Abstract
Formation of metastasis is the most important and lethal step in cancer progression. Circulating and disseminated cancer cells (CTCs/DTCs) in blood and bone marrow are considered as potential metastases-inducing cells. Their detection and characterization has, therefore, become a field of major interest in translational and clinical research in oncology. The main strategy to detect these cells relies thus far on the epithelial characteristics of carcinoma cells and epithelial cell adhesion molecule (EpCAM) represents the most commonly used epithelial marker to capture CTCs/DTCs. Recent data, however, demonstrated a dynamic expression of EpCAM associated with a loss during epithelial-to-mesenchymal transition. The present review summarizes the potential mechanisms and reasons for a dynamic expression of EpCAM.
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Klein CA (2009) Parallel progression of primary tumours and metastases. Nat Rev Cancer 9(4):302–312. doi:10.1038/nrc2627
Klein CA, Stoecklein NH (2009) Lessons from an aggressive cancer: evolutionary dynamics in esophageal carcinoma. Cancer Res 69(13):5285–5288. doi:10.1158/0008-5472.CAN-08-4586
Stoecklein NH, Klein CA (2010) Genetic disparity between primary tumours, disseminated tumour cells, and manifest metastasis. Int J Cancer 126(3):589–598. doi:10.1002/ijc.24916
Coumans FA, Siesling S, Terstappen LW (2013) Detection of cancer before distant metastasis. BMC Cancer 13(1):283. doi:10.1186/1471-2407-13-283
Aprile G, Giuliani F, Cordio S, Sartore-Bianchi A, Bencardino K, Ongaro E, Martines C, Giampieri R, Bordonaro R, Siena S, Cascinu S, Scartozzi M (2014) Translational challenges from the 2014 Gastrointestinal Cancers Symposium: toward a true tailored therapy through effective research. Future Oncol 10(7):1125–1128. doi:10.2217/fon.14.54
Lehmann BD, Pietenpol JA (2014) Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol 232(2):142–150. doi:10.1002/path.4280
Yap TA, Lorente D, Omlin A, Olmos D, de Bono JS (2014) Circulating tumor cells: a multifunctional biomarker. Clin Cancer Res 20(10):2553–2568. doi:10.1158/1078-0432.CCR-13-2664
Pantel K, Alix-Panabieres C (2010) Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med 16(9):398–406. doi:10.1016/j.molmed.2010.07.001
Pantel K, Alix-Panabieres C, Riethdorf S (2009) Cancer micrometastases. Nat Rev Clin Oncol 6(6):339–351. doi:10.1038/nrclinonc.2009.44
Becker TM, Caixeiro NJ, Lim SH, Tognela A, Kienzle N, Scott KF, Spring KJ, de Souza P (2014) New frontiers in circulating tumor cell analysis: a reference guide for biomolecular profiling toward translational clinical use. Int J Cancer 134(11):2523–2533. doi:10.1002/ijc.28516
Fischer JC, Niederacher D, Topp SA, Honisch E, Schumacher S, Schmitz N, Zacarias Fohrding L, Vay C, Hoffmann I, Kasprowicz NS, Hepp PG, Mohrmann S, Nitz U, Stresemann A, Krahn T, Henze T, Griebsch E, Raba K, Rox JM, Wenzel F, Sproll C, Janni W, Fehm T, Klein CA, Knoefel WT, Stoecklein NH (2013) Diagnostic leukapheresis enables reliable detection of circulating tumor cells of nonmetastatic cancer patients. Proc Natl Acad Sci USA 110(41):16580–16585. doi:10.1073/pnas.1313594110
Coumans FA, Ligthart ST, Uhr JW, Terstappen LW (2012) Challenges in the enumeration and phenotyping of CTC. Clin Cancer Res 18(20):5711–5718. doi:10.1158/1078-0432.CCR-12-1585
Saucedo-Zeni N, Mewes S, Niestroj R, Gasiorowski L, Murawa D, Nowaczyk P, Tomasi T, Weber E, Dworacki G, Morgenthaler NG, Jansen H, Propping C, Sterzynska K, Dyszkiewicz W, Zabel M, Kiechle M, Reuning U, Schmitt M, Lucke K (2012) A novel method for the in vivo isolation of circulating tumor cells from peripheral blood of cancer patients using a functionalized and structured medical wire. Int J Oncol 41(4):1241–1250. doi:10.3892/ijo.2012.1557
Schlimok G, Gottlinger H, Funke I, Swierkot S, Hauser H, Riethmuller G (1986) In vivo and in vitro labelling of epithelial tumor cells with anti 17-1A monoclonal antibodies in bone marrow of cancer patients. Hybridoma 5(Suppl 1):S163–S170
Barradas AM, Terstappen LW (2013) Towards the biological understanding of CTC: capture technologies, definitions and potential to create metastasis. Cancers 5(4):1619–1642. doi:10.3390/cancers5041619
Liu L, Liao GQ, He P, Zhu H, Liu PH, Qu YM, Song XM, Xu QW, Gao Q, Zhang Y, Chen WF, Yin YH (2008) Detection of circulating cancer cells in lung cancer patients with a panel of marker genes. Biochem Biophys Res Commun 372(4):756–760. doi:10.1016/j.bbrc.2008.05.101
Went PT, Lugli A, Meier S, Bundi M, Mirlacher M, Sauter G, Dirnhofer S (2004) Frequent EpCam protein expression in human carcinomas. Hum Pathol 35(1):122–128
Balzar M, Winter MJ, de Boer CJ, Litvinov SV (1999) The biology of the 17-1A antigen (Ep-CAM). J Mol Med 77(10):699–712
Baeuerle PA, Gires O (2007) EpCAM (CD326) finding its role in cancer. Br J Cancer 96(3):417–423
Imrich S, Hachmeister M, Gires O (2012) EpCAM and its potential role in tumor-initiating cells. Cell Adh Migr 6(1):30–38. doi:10.4161/cam.18953
Gonzalez B, Denzel S, Mack B, Conrad M, Gires O (2009) EpCAM is involved in maintenance of the murine embryonic stem cell phenotype. Stem Cells 27(8):1782–1791. doi:10.1002/stem.97
Ng VY, Ang SN, Chan JX, Choo AB (2009) Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. Stem Cells. doi:10.1002/stem.221
Terstappen LW, Rao C, Gross S, Kotelnikov V, Racilla E, Uhr J, Weiss A (1998) Flow cytometry–principles and feasibility in transfusion medicine. Enumeration of epithelial derived tumor cells in peripheral blood. Vox Sang 74(Suppl 2):269–274
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351(8):781–791. doi:10.1056/NEJMoa040766
Wallwiener M, Hartkopf AD, Baccelli I, Riethdorf S, Schott S, Pantel K, Marme F, Sohn C, Trumpp A, Rack B, Aktas B, Solomayer EF, Muller V, Janni W, Schneeweiss A, Fehm TN (2013) The prognostic impact of circulating tumor cells in subtypes of metastatic breast cancer. Breast Cancer Res Treat 137(2):503–510. doi:10.1007/s10549-012-2382-0
Zhang L, Riethdorf S, Wu G, Wang T, Yang K, Peng G, Liu J, Pantel K (2012) Meta-analysis of the prognostic value of circulating tumor cells in breast cancer. Clin Cancer Res 18(20):5701–5710. doi:10.1158/1078-0432.CCR-12-1587
Danila DC, Heller G, Gignac GA, Gonzalez-Espinoza R, Anand A, Tanaka E, Lilja H, Schwartz L, Larson S, Fleisher M, Scher HI (2007) Circulating tumor cell number and prognosis in progressive castration-resistant prostate cancer. Clin Cancer Res 13(23):7053–7058. doi:10.1158/1078-0432.CCR-07-1506
Cohen SJ, Punt CJ, Iannotti N, Saidman BH, Sabbath KD, Gabrail NY, Picus J, Morse M, Mitchell E, Miller MC, Doyle GV, Tissing H, Terstappen LW, Meropol NJ (2008) Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol 26(19):3213–3221. doi:10.1200/JCO.2007.15.8923
Lucci A, Hall CS, Lodhi AK, Bhattacharyya A, Anderson AE, Xiao L, Bedrosian I, Kuerer HM, Krishnamurthy S (2012) Circulating tumour cells in non-metastatic breast cancer: a prospective study. Lancet Oncol 13(7):688–695. doi:10.1016/S1470-2045(12)70209-7
Rack B, Schindlbeck C, Juckstock J, Andergassen U, Hepp P, Zwingers T, Friedl TW, Lorenz R, Tesch H, Fasching PA, Fehm T, Schneeweiss A, Lichtenegger W, Beckmann MW, Friese K, Pantel K, Janni W, Group SS (2014) Circulating tumor cells predict survival in early average-to-high risk breast cancer patients. J Natl Cancer Inst 106(5). doi:10.1093/jnci/dju066
Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bauerle T, Wallwiener M, Holland-Letz T, Hofner T, Sprick M, Scharpff M, Marme F, Sinn HP, Pantel K, Weichert W, Trumpp A (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544. doi:10.1038/nbt.2576
Litvinov SV, Bakker HA, Gourevitch MM, Velders MP, Warnaar SO (1994) Evidence for a role of the epithelial glycoprotein 40 (Ep-CAM) in epithelial cell–cell adhesion. Cell Adhes Commun 2(5):417–428
Punnoose EA, Atwal SK, Spoerke JM, Savage H, Pandita A, Yeh RF, Pirzkall A, Fine BM, Amler LC, Chen DS, Lackner MR (2010) Molecular biomarker analyses using circulating tumor cells. PLoS ONE 5(9):e12517. doi:10.1371/journal.pone.0012517
Sieuwerts AM, Kraan J, Bolt J, van der Spoel P, Elstrodt F, Schutte M, Martens JW, Gratama JW, Sleijfer S, Foekens JA (2009) Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. J Natl Cancer Inst 101(1):61–66. doi:10.1093/jnci/djn419
Rao CG, Chianese D, Doyle GV, Miller MC, Russell T, Sanders RA Jr, Terstappen LW (2005) Expression of epithelial cell adhesion molecule in carcinoma cells present in blood and primary and metastatic tumors. Int J Oncol 27(1):49–57
Steinert G, Scholch S, Niemietz T, Iwata N, Garcia SA, Behrens B, Voigt A, Kloor M, Benner A, Bork U, Rahbari NN, Buchler MW, Stoecklein NH, Weitz J, Koch M (2014) Immune escape and survival mechanisms in circulating tumor cells of colorectal cancer. Cancer Res 74(6):1694–1704. doi:10.1158/0008-5472.CAN-13-1885
Driemel C, Kremling H, Schumacher S, Will D, Wolters J, Lindenlauf N, Mack B, Baldus SA, Hoya V, Pietsch JM, Panagiotidou P, Raba K, Vay C, Vallbohmer D, Harreus U, Knoefel WT, Stoecklein NH, Gires O (2013) Context-dependent adaption of EpCAM expression in early systemic esophageal cancer. Oncogene. doi:10.1038/onc.2013.441
Zhang L, Ridgway LD, Wetzel MD, Ngo J, Yin W, Kumar D, Goodman JC, Groves MD, Marchetti D (2013) The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci Transl Med 5((180)):180ra148. doi:10.1126/scitranslmed.3005109
Gorges TM, Tinhofer I, Drosch M, Rose L, Zollner TM, Krahn T, von Ahsen O (2012) Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition. BMC Cancer 12:178. doi:10.1186/1471-2407-12-178
Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890. doi:10.1016/j.cell.2009.11.007
Thiery JP, Lim CT (2013) Tumor dissemination: an EMT affair. Cancer Cell 23(3):272–273. doi:10.1016/j.ccr.2013.03.004
Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 5(9):744–749. doi:10.1038/nrc1694
Yang J, Weinberg RA (2008) Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell 14(6):818–829. doi:10.1016/j.devcel.2008.05.009
Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22(6):725–736. doi:10.1016/j.ccr.2012.09.022
Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ, Bell G, Guo W, Rubin J, Richardson AL, Weinberg RA (2011) Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145(6):926–940. doi:10.1016/j.cell.2011.04.029
Heldin CH, Landstrom M, Moustakas A (2009) Mechanism of TGF-beta signaling to growth arrest, apoptosis, and epithelial-mesenchymal transition. Curr Opin Cell Biol 21(2):166–176. doi:10.1016/j.ceb.2009.01.021
Moustakas A, Heldin CH (2007) Signaling networks guiding epithelial-mesenchymal transitions during embryogenesis and cancer progression. Cancer Sci 98(10):1512–1520. doi:10.1111/j.1349-7006.2007.00550.x
Kim K, Lu Z, Hay ED (2002) Direct evidence for a role of beta-catenin/LEF-1 signaling pathway in induction of EMT. Cell Biol Int 26(5):463–476
Tam WL, Weinberg RA (2013) The epigenetics of epithelial-mesenchymal plasticity in cancer. Nat Med 19(11):1438–1449. doi:10.1038/nm.3336
Nakaya Y, Kuroda S, Katagiri YT, Kaibuchi K, Takahashi Y (2004) Mesenchymal-epithelial transition during somitic segmentation is regulated by differential roles of Cdc42 and Rac1. Dev Cell 7(3):425–438. doi:10.1016/j.devcel.2004.08.003
Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, Vadas MA, Khew-Goodall Y, Goodall GJ (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601. doi:10.1038/ncb1722
Massoner P, Thomm T, Mack B, Untergasser G, Martowicz A, Bobowski K, Klocker H, Gires O, Puhr M (2014) EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205. Br J Cancer. doi:10.1038/bjc.2014.366
Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES (2011) Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146(4):633–644. doi:10.1016/j.cell.2011.07.026
Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, Isakoff SJ, Ciciliano JC, Wells MN, Shah AM, Concannon KF, Donaldson MC, Sequist LV, Brachtel E, Sgroi D, Baselga J, Ramaswamy S, Toner M, Haber DA, Maheswaran S (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584. doi:10.1126/science.1228522
Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S (2009) Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 11(4):R46. doi:10.1186/bcr2333
Cierna Z, Mego M, Janega P, Karaba M, Minarik G, Benca J, Sedlackova T, Cingelova S, Gronesova P, Manasova D, Pindak D, Sufliarsky J, Danihel L, Reuben JM, Mardiak J (2014) Matrix metalloproteinase 1 and circulating tumor cells in early breast cancer. BMC Cancer 14:472. doi:10.1186/1471-2407-14-472
Winkler J, Martin-Killias P, Pluckthun A, Zangemeister-Wittke U (2009) EpCAM-targeted delivery of nanocomplexed siRNA to tumor cells with designed ankyrin repeat proteins. Mol Cancer Ther 8(9):2674–2683. doi:10.1158/1535-7163.MCT-09-0402
Gosens MJ, van Kempen LC, van de Velde CJ, van Krieken JH, Nagtegaal ID (2007) Loss of membranous Ep-CAM in budding colorectal carcinoma cells. Mod Pathol 20(2):221–232. doi:10.1038/modpathol.3800733
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 (2012) Cytoplasmic Trop-1/Ep-CAM overexpression is associated with a favorable outcome in node-positive breast cancer. Jpn J Clin Oncol 42(12):1128–1137. doi:10.1093/jjco/hys159
Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69(14):5627–5629. doi:10.1158/0008-5472.CAN-09-0654
Carpenter G, Red Brewer M (2009) EpCAM: another surface-to-nucleus missile. Cancer Cell 15(3):165–166. doi:10.1016/j.ccr.2009.02.005
Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, Gires O (2009) Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11(2):162–171. doi:10.1038/ncb1824
Hachmeister M, Bobowski KD, Hogl S, Dislich B, Fukumori A, Eggert C, Mack B, Kremling H, Sarrach S, Coscia F, Zimmermann W, Steiner H, Lichtenthaler SF, Gires O (2013) Regulated intramembrane proteolysis and degradation of murine epithelial cell adhesion molecule mEpCAM. PLoS ONE 8(8):e71836. doi:10.1371/journal.pone.0071836
Spizzo G, Gastl G, Obrist P, Fong D, Haun M, Grunewald K, Parson W, Eichmann C, Millinger S, Fiegl H, Margreiter R, Amberger A (2006) Methylation status of the Ep-CAM promoter region in human breast cancer cell lines and breast cancer tissue. Cancer Lett 246(1):253–261
Lu TY, Lu RM, Liao MY, Yu J, Chung CH, Kao CF, Wu HC (2010) Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chem 285(12):8719–8732. doi:10.1074/jbc.M109.077081
Tai KY, Shiah SG, Shieh YS, Kao YR, Chi CY, Huang E, Lee HS, Chang LC, Yang PC, Wu CW (2007) DNA methylation and histone modification regulate silencing of epithelial cell adhesion molecule for tumor invasion and progression. Oncogene 26(27):3989–3997
Vannier C, Mock K, Brabletz T, Driever W (2013) Zeb1 regulates E-cadherin and Epcam expression to control cell behavior in early zebrafish development. J Biol Chem. doi:10.1074/jbc.M113.467787
Lynch HT, Lynch JF, Snyder CL, Riegert-Johnson D (2011) EPCAM deletions, lynch syndrome, and cancer risk. Lancet Oncol 12(1):5–6. doi:10.1016/S1470-2045(10)70291-6
Kastrinos F, Stoffel EM (2014) History, genetics, and strategies for cancer prevention in lynch syndrome. Clin Gastroenterol Hepatol 12(5):715–727. doi:10.1016/j.cgh.2013.06.031
Slanchev K, Carney TJ, Stemmler MP, Koschorz B, Amsterdam A, Schwarz H, Hammerschmidt M (2009) The epithelial cell adhesion molecule EpCAM is required for epithelial morphogenesis and integrity during zebrafish epiboly and skin development. PLoS Genet 5(7):e1000563. doi:10.1371/journal.pgen.1000563
Maghzal N, Vogt E, Reintsch W, Fraser JS, Fagotto F (2010) The tumor-associated EpCAM regulates morphogenetic movements through intracellular signaling. J Cell Biol 191(3):645–659. doi:10.1083/jcb.201004074
Maghzal N, Kayali HA, Rohani N, Kajava AV, Fagotto F (2013) EpCAM controls actomyosin contractility and cell adhesion by direct inhibition of PKC. Dev Cell 27(3):263–277. doi:10.1016/j.devcel.2013.10.003
Balzar M, Briaire-de Bruijn IH, Rees-Bakker HA, Prins FA, Helfrich W, de Leij L, Riethmuller G, Alberti S, Warnaar SO, Fleuren GJ, Litvinov SV (2001) Epidermal growth factor-like repeats mediate lateral and reciprocal interactions of Ep-CAM molecules in homophilic adhesions. Mol Cell Biol 21(7):2570–2580
Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, Warnaar SO (1997) Epithelial cell adhesion molecule (Ep-CAM) modulates cell–cell interactions mediated by classic cadherins. J Cell Biol 139(5):1337–1348
Lei Z, Maeda T, Tamura A, Nakamura T, Yamazaki Y, Shiratori H, Yashiro K, Tsukita S, Hamada H (2012) EpCAM contributes to formation of functional tight junction in the intestinal epithelium by recruiting claudin proteins. Dev Biol 371(2):136–145. doi:10.1016/j.ydbio.2012.07.005
Guerra E, Lattanzio R, La Sorda R, Dini F, Tiboni GM, Piantelli M, Alberti S (2012) mTrop1/Epcam knockout mice develop congenital tufting enteropathy THROUGH dysregulation of intestinal E-cadherin/beta-catenin. PLoS ONE 7(11):e49302. doi:10.1371/journal.pone.0049302
Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE (2004) EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 64(16):5818–5824
Sankpal NV, Willman MW, Fleming TP, Mayfield JD, Gillanders WE (2009) Transcriptional repression of epithelial cell adhesion molecule contributes to p53 control of breast cancer invasion. Cancer Res 69(3):753–757
Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE, Mackenzie IC (2011) Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71(15):5317–5326. doi:10.1158/0008-5472.CAN-11-1059
Martowicz A, Spizzo G, Gastl G, Untergasser G (2012) Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines. BMC Cancer 12:501. doi:10.1186/1471-2407-12-501
Soysal SD, Muenst S, Barbie T, Fleming T, Gao F, Spizzo G, Oertli D, Viehl CT, Obermann EC, Gillanders WE (2013) EpCAM expression varies significantly and is differentially associated with prognosis in the luminal B HER2(+), basal-like, and HER2 intrinsic subtypes of breast cancer. Br J Cancer 108(7):1480–1487. doi:10.1038/bjc.2013.80
Munz M, Hofmann T, Scheibe B, Gange M, Junghanns K, Zeidler R, Gires O (2004) The carcinoma-associated antigen EpCAM induces glyoxalase 1 resulting in enhanced methylglyoxal turnover. Cancer Genomics Proteomics 1(3):241–247
Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O (2004) The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23(34):5748–5758
Munz M, Zeidler R, Gires O (2005) The tumor-associated antigen EpCAM up-regulates the fatty acid binding protein E-FABP. Cancer Lett 225(1):151–157
Chaves-Perez A, Mack B, Maetzel D, Kremling H, Eggert C, Harreus U, Gires O (2013) EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene 32(5):641–650. doi:10.1038/onc.2012.75
Lu H, Ma J, Yang Y, Shi W, Luo L (2013) EpCAM is an endoderm-specific Wnt derepressor that licenses hepatic development. Dev Cell 24(5):543–553. doi:10.1016/j.devcel.2013.01.021
Fong D, Moser P, Kasal A, Seeber A, Gastl G, Martowicz A, Wurm M, Mian C, Obrist P, Mazzoleni G, Spizzo G (2014) Loss of membranous expression of the intracellular domain of EpCAM is a frequent event and predicts poor survival in patients with pancreatic cancer. Histopathology 64(5):683–692. doi:10.1111/his.12307
Ralhan R, Cao J, Lim T, Macmillan C, Freeman JL, Walfish PG (2010) EpCAM nuclear localization identifies aggressive thyroid cancer and is a marker for poor prognosis. BMC Cancer 10(1):331. doi:10.1186/1471-2407-10-331
He HC, Kashat L, Kak I, Kunavisarut T, Gundelach R, Kim D, So AK, Macmillan C, Freeman JL, Ralhan R, Walfish PG (2012) An Ep-ICD based index is a marker of aggressiveness and poor prognosis in thyroid carcinoma. PLoS ONE 7(9):e42893. doi:10.1371/journal.pone.0042893
Ralhan R, He HC, So AK, Tripathi SC, Kumar M, Hasan MR, Kaur J, Kashat L, MacMillan C, Chauhan SS, Freeman JL, Walfish PG (2010) Nuclear and cytoplasmic accumulation of Ep-ICD is frequently detected in human epithelial cancers. PLoS ONE 5(11):e14130. doi:10.1371/journal.pone.0014130
Maaser K, Borlak J (2008) A genome-wide expression analysis identifies a network of EpCAM-induced cell cycle regulators. Br J Cancer 99(10):1635–1643
Yoshida GJ, Saya H (2014) EpCAM expression in the prostate cancer makes the difference in the response to growth factors. Biochem Biophys Res Commun 443(1):239–245. doi:10.1016/j.bbrc.2013.11.093
Coumans FA, van Dalum G, Beck M, Terstappen LW (2013) Filtration parameters influencing circulating tumor cell enrichment from whole blood. PLoS ONE 8(4):e61774. doi:10.1371/journal.pone.0061774
Lin HK, Zheng S, Williams AJ, Balic M, Groshen S, Scher HI, Fleisher M, Stadler W, Datar RH, Tai YC, Cote RJ (2010) Portable filter-based microdevice for detection and characterization of circulating tumor cells. Clin Cancer Res 16(20):5011–5018. doi:10.1158/1078-0432.CCR-10-1105
Schulze K, Gasch C, Staufer K, Nashan B, Lohse AW, Pantel K, Riethdorf S, Wege H (2013) Presence of EpCAM-positive circulating tumor cells as biomarker for systemic disease strongly correlates to survival in patients with hepatocellular carcinoma. Int J Cancer 133(9):2165–2171. doi:10.1002/ijc.28230
Peeters DJ, van Dam PJ, Van den Eynden GG, Rutten A, Wuyts H, Pouillon L, Peeters M, Pauwels P, Van Laere SJ, van Dam PA, Vermeulen PB, Dirix LY (2014) Detection and prognostic significance of circulating tumour cells in patients with metastatic breast cancer according to immunohistochemical subtypes. Br J Cancer 110(2):375–383. doi:10.1038/bjc.2013.743
Riethdorf S, Fritsche H, Muller V, Rau T, Schindlbeck C, Rack B, Janni W, Coith C, Beck K, Janicke F, Jackson S, Gornet T, Cristofanilli M, Pantel K (2007) Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: a validation study of the Cell Search system. Clin Cancer Res 13(3):920–928
Simon M, Stefan N, Pluckthun A, Zangemeister-Wittke U (2013) Epithelial cell adhesion molecule-targeted drug delivery for cancer therapy. Expert Opin Drug Deliv 10(4):451–468. doi:10.1517/17425247.2013.759938
Armstrong A, Eck SL (2003) EpCAM: a new therapeutic target for an old cancer antigen. Cancer Biol Ther 2(4):320–326
Acknowledgements
O. Gires and N. H. Stoecklein were funded by the Wilhelm-Sander-Stiftung (2009.083.1); O. Gires was funded by the Deutsche Forschungsgemeinschaft (DFG GI 540/3-1) and the Wilhelm-Sander-Stiftung (2012.051.1); N. H. Stoecklein was funded by the Deutsche Forschungsgemeinschaft (DFG STO464/2-2), and the Deutsche Krebshilfe e.V. (109600).
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Gires, O., Stoecklein, N.H. Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences. Cell. Mol. Life Sci. 71, 4393–4402 (2014). https://doi.org/10.1007/s00018-014-1693-1
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DOI: https://doi.org/10.1007/s00018-014-1693-1