Материал и методы

oncotomsk

Сибирский онкологический журнал

Siberian journal of oncology

1814-48612312-3168

Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences

10.21294/1814-4861-2024-23-5-133-145

oncotomsk-3277

Research Article

ОБЗОРЫ

REVIEWS

Патогенетическое и клиническое значение особенностей экспрессии EpCАM в опухоли и циркулирующих опухолевых клетках

Pathogenetic and clinical signifcance of EpCАM expression features in tumors and circulating tumor cells

https://orcid.org/0000-0002-7633-9620

Перельмутер

В. М.

Perelmuter

V. M.

Перельмутер Владимир Михайлович, доктор медицинских наук, профессор, главный научный сотрудник отделения общей и молекулярной патологии,

634009, г. Томск, пер. Кооперативный, 5

Vladimir M. Perelmuter, MD, DSc, Professor, Chief Researcher, Department of General and Molecular Pathology,

5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0003-2061-8417

Таширева

Л. А.

Tashireva

L. A.

Таширева Любовь Александровна, доктор медицинских наук, заведующая лабораторией молекулярной терапии рака,

634009, г. Томск, пер. Кооперативный, 5

Liubov A. Tashireva, MD, DSc, Head of the Laboratory of Molecular Cancer Therapy,

5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0003-4737-8951

Григорьева

Е. С.

Grigoryeva

E. S.

Григорьева Евгения Сергеевна, кандидат медицинских наук, старший научный сотрудник лаборатории молекулярной терапии рака, старший научный сотрудник лаборатории молекулярной онкологии и иммунологии,

634009, г. Томск, пер. Кооперативный, 5

Evgeniya S. Grigoryeva, MD, PhD, Senior Researcher, Laboratory of Molecular Cancer Therapy, Senior Researcher, Laboratory of Molecular Oncology and Immunology,

5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0002-3025-4445

Алифанов

В. В.

Alifanov

V. V.

Алифанов Владимир Валерьевич, кандидат медицинских наук, научный сотрудник отделения общей и молекулярной патологии,

634009, г. Томск, пер. Кооперативный, 5

Vladimir V. Alifanov, MD, PhD, Researcher, Department of General and Molecular Pathology

5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0003-0909-9206

Пудова

Е. С.

Pudova

E. S.

Пудова Елена Сергеевна, младший научный сотрудник отделения общей и молекулярной патологии, 634009, г. Томск, пер. Кооперативный, 5;

ассистент кафедры патологической анатомии, 634050, г. Томск, Московский тракт, 2

Elena S. Pudova, Junior Researcher, Department of General and Molecular Pathology, 5, Kooperativny St., Tomsk, 634009;

Assistant Professor, Pathology Department, 2, Moskovsky trakt, Tomsk, 634050

elenasergeevna9607@gmail.com

https://orcid.org/0000-0001-5100-3592

Бузенкова

А. В.

Buzenkova

A. V.

Бузенкова Ангелина Владиславовна, кандидат медицинских наук, младший научный сотрудник отделения общей и молекулярной патологии,

634009, г. Томск, пер. Кооперативный, 5

Angelina V. Buzenkova, MD, PhD, Junior Researcher, Department of General and Molecular Pathology,

5, Kooperativny St., Tomsk, 634009

https://orcid.org/0000-0001-9429-9813

Завьялова

М. В.

Zavyalova

M. V.

Завьялова Марина Викторовна, доктор медицинских наук, профессор, ведущий научный сотрудник отделения общей и молекулярной патологии, 634009, г. Томск, пер. Кооперативный, 5;

заведующая кафедрой патологической анатомии, 634050, г. Томск, Московский тракт, 2

Marina V. Zavyalova, MD, DSc, Professor, Leading Researcher, Department of General and Molecular Pathology, 5, Kooperativny St., Tomsk, 634009;

Head of Pathology Department, 2, Moskovsky trakt, Tomsk, 634050

https://orcid.org/0000-0003-1526-9013

Чердынцева

Н. В.

Cherdyntseva

N. V.

Чердынцева Надежда Викторовна, доктор биологических наук, профессор, член-корреспондент РАН, заместитель директора по научной работе, заведующая лабораторией молекулярной онкологии и иммунологии,

634009, г. Томск, пер. Кооперативный, 5

Nadezhda V. Cherdyntseva, DSc, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy Director, Head of the Laboratory of Molecular Oncology and Immunology,

5, Kooperativny St., Tomsk, 634009

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian Federation

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences; Siberian State Medical University of the Ministry of Health of RussiaRussian Federation

2024

14112024

235133145

2024

Перельмутер В.М., Таширева Л.А., Григорьева Е.С., Алифанов В.В., Пудова Е.С., Бузенкова А.В., Завьялова М.В., Чердынцева Н.В.

Perelmuter V.M., Tashireva L.A., Grigoryeva E.S., Alifanov V.V., Pudova E.S., Buzenkova A.V., Zavyalova M.V., Cherdyntseva N.V.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://www.siboncoj.ru/jour/article/view/3277

Цель исследования – обобщение имеющихся данных о структуре и функции EpCAM и его доменов, их участии в развитии пролиферации, ЭМП, в проявлении стволовости клеток, во взаимодействии с молекулами клеточной адгезии и инвазии.

Материал и методы

Материал и методы. Проведен поиск русско- и англоязычных статей в научных базах PubMed, Scopus, Web of Science, E-library. Для написания обзора были использованы 79 статей, опубликованных с 1996 по 2024 г.

Результаты

Результаты. Проведен анализ патогенетического и клинического значения разных вариантов экспрессии: EpCAMhigh, EpCAMlow и EpCAMloss. Описаны причины и механизмы потери мембранной экспрессии EpCAM, которые имеют разное биологическое и клиническое значение. Освещены особенности экспрессии EpCAM в нормальных эпителиальных тканях, при регенерации и дисплазии/неоплазии и при карциномах. Клиническое значение экспрессии EpCAM неоднозначно. Гиперэкспрессия EpCAM может быть ассоциирована как с неблагоприятным, так и с благоприятным прогнозом. Особое внимание уделяется вариантам экспрессии EpCAM в циркулирующих опухолевых клетках, диссеминированных клетках и метастазах карцином.

Заключение

Заключение. Патогенетическое и клиническое значение экспрессии EpCAM неоднозначно при разных нозологических формах карцином. Слабая экспрессия или ее отсутствие являются самостоятельными факторами, обусловливающими особенности прогрессирования. Достижение успеха в понимании роли EpCAM требует одновременного изучения внеклеточного и внутриклеточного доменов.

Purpose of the study

Purpose of the study: to summarize the available data on the structure and function of EpCAM and its domains, their roles in promoting proliferation and epithelial-mesenchymal transition (EMT), contributing to cell stemness, and facilitating interactions with cell adhesion and invasion molecules.

Material and Methods

Material and Methods. A comprehensive search was conducted for articles in Russian and English within the scientifc databases PubMed, Scopus, Web of Science, and E-library. A total of seventy-nine articles ranging from 1996 to 2024 were utilized to compile this review.

Results

Results. This review summarized the pathogenetic and clinical signifcance of various EpCAM expression variants: EpCAM^high, EpCAM^low, and EpCAM^loss. It described the causes and mechanisms behind the loss of membrane EpCAM expression, each holding distinct biological and clinical implications. Features of EpCAM expression in normal epithelial tissues, during regeneration, and in dysplasia/ neoplasia as well as carcinomas were carefully outlined. The clinical implications of EpCAM expression remain a subject of debate; overexpression of EpCAM has been linked to both unfavorable and favorable prognoses. Special emphasis was placed on the expression variants of EpCAM in circulating tumor cells, disseminated cells, and carcinoma metastases.

Conclusion

Conclusion. The pathogenetic and clinical signifcance of EpCAM expression in various nosological forms of carcinoma is complex and multifaceted. Weak expression or absence of EpCAM acts as independent factors infuencing the unique progression patterns of these diseases. Achieving a deeper understanding of the role of EpCAM in disease progression necessitates the simultaneous examination of both its extracellular and intracellular domains.

EpCAMEpCAMhigh/low/lossциркулирующие опухолевые клеткиэпителиально-мезенхимальный переходкарциномырак молочной железыинвазиястволовость

EpCAMEpCAMhigh/low/losscirculating tumor cellsepithelial-mesenchymal transitioncarcinomasbreast cancerinvasionstemness

Исследование выполнено при финансовой поддержке гранта Российского научного фонда № 23-15-00135

The study was carried out with financial support from the Russian Science Foundation, grant No. 23-15-00135.

References1

Brown T.C., Sankpal N.V., Gillanders W.E. Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-toMesenchymal Transition. Biomolecules. 2021; 11(7): 956. doi: 10.3390/biom11070956.

Perelmuter V.M., Grigoryeva E.S., Savelieva O.E., Alifanov V.V., Andruhova E.S., Zavyalova M.V., Bragina O.D., Garbukov E.Y., Menyailo M.E., Khozyainova A.A., Denisov E.V., Cherdyntseva N.V., Tashireva L.A. EpCAM-CD24+ circulating cells associated with poor prognosis in breast cancer patients. Sci Rep. 2024; 14(1). doi: 10.1038/s41598-024-61516-2.

Yahyazadeh Mashhadi S.M., Kazemimanesh M., Arashkia A., Azadmanesh K., Meshkat Z., Golichenari B., Sahebkar A. Shedding light on the EpCAM: An overview. J Cell Physiol. 2019; 234(8): 12569–80. doi: 10.1002/jcp.28132.

Nicolazzo C., Raimondi C., Francescangeli F., Ceccarelli S., Trenta P., Magri V., Marchese C., Zeuner A., Gradilone A., Gazzaniga P. EpCAM-expressing circulating tumor cells in colorectal cancer. Int J Biol Markers. 2017; 32(4): 415–20. doi: 10.5301/ijbm.5000284.

Mohtar M.A., Syafruddin S.E., Nasir S.N., Low T.Y. Revisiting the Roles of Pro-Metastatic EpCAM in Cancer. Biomolecules. 2020; 10(2). doi: 10.3390/biom10020255.

The Cancer Genome Atlas Program (TCGA) [Internet]. Center for Cancer Genomics at the National Cancer Institute. [cited 2024 Sep 2]. URL: https://www.cancer.gov/tcga.

Hatami R., Sieuwerts A.M., Izadmehr S., Yao Z., Qiao R.F., Papa L., Look M.P., Smid M., Ohlssen J., Levine A.C., Germain D., Burstein D., Kirschenbaum A., DiFeo A., Foekens J.A., Narla G. KLF6-SV1 drives breast cancer metastasis and is associated with poor survival. Sci Transl Med. 2013; 5(169). doi: 10.1126/scitranslmed.3004688.

Schnell U., Cirulli V., Giepmans B.N. EpCAM: structure and function in health and disease. Biochim Biophys Acta. 2013; 1828(8): 1989–2001. doi: 10.1016/j.bbamem.2013.04.018.

Raimondi C., Nicolazzo C., Gradilone A. Circulating tumor cells isolation: the “post-EpCAM era”. Chin J Cancer Res. 2015; 27(5): 461–70. doi: 10.3978/j.issn.1000-9604.2015.06.02.

Eslami-S Z., Cortés-Hernández L.E., Alix-Panabières C. Epithelial Cell Adhesion Molecule: An Anchor to Isolate Clinically Relevant Circulating Tumor Cells. Cells. 2020; 9(8). doi: 10.3390/cells9081836.

Paschkowsky S., Hsiao J.M., Young J.C., Munter L.M. The discovery of proteases and intramembrane proteolysis 1. Biochem Cell Biol. 2019; 97(3): 265–9. doi: 10.1139/bcb-2018-0186.

Liang K.H., Tso H.C., Hung S.H., Kuan I.I., Lai J.K., Ke F.Y., Chuang Y.T., Liu I.J., Wang Y.P., Chen R.H., Wu H.C. Extracellular domain of EpCAM enhances tumor progression through EGFR signaling in colon cancer cells. Cancer Lett. 2018; 433: 165–75. doi: 10.1016/j.canlet.2018.06.040.

Gires O., Stoecklein N.H. Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences. Cell Mol Life Sci. 2014; 71(22): 4393–402. doi: 10.1007/s00018-014-1693-1.

Huang Y., Chanou A., Kranz G., Pan M., Kohlbauer V., Ettinger A., Gires O. Membrane-associated epithelial cell adhesion molecule is slowly cleaved by γ-secretase prior to efcient proteasomal degradation of its intracellular domain. J Biol Chem. 2019; 294(9): 3051–64. doi: 10.1074/jbc.RA118.005874.

Gerlach J.C., Foka H.G., Thompson R.L., Gridelli B., Schmelzer E. Epithelial cell adhesion molecule fragments and signaling in primary human liver cells. J Cell Physiol. 2018; 233(6): 4841–51. doi: 10.1002/jcp.26286.

Schnell U., Kuipers J., Giepmans B.N. EpCAM proteolysis: new fragments with distinct functions? Biosci Rep. 2013; 33(2). doi: 10.1042/BSR20120128.

Ralhan R., Cao J., Lim T., Macmillan C., Freeman J.L., Walfsh P.G. EpCAM nuclear localization identifes aggressive thyroid cancer and is a marker for poor prognosis. BMC Cancer. 2010; 10. doi: 10.1186/1471-2407-10-331.

Hachmeister M., Bobowski K.D., Hogl S., Dislich B., Fukumori A., Eggert C., Mack B., Kremling H., Sarrach S., Coscia F., Zimmermann W., Steiner H., Lichtenthaler S.F., Gires O. Regulated intramembrane proteolysis and degradation of murine epithelial cell adhesion molecule mEpCAM. PLoS One. 2013; 8(8). doi: 10.1371/journal.pone.0071836.

Fong D., Moser P., Kasal A., Seeber A., Gastl G., Martowicz A., Wurm M., Mian C., Obrist P., Mazzoleni G., Spizzo G. Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer. Histopathology. 2014; 64(5): 683–92. doi: 10.1111/his.12307.

Winter M.J., Nagelkerken B., Mertens A.E., Rees-Bakker H.A., Briaire-de Bruijn I.H., Litvinov S.V. Expression of Ep-CAM shifts the state of cadherin-mediated adhesions from strong to weak. Exp Cell Res. 2003; 285(1): 50–8. doi: 10.1016/s0014-4827(02)00045-9.

van der Gun B.T., Melchers L.J., Ruiters M.H., de Leij L.F., McLaughlin P.M., Rots M.G. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis. 2010; 31(11): 1913–21. doi: 10.1093/carcin/bgq187.

Chaves-Perez A., Mack B., Maetzel D., Kremling H., Eggert C., Harreus U., Gires O. EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene. 2013; 32(5): 641–50. doi: 10.1038/onc.2012.75.

Maaser K., Borlak J. A genome-wide expression analysis identifes a network of EpCAM-induced cell cycle regulators. Br J Cancer. 2008; 99(10): 1635–43. doi: 10.1038/sj.bjc.6604725.

Pan M., Schinke H., Luxenburger E., Kranz G., Shakhtour J., Libl D., Huang Y., Gaber A., Pavšič M., Lenarčič B., Kitz J., Jakob M., Schwenk-Zieger S., Canis M., Hess J., Unger K., Baumeister P., Gires O. EpCAM ectodomain EpEX is a ligand of EGFR that counteracts EGFmediated epithelial-mesenchymal transition through modulation of phospho-ERK1/2 in head and neck cancers. PLoS Biol. 2018; 16(9). doi: 10.1371/journal.pbio.2006624.

Lin C.W., Liao M.Y., Lin W.W., Wang Y.P., Lu T.Y., Wu H.C. Epithelial cell adhesion molecule regulates tumor initiation and tumorigenesis via activating reprogramming factors and epithelial-mesenchymal transition gene expression in colon cancer. J Biol Chem. 2012; 287(47): 39449–59. doi: 10.1074/jbc.M112.386235.

Driemel C., Kremling H., Schumacher S., Will D., Wolters J., Lindenlauf N., Mack B., Baldus S.A., Hoya V., Pietsch J.M., Panagiotidou P., Raba K., Vay C., Vallböhmer D., Harréus U., Knoefel W.T., Stoecklein N.H., Gires O. Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene. 2014; 33(41): 4904–15. doi: 10.1038/onc.2013.441.

Martowicz A., Spizzo G., Gastl G., Untergasser G. Phenotype-dependent efects of EpCAM expression on growth and invasion of human breast cancer cell lines. BMC Cancer. 2012; 12. doi: 10.1186/1471-2407-12-501.

Gosens M.J., van Kempen L.C., van de Velde C.J., van Krieken J.H., Nagtegaal I.D. Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol. 2007; 20(2): 221–32. doi: 10.1038/modpathol.3800733.

Shi R., Liu L., Wang F., He Y., Niu Y., Wang C., Zhang X., Zhang X., Zhang H., Chen M., Wang Y. Down-regulation of cytokeratin 18 induces cellular partial EMT and stemness through increasing EpCAM expression in breast cancer. Cell Signal. 2020; 76. doi: 10.1016/j.cellsig.2020.109810.

Huang H.P., Chen P.H., Yu C.Y., Chuang C.Y., Stone L., Hsiao W.C., Li C.L., Tsai S.C., Chen K.Y., Chen H.F., Ho H.N., Kuo H.C. Epithelial cell adhesion molecule (EpCAM) complex proteins promote transcription factor-mediated pluripotency reprogramming. J Biol Chem. 2011; 286(38): 33520–32. doi: 10.1074/jbc.M111.256164.

Zhang D., Yang L., Liu X., Gao J., Liu T., Yan Q., Yang X. Hypoxia modulates stem cell properties and induces EMT through N-glycosylation of EpCAM in breast cancer cells. J Cell Physiol. 2020; 235(4): 3626–33. doi: 10.1002/jcp.29252.

Nicolazzo C., Massimi I., Lotti L.V., Vespa S., Raimondi C., Pulcinelli F.M., Gradilone A., Gazzaniga P. Impact of chronic exposure to bevacizumab on EpCAM-based detection of circulating tumor cells. Chin J Cancer Res. 2015; 27(5): 491–6. doi: 10.3978/j.issn.1000-9604.2015.04.09.

Lu T.Y., Lu R.M., Liao M.Y., Yu J., Chung C.H., Kao C.F., Wu H.C. Epithelial cell adhesion molecule regulation is associated with the maintenance of the undiferentiated phenotype of human embryonic stem cells. J Biol Chem. 2010; 285(12): 8719–32. doi: 10. 1074/jbc.M109.077081.

Gorges T.M., Tinhofer I., Drosch M., Röse L., Zollner T.M., Krahn T., von Ahsen O. Circulating tumour cells escape from EpCAMbased detection due to epithelial-to-mesenchymal transition. BMC Cancer. 2012; 12. doi: 10.1186/1471-2407-12-178.

Königsberg R., Obermayr E., Bises G., Pfeiler G., Gneist M., Wrba F., de Santis M., Zeillinger R., Hudec M., Dittrich C. Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. Acta Oncol. 2011; 50(5). doi: 10.3109/0284186X.2010.549151.

Alberti S., Ambrogi F., Boracchi P., Fornili M., Querzoli P., Pedriali M., La Sorda R., Lattanzio R., Tripaldi R., Piantelli M., Biganzoli E., Coradini D. Cytoplasmic Trop-1/Ep-CAM overexpression is associated with a favorable outcome in node-positive breast cancer. Jpn J Clin Oncol. 2012; 42(12): 1128–37. doi: 10.1093/jjco/hys159.

Rao C.G., Chianese D., Doyle G.V., Miller M.C., Russell T., Sanders R.A. Jr, Terstappen L.W. Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol. 2005; 27(1): 49–57.

Seeber A., Untergasser G., Spizzo G., Terracciano L., Lugli A., Kasal A., Kocher F., Steiner N., Mazzoleni G., Gastl G., Fong D. Predominant expression of truncated EpCAM is associated with a more aggressive phenotype and predicts poor overall survival in colorectal cancer. Int J Cancer. 2016; 139(3): 657–63. doi: 10.1002/ijc.30099.

The human protein atlas. [Internet]. [cited 2024 Sep 2]. URL: https://www.proteinatlas.org/ENSG00000119888-EPCAM/tissue.

Bantikassegn A., Song X., Politi K. Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogeneinduced lung adenocarcinomas. Am J Respir Cell Mol Biol. 2015; 52(4): 409–17. doi: 10.1165/rcmb.2014-0312MA.

Hattoum A., Rubin E., Orr A., Michalopoulos G.K. Expression of hepatocyte epidermal growth factor receptor, FAS and glypican 3 in EpCAM-positive regenerative clusters of hepatocytes, cholangiocytes, and progenitor cells in human liver failure. Hum Pathol. 2013; 44(5): 743–9. doi: 10.1016/j.humpath.2012.07.018.

Litvinov S.V., van Driel W., van Rhijn C.M., Bakker H.A., van Krieken H., Fleuren G.J., Warnaar S.O. Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal diferentiation. Am J Pathol. 1996; 148(3): 865–75.

Went P., Vasei M., Bubendorf L., Terracciano L., Tornillo L., Riede U., Kononen J., Simon R., Sauter G., Baeuerle P.A. Frequent highlevel expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer. 2006; 94(1): 128-35. doi: 10.1038/sj.bjc.6602924.

Poczatek R.B., Myers R.B., Manne U., Oelschlager D.K., Weiss H.L., Bostwick D.G., Grizzle W.E. Ep-Cam levels in prostatic adenocarcinoma and prostatic intraepithelial neoplasia. J Urol. 1999; 162(4): 1462–6.

Gabriel M.T., Calleja L.R., Chalopin A., Ory B., Heymann D. Circulating Tumor Cells: A Review of Non-EpCAM-Based Approaches for Cell Enrichment and Isolation. Clin Chem. 2016; 62(4): 571–81. doi: 10.1373/clinchem.2015.249706.

Yanamoto S., Kawasaki G., Yoshitomi I., Iwamoto T., Hirata K., Mizuno A. Clinicopathologic significance of EpCAM expression in squamous cell carcinoma of the tongue and its possibility as a potential target for tongue cancer gene therapy. Oral Oncol. 2007; 43(9): 869–77. doi: 10.1016/j.oraloncology.2006.10.010.

Went P.T., Lugli A., Meier S., Bundi M., Mirlacher M., Sauter G., Dirnhofer S. Frequent EpCam protein expression in human carcinomas. Hum Pathol. 2004; 35(1): 122–8. doi: 10.1016/j.humpath.2003.08.026.

Assi J., Srivastava G., Matta A., MacMillan C., Ralhan R., Walfsh P.G. Nuclear Ep-ICD expression is a predictor of poor prognosis in “low risk” prostate adenocarcinomas. PLoS One. 2015; 10(2). doi: 10.1371/journal.pone.0107586.

Ralhan R., He H.C., So A.K., Tripathi S.C., Kumar M., Hasan M.R., Kaur J., Kashat L., MacMillan C., Chauhan S.S., Freeman J.L., Walfsh P.G. Nuclear and cytoplasmic accumulation of Ep-ICD is frequently detected in human epithelial cancers. PLoS One. 2010; 5(11). doi: 10.1371/journal.pone.0014130.

Fan Q., Cheng J.C., Qiu X., Chang H.M., Leung P.C. EpCAM is up-regulated by EGF via ERK1/2 signaling and suppresses human epithelial ovarian cancer cell migration. Biochem Biophys Res Commun. 2015; 457(3): 256–61. doi: 10.1016/j.bbrc.2014.12.097.

Spizzo G., Went P., Dirnhofer S., Obrist P., Simon R., Spichtin H., Maurer R., Metzger U., von Castelberg B., Bart R., Stopatschinskaya S., Köchli O.R., Haas P., Mross F., Zuber M., Dietrich H., Bischoff S., Mirlacher M., Sauter G., Gastl G. High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat. 2004; 86(3): 207–13. doi: 10.1023/B:BREA.0000036787.59816.01.

Spizzo G., Went P., Dirnhofer S., Obrist P., Moch H., Baeuerle P.A., Mueller-Holzner E., Marth C., Gastl G., Zeimet A.G. Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer. Gynecol Oncol. 2006; 103(2): 483–8. doi: 10.1016/j.ygyno.2006.03.035.

Somasundaram R.T., Kaur J., Leong I., MacMillan C., Witterick I.J., Walfsh P.G., Ralhan R. Subcellular diferential expression of Ep-ICD in oral dysplasia and cancer is associated with disease progression and prognosis. BMC Cancer. 2016; 16. doi: 10.1186/s12885-016-2507-7.

Kunavisarut T., Kak I., Macmillan C., Ralhan R., Walfsh P.G. Immunohistochemical analysis based Ep-ICD subcellular localization index (ESLI) is a novel marker for metastatic papillary thyroid microcarcinoma. BMC Cancer. 2012; 12. doi: 10.1186/1471-2407-12-523.

Srivastava G., Assi J., Kashat L., Matta A., Chang M., Walfsh P.G., Ralhan R. Nuclear Ep-ICD accumulation predicts aggressive clinical course in early stage breast cancer patients. BMC Cancer. 2014; 14. doi: 10.1186/1471-2407-14-726.

Songun I., Litvinov S.V., van de Velde C.J., Pals S.T., Hermans J., van Krieken J.H. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer. 2005; 92(9): 1767–72. doi: 10.1038/sj.bjc.6602519.

Kim Y., Kim H.S., Cui Z.Y., Lee H.S., Ahn J.S., Park C.K., Park K., Ahn M.J. Clinicopathological implications of EpCAM expression in adenocarcinoma of the lung. Anticancer Res. 2009; 29(5): 1817–22.

Kimura H., Kato H., Faried A., Sohda M., Nakajima M., Fukai Y., Miyazaki T., Masuda N., Fukuchi M., Kuwano H. Prognostic signifcance of EpCAM expression in human esophageal cancer. Int J Oncol. 2007; 30(1): 171–9.

Stoecklein N.H., Siegmund A., Scheunemann P., Luebke A.M., Erbersdobler A., Verde P.E., Eisenberger C.F., Peiper M., Rehders A., Esch J.S., Knoefel W.T., Hosch S.B. Ep-CAM expression in squamous cell carcinoma of the esophagus: a potential therapeutic target and prognostic marker. BMC Cancer. 2006; 6. doi: 10.1186/1471-2407-6-165.

Osta W.A., Chen Y., Mikhitarian K., Mitas M., Salem M., Hannun Y.A., Cole D.J., Gillanders W.E. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004; 64(16): 5818–24. doi: 10.1158/0008-5472.CAN-04-0754.

Soysal S.D., Muenst S., Barbie T., Fleming T., Gao F., Spizzo G., Oertli D., Viehl C.T., Obermann E.C., Gillanders W.E. EpCAM expression varies signifcantly and is diferentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer. Br J Cancer. 2013; 108(7): 1480–7. doi: 10.1038/bjc.2013.80.

de Wit S., Manicone M., Rossi E., Lampignano R., Yang L., Zill B., Rengel-Puertas A., Ouhlen M., Crespo M., Berghuis A.M.S., Andree K.C., Vidotto R., Trapp E.K., Tzschaschel M., Colomba E., Fowler G., Flohr P., Rescigno P., Fontes M.S., Zamarchi R., Fehm T., Neubauer H., Rack B., Alunni-Fabbroni M., Farace F., De Bono J., IJzerman M.J., Terstappen L.W.M.M. EpCAMhigh and EpCAMlow circulating tumor cells in metastatic prostate and breast cancer patients. Oncotarget. 2018; 9(86): 35705–16. doi: 10.18632/oncotarget.26298.

Frederick B.A., Helfrich B.A., Coldren C.D., Zheng D., Chan D., Bunn P.A. Jr, Raben D. Epithelial to mesenchymal transition predicts geftinib resistance in cell lines of head and neck squamous cell carcinoma and non-small cell lung carcinoma. Mol Cancer Ther. 2007; 6(6): 1683–91. doi: 10.1158/1535-7163.MCT-07-0138.

Santisteban M., Reiman J.M., Asiedu M.K., Behrens M.D., Nassar A., Kalli K.R., Haluska P., Ingle J.N., Hartmann L.C., Manjili M.H., Radisky D.C., Ferrone S., Knutson K.L. Immune-induced epithelial to mesenchymal transition in vivo generates breast cancer stem cells. Cancer Res; 69(7): 2887–95. doi: 10.1158/0008-5472.CAN-08-3343.

de Wit S., van Dalum G., Lenferink A.T., Tibbe A.G., Hiltermann T.J., Groen H.J., van Rijn C.J., Terstappen L.W. The detection of EpCAM(+) and EpCAM(-) circulating tumor cells. Sci Rep. 2015; 5. doi: 10.1038/srep12270.

Nicolazzo C., Gradilone A., Loreni F., Raimondi C., Gazzaniga P. EpCAMlow Circulating Tumor Cells: Gold in the Waste. Dis Markers. 2019. doi: 10.1155/2019/1718920.

Miki Y., Yashiro M., Okuno T., Kitayama K., Tamura T., Toyokawa T., Tanaka H., Muguruma K., Hirakawa K., Ohira M. Clinical signifcance of EpCAM-negative and CEA-positive circulating tumor cells in gastric carcinoma. Cancer Research. 2017; 77(13). doi: 10.1158/1538-7445.AM2017-3791.

Wen K.C., Sung P.L., Chou Y.T., Pan C.M., Wang P.H., Lee O.K., Wu C.W. The role of EpCAM in tumor progression and the clinical prognosis of endometrial carcinoma. Gynecol Oncol. 2018; 148(2): 383–92. doi: 10.1016/j.ygyno.2017.11.033.

Gazzaniga P., Raimondi C., Gradilone A., Di Seri M., Longo F., Cortesi E., Frati L. Circulating tumor cells, colon cancer and bevacizumab: the meaning of zero. Ann Oncol. 2011; 22(8): 1929–30. doi: 10.1093/annonc/mdr292.

Mego M., De Giorgi U., Dawood S., Wang X., Valero V., Andreopoulou E., Handy B., Ueno N.T., Reuben J.M., Cristofanilli M. Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells. Int J Cancer. 2011; 129(2): 417–23. doi: 10.1002/ijc.25690.

Lustberg M.B., Balasubramanian P., Miller B., Garcia-Villa A., Deighan C., Wu Y., Carothers S., Berger M., Ramaswamy B., Macrae E.R., Wesolowski R., Layman R.M., Mrozek E., Pan X., Summers T.A., Shapiro C.L., Chalmers J.J. Heterogeneous atypical cell populations are present in blood of metastatic breast cancer patients. Breast Cancer Res. 2014; 16(2). doi: 10.1186/bcr3622.

Satelli A., Brownlee Z., Mitra A., Meng Q.H., Li S. Circulating tumor cell enumeration with a combination of epithelial cell adhesion molecule- and cell-surface vimentin-based methods for monitoring breast cancer therapeutic response. Clin Chem. 2015; 61(1): 259–66. doi: 10.1373/clinchem.2014.228122.

Steinert G., Schölch S., Niemietz T., Iwata N., García S.A., Behrens B., Voigt A., Kloor M., Benner A., Bork U., Rahbari N.N., Büchler M.W., Stoecklein N.H., Weitz J., Koch M. Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res. 2014; 74(6): 1694–704. doi: 10.1158/0008-5472.CAN-13-1885.

Scheunemann P., Stoecklein N.H., Hermann K., Rehders A., Eisenberger C.F., Knoefel W.T., Hosch S.B. Occult disseminated tumor cells in lymph nodes of patients with gastric carcinoma. A critical appraisal of assessment and relevance. Langenbecks Arch Surg. 2009; 394(1): 105–13. doi: 10.1007/s00423-008-0369-4.

Went P., Dirnhofer S., Salvisberg T., Amin M.B., Lim S.D., Diener P.A., Moch H. Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors. Am J Surg Pathol. 2005; 29(1): 83–8. doi: 10.1097/01.pas.0000.146028.70868.7a.

Cimino A., Halushka M., Illei P., Wu X., Sukumar S., Argani P. Epithelial cell adhesion molecule (EpCAM) is overexpressed in breast cancer metastases. Breast Cancer Res Treat. 2010; 123(3): 701–8. doi: 10.1007/s10549-009-0671-z.

Massoner P., Thomm T., Mack B., Untergasser G., Martowicz A., Bobowski K., Klocker H., Gires O., Puhr M. EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205. Br J Cancer. 2014; 111(5): 955–64. doi: 10.1038/bjc.2014.366.

Bellone S., Siegel E.R., Cocco E., Cargnelutti M., Silasi D.A., Azodi M., Schwartz P.E., Rutherford T.J., Pecorelli S., Santin A.D. Overexpression of epithelial cell adhesion molecule in primary, metastatic, and recurrent/chemotherapy-resistant epithelial ovarian cancer: implications for epithelial cell adhesion molecule-specifc immunotherapy. Int J Gynecol Cancer. 2009; 19(5): 860–6. doi: 10.1111/IGC.0b013e3181a8331f.

Jojović M., Adam E., Zangemeister-Wittke U., Schumacher U. Epithelial glycoprotein-2 expression is subject to regulatory processes in epithelial-mesenchymal transitions during metastases: an investigation of human cancers transplanted into severe combined immunodefcient mice. Histochem J. 1998; 30(10): 723–9. doi: 10.1023/a:1003486630314.

The authors declare that there are no conflicts of interest present.