evolution and prognosis of advanced cancers","volume":"50","author":"Bielski","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1038\/ng.2760","article-title":"Pan-cancer patterns of somatic copy number alteration","volume":"45","author":"Zack","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.ccell.2018.03.007","article-title":"Genomic and Functional Approaches to Understanding Cancer Aneuploidy","volume":"33","author":"Taylor","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/s43018-021-00179-8","article-title":"Bone marrow NG2(+)\/Nestin(+) mesenchymal stem cells drive DTC dormancy via TGFbeta2","volume":"2","author":"Nobre","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e174458","DOI":"10.1172\/jci.insight.174458","article-title":"Dormant tumors circumvent tumor-specific adaptive immunity by establishing a Treg-dominated niche via DKK3","volume":"8","author":"Trotter","year":"2023","journal-title":"JCI Insight"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2169","DOI":"10.1083\/jcb.201902143","article-title":"Intrinsic checkpoint deficiency during cell cycle re-entry from quiescence","volume":"218","author":"Matson","year":"2019","journal-title":"J. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Coller, H.A., Sang, L., and Roberts, J.M. (2006). A new description of cellular quiescence. PLoS Biol., 4.","DOI":"10.1371\/journal.pbio.0040083"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/nature17038","article-title":"Metastatic colonization by circulating tumour cells","volume":"529","author":"Massague","year":"2016","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6170","DOI":"10.1038\/ncomms7170","article-title":"NR2F1 controls tumour cell dormancy via SOX9- and RARbeta-driven quiescence programmes","volume":"6","author":"Sosa","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1038\/s43018-022-00424-8","article-title":"ZFP281 drives a mesenchymal-like dormancy program in early disseminated breast cancer cells that prevents metastatic outgrowth in the lung","volume":"3","author":"Nobre","year":"2022","journal-title":"Nat. Cancer"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"56","DOI":"10.20892\/j.issn.2095-3941.2022.0432","article-title":"Acetylated-PPARgamma expression is regulated by different P53 genotypes associated with the adipogenic differentiation of polyploid giant cancer cells with daughter cells","volume":"20","author":"Zhang","year":"2023","journal-title":"Cancer Biol. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13046-020-01588-w","article-title":"Different p53 genotypes regulating different phosphorylation sites and subcellular location of CDC25C associated with the formation of polyploid giant cancer cells","volume":"39","author":"Liu","year":"2020","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e1567","DOI":"10.1002\/ctm2.1567","article-title":"Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis","volume":"14","author":"Jiao","year":"2024","journal-title":"Clin. Transl. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e281","DOI":"10.1038\/oncsis.2016.75","article-title":"Linking genomic reorganization to tumor initiation via the giant cell cycle","volume":"5","author":"Niu","year":"2016","journal-title":"Oncogenesis"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Casotti, M.C., Meira, D.D., Zetum, A.S.S., Araujo, B.C., Silva, D., Santos, E., Garcia, F.M., Paula, F., Santana, G.M., and Louro, L.S. (2023). Computational Biology Helps Understand How Polyploid Giant Cancer Cells Drive Tumor Success. Genes, 14.","DOI":"10.3390\/genes14040801"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1093\/biolre\/ioab102","article-title":"Polyploid giant cancer cells and ovarian cancer: New insights into mitotic regulators and polyploidydagger","volume":"105","author":"Richards","year":"2021","journal-title":"Biol. Reprod."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s10585-023-10216-8","article-title":"Cells in the polyaneuploid cancer cell (PACC) state have increased metastatic potential","volume":"40","author":"Mallin","year":"2023","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41586-022-04774-2","article-title":"Stromal changes in the aged lung induce an emergence from melanoma dormancy","volume":"606","author":"Fane","year":"2022","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1038\/s41416-023-02401-z","article-title":"A cell cycle centric view of tumour dormancy","volume":"129","author":"Weston","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/j.cell.2008.03.027","article-title":"The epithelial-mesenchymal transition generates cells with properties of stem cells","volume":"133","author":"Mani","year":"2008","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1186\/s12967-023-04585-7","article-title":"Molecular mechanism of vimentin nuclear localization associated with the migration and invasion of daughter cells derived from polyploid giant cancer cells","volume":"21","author":"Fan","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/nature05529","article-title":"Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas","volume":"445","author":"Xue","year":"2007","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1038\/nature10599","article-title":"Senescence surveillance of pre-malignant hepatocytes limits liver cancer development","volume":"479","author":"Kang","year":"2011","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2853","DOI":"10.1371\/journal.pbio.0060301","article-title":"Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor","volume":"6","author":"Coppe","year":"2008","journal-title":"PLoS Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4212","DOI":"10.1093\/emboj\/cdg417","article-title":"Reversal of human cellular senescence: Roles of the p53 and p16 pathways","volume":"22","author":"Beausejour","year":"2003","journal-title":"EMBO J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"4546","DOI":"10.1038\/s41388-018-0272-6","article-title":"Multi-nucleated cells use ROS to induce breast cancer chemo-resistance in vitro and in vivo","volume":"37","author":"Parekh","year":"2018","journal-title":"Oncogene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.semcancer.2021.03.017","article-title":"Polyploid giant cancer cell characterization: New frontiers in predicting response to chemotherapy in breast cancer","volume":"81","author":"Saini","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/s12935-023-02971-1","article-title":"Polyploid giant cancer cells, cytokines and cytomegalovirus in breast cancer progression","volume":"23","author":"Herbein","year":"2023","journal-title":"Cancer Cell Int."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"360","DOI":"10.2174\/1568009618666180703154233","article-title":"Polyploid Giant Cancer Cells (PGCCs): The Evil Roots of Cancer","volume":"19","author":"Chen","year":"2019","journal-title":"Curr. Cancer Drug Targets"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/s41389-021-00349-4","article-title":"IL-6 promotes drug resistance through formation of polyploid giant cancer cells and stromal fibroblast reprogramming","volume":"10","author":"Niu","year":"2021","journal-title":"Oncogenesis"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s10585-019-09958-1","article-title":"The role of heterogeneous environment and docetaxel gradient in the emergence of polyploid, mesenchymal and resistant prostate cancer cells","volume":"36","author":"Lin","year":"2019","journal-title":"Clin. Exp. Metastasis"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kostecka, L.G., Pienta, K.J., and Amend, S.R. (2021). Polyaneuploid Cancer Cell Dormancy: Lessons From Evolutionary Phyla. Front. Ecol. Evol., 9.","DOI":"10.3389\/fevo.2021.660755"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/s41598-022-27090-1","article-title":"Zoledronic acid targets chemo-resistant polyploid giant cancer cells","volume":"13","author":"Adibi","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"El Baba, R., Pasquereau, S., Haidar Ahmad, S., Diab-Assaf, M., and Herbein, G. (2022). Oncogenic and Stemness Signatures of the High-Risk HCMV Strains in Breast Cancer Progression. Cancers, 14.","DOI":"10.3390\/cancers14174271"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"15027","DOI":"10.1038\/s41598-023-42368-8","article-title":"A mathematical investigation of polyaneuploid cancer cell memory and cross-resistance in state-structured cancer populations","volume":"13","author":"Bukkuri","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1093\/jnci\/djab064","article-title":"Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy","volume":"113","author":"Prasanna","year":"2021","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.semcancer.2021.03.003","article-title":"Polyploidy formation in cancer cells: How a Trojan horse is born","volume":"81","author":"Was","year":"2022","journal-title":"Semin. Cancer Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/j.ajpath.2019.02.006","article-title":"An Overview of the Derivation and Function of Multinucleated Giant Cells and Their Role in Pathologic Processes","volume":"189","author":"Brooks","year":"2019","journal-title":"Am. J. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41392-020-0110-5","article-title":"Targeting cancer stem cell pathways for cancer therapy","volume":"5","author":"Yang","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Chinen, L.T.D., Torres, J.A., Calsavara, V.F., Brito, A.B.C., Silva, V.S.E., Novello, R.G.S., Fernandes, T.C., Decina, A., Dachez, R., and Paterlini-Brechot, P. (2024). Circulating Polyploid Giant Cancer Cells, a Potential Prognostic Marker in Patients with Carcinoma. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25189841"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1038\/s41374-018-0095-7","article-title":"Nuclear shape and orientation features from H&E images predict survival in early-stage estrogen receptor-positive breast cancers","volume":"98","author":"Lu","year":"2018","journal-title":"Lab. Invest."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1038\/modpathol.2017.98","article-title":"An oral cavity squamous cell carcinoma quantitative histomorphometric-based image classifier of nuclear morphology can risk stratify patients for disease-specific survival","volume":"30","author":"Lu","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s12967-019-1839-x","article-title":"Nuclear shape, architecture and orientation features from H&E images are able to predict recurrence in node-negative gastric adenocarcinoma","volume":"17","author":"Ji","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"100906","DOI":"10.1016\/j.neo.2023.100906","article-title":"Nuclear morphology predicts cell survival to cisplatin chemotherapy","volume":"42","author":"Kim","year":"2023","journal-title":"Neoplasia"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1002\/pros.24459","article-title":"Presence of cells in the polyaneuploid cancer cell (PACC) state predicts the risk of recurrence in prostate cancer","volume":"83","author":"Trabzonlu","year":"2023","journal-title":"Prostate"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Chen, Z., Liu, J., and Min, L. (2022). Clinicopathological characteristics, survival outcomes and prognostic factors in pleomorphic carcinoma: A SEER population-based study. BMC Pulm. Med., 22.","DOI":"10.1186\/s12890-022-01915-1"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.jamcollsurg.2012.06.418","article-title":"Clinical outcomes for anaplastic pancreatic cancer: A population-based study","volume":"215","author":"Clark","year":"2012","journal-title":"J. Am. Coll. Surg."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Imaoka, H., Ikeda, M., Maehara, K., Umemoto, K., Ozaka, M., Kobayashi, S., Terashima, T., Inoue, H., Sakaguchi, C., and Tsuji, K. (2020). Clinical outcomes of chemotherapy in patients with undifferentiated carcinoma of the pancreas: A retrospective multicenter cohort study. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07462-4"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1038\/s41416-023-02408-6","article-title":"Histological diagnosis of polyploidy discriminates an aggressive subset of hepatocellular carcinomas with poor prognosis","volume":"129","author":"Matsuura","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1007\/s00428-024-03858-w","article-title":"Giant cell carcinoma of the urinary bladder: Clinicopathologic analysis and oncological outcomes","volume":"485","author":"Paner","year":"2024","journal-title":"Virchows Arch."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/cas.14726","article-title":"Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes","volume":"112","author":"Tan","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1097\/PAS.0000000000001112","article-title":"Prostatic Adenocarcinoma With Focal Pleomorphic Giant Cell Features: A Series of 30 Cases","volume":"42","author":"Alharbi","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1038\/s41388-024-03212-z","article-title":"Polyploid cancer cells reveal signatures of chemotherapy resistance","volume":"44","author":"Schmidt","year":"2024","journal-title":"Oncogene"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/S0169-5002(01)00224-0","article-title":"Pulmonary pleomorphic (spindle) cell carcinoma: Peculiar clinicopathologic manifestations different from ordinary non-small cell carcinoma","volume":"34","author":"Chang","year":"2001","journal-title":"Lung Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.lungcan.2007.05.006","article-title":"Palliative chemotherapy for pulmonary pleomorphic carcinoma","volume":"58","author":"Bae","year":"2007","journal-title":"Lung Cancer"},{"key":"ref_80","doi-asserted-by":"crossref","unstructured":"Tamura, Y., Fujiwara, Y., Yamamoto, N., Nokihara, H., Horinouchi, H., Kanda, S., Goto, Y., Kubo, E., Kitahara, S., and Tsuruoka, K. (2015). Retrospective analysis of the efficacy of chemotherapy and molecular targeted therapy for advanced pulmonary pleomorphic carcinoma. BMC Res. Notes, 8.","DOI":"10.1186\/s13104-015-1762-z"},{"key":"ref_81","first-page":"460","article-title":"Pulmonary pleomorphic carcinoma: A clinicopathological study including EGFR mutation analysis","volume":"5","author":"Kaira","year":"2010","journal-title":"J. Thorac. Oncol. Off. Publ. Int. Assoc. Study Lung Cancer"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1245\/s10434-011-1621-7","article-title":"EGFR and p53 status of pulmonary pleomorphic carcinoma: Implications for EGFR tyrosine kinase inhibitors therapy of an aggressive lung malignancy","volume":"18","author":"Chang","year":"2011","journal-title":"Ann. Surg. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41698-021-00201-3","article-title":"Comprehensive molecular profiling of pulmonary pleomorphic carcinoma","volume":"5","author":"Nagano","year":"2021","journal-title":"npj Precis. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2501","DOI":"10.21873\/anticanres.15028","article-title":"PD-L1 Expression Status Predicting Survival in Pulmonary Pleomorphic Carcinoma","volume":"41","author":"Hisakane","year":"2021","journal-title":"Anticancer. Res."},{"key":"ref_85","unstructured":"WHO Classification of Tumours Editorial Board (2019). WHO Classification of Tumours of the Digestive System, International Agency for Research on Cancer (IARC). [5th ed.]."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1053\/j.gastro.2020.01.026","article-title":"Mice With Increased Numbers of Polyploid Hepatocytes Maintain Regenerative Capacity But Develop Fewer Hepatocellular Carcinomas Following Chronic Liver Injury","volume":"158","author":"Lin","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/s41467-021-20916-y","article-title":"Proliferative polyploid cells give rise to tumors via ploidy reduction","volume":"12","author":"Matsumoto","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1136\/gutjnl-2018-318021","article-title":"Polyploidy spectrum: A new marker in HCC classification","volume":"69","author":"Caruso","year":"2020","journal-title":"Gut"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"469","DOI":"10.7150\/jca.17012","article-title":"Daughter Cells and Erythroid Cells Budding from PGCCs and Their Clinicopathological Significances in Colorectal Cancer","volume":"8","author":"Zhang","year":"2017","journal-title":"J. Cancer"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4810734","DOI":"10.1155\/2016\/4810734","article-title":"Tumor Budding, Micropapillary Pattern, and Polyploidy Giant Cancer Cells in Colorectal Cancer: Current Status and Future Prospects","volume":"2016","author":"Zhang","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"104056","DOI":"10.1016\/j.ebiom.2022.104056","article-title":"Polyploid giant cancer cells, EZH2 and Myc upregulation in mammary epithelial cells infected with high-risk human cytomegalovirus","volume":"80","author":"Nehme","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1038\/s41388-023-02813-4","article-title":"Polyploidy, EZH2 upregulation, and transformation in cytomegalovirus-infected human ovarian epithelial cells","volume":"42","author":"Monnien","year":"2023","journal-title":"Oncogene"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1002\/lio2.667","article-title":"Characteristics and clinical significance of polyploid giant cancer cells in laryngeal carcinoma","volume":"6","author":"Liu","year":"2021","journal-title":"Laryngoscope Investig. Otolaryngol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1097\/CMR.0000000000000491","article-title":"Clinical characteristics and preliminary morphological observation of 47 cases of primary anorectal malignant melanomas","volume":"28","author":"Liu","year":"2018","journal-title":"Melanoma Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/1756-9966-32-75","article-title":"Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma","volume":"32","author":"Qu","year":"2013","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1111\/cns.13892","article-title":"Hypoxia-induced polypoid giant cancer cells in glioma promote the transformation of tumor-associated macrophages to a tumor-supportive phenotype","volume":"28","author":"Liu","year":"2022","journal-title":"CNS Neurosci. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s13046-015-0277-8","article-title":"The number of polyploid giant cancer cells and epithelial-mesenchymal transition-related proteins are associated with invasion and metastasis in human breast cancer","volume":"34","author":"Fei","year":"2015","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1158\/1535-7163.MCT-21-0873","article-title":"Targeting Therapeutic Resistance and Multinucleate Giant Cells in CCNE1-Amplified HR-Proficient Ovarian Cancer","volume":"21","author":"Bai","year":"2022","journal-title":"Mol. Cancer Ther."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2083","DOI":"10.1158\/1535-7163.MCT-17-0089","article-title":"Disruption of Aneuploidy and Senescence Induced by Aurora Inhibition Promotes Intrinsic Apoptosis in Double Hit or Double Expressor Diffuse Large B-cell Lymphomas","volume":"16","author":"Islam","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1200\/JCO.18.00899","article-title":"Randomized Phase III Study of Alisertib or Investigator\u2019s Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma","volume":"37","author":"Ozcan","year":"2019","journal-title":"J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/annonc\/mdv472.03","article-title":"Systemic chemotherapy for pulmonary pleomorphic carcinoma","volume":"26","author":"Nosaki","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/s41573-021-00155-y","article-title":"Beyond immune checkpoint blockade: Emerging immunological strategies","volume":"20","author":"Kubli","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/25292","article-title":"Genetic instabilities in human cancers","volume":"396","author":"Lengauer","year":"1998","journal-title":"Nature"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1056\/NEJMoa2508820","article-title":"Phase 1 Study of Rezatapopt, a p53 Reactivator, in TP53 Y220C-Mutated Tumors","volume":"394","author":"Dumbrava","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1433","DOI":"10.1016\/S1470-2045(20)30441-1","article-title":"Tazemetostat for patients with relapsed or refractory follicular lymphoma: An open-label, single-arm, multicentre, phase 2 trial","volume":"21","author":"Morschhauser","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/S1470-2045(20)30451-4","article-title":"Tazemetostat in advanced epithelioid sarcoma with loss of INI1\/SMARCB1: An international, open-label, phase 2 basket study","volume":"21","author":"Gounder","year":"2020","journal-title":"Lancet Oncol."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T12:41:53Z","timestamp":1780317713000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/11\/1818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,1]]},"references-count":106,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18111818"],"URL":"https:\/\/doi.org\/10.3390\/cancers18111818","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,1]]}}}