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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review TACSTD1 (tumor-associated calcium signal transducer 1) Olivier Gires Clinical Cooperation Group Molecular Oncology, Munich Medical Center, Ludwig-Maximilians-University, Marchioninistr. 15, D-81377 Munich, Germany, and HelmholtzZentrum munchen, German Research Center for Environmental Health, Marchioninistr. 25, D-81377 Munich, Germany Published in Atlas Database: February 2008 Online updated version: http://AtlasGeneticsOncology.org/Genes/TACSTD1ID42459ch2p21.html DOI: 10.4267/2042/38601 This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence. © 2008 Atlas of Genetics and Cytogenetics in Oncology and Haematology Localisation Identity Plasma membrane; baso-lateral in normal cells; redistribution on entire plasma membrane in vitro and in carcinoma cells. Hugo: TACSTD1 Other names: EpCAM; Ep-CAM; CD326; CO17-1A; EGP; EGP40; GA733-2; KSA; Ly74; M1S2; M4S1; MIC18; MK-1; TROP1; hEGP-2 Location: 2p21 Function Homophilic cell-to-cell adhesion molecule (Litvinov et al., 1994); regulation of cadherin-mediated cell-to-cell adhesion (Litvinov et al., 1997); oncogenic signalling molecule, which is over-expressed in a plethora of carcinomas (Baeuerle and Gires, 2007); induces cell proliferation via induction of the proto-oncogene c-myc (Munz et al., 2004); intracellular domain of TACSTD1 /EpCAM is mandatory and sufficient for induction of cmyc gene expression; inhibition results in decreased proliferation and invasion (Osta et al., 2004); frequent use as a prognostic marker (Went et al., 2006; Spizzo et al., 2006) and therapeutic target (Baeuerle and Gires, 2007; RiethMüller et al., 1994; Schweizer et al., 2002; Amann et al., 2008; Ruf et al., 2007). DNA/RNA Description The gene is composed of 9 exons and encompasses. Transcription 1.528 kb mRNA; 945 bp open reading frame from base pairs 179 to 1123, (NM_002354). Pseudogene No pseudogene described so far. Protein Homology Description Retroposon GA733-1; gp50/TROP-2 (Fornaro et al., 1995), single-copy gene localised at chrom 1p32-31 TACSTD2, Accession CAA54801, 323 amino acids, calcium-dependent signalling protein. High homology of TACSTD1/EpCAM to TACSTD2/TROP-2/GA7331), especially in the extracellular domain including cystein-rich EGF-like domains, conserved region similar to thyroglobulin type I repeat (Thyr I-like repeat). 314 amino acids (aa); 265 aa extracellular domain, 23 aa transmembrane domain, 26 aa intracellular domain; 34-42 kDa glycoprotein; differential glycosylation in tumours vesus normal mucosa (Pauli et al., 2003). Expression Restricted to epithelia; mainly in simple epithelium and basal membrane cells; strong overexpression in malignancies already at the stage of dysplasia (Litvinov et al., 1996). Atlas Genet Cytogenet Oncol Haematol. 2008;12(6) 443 TACSTD1 (tumor-associated calcium signal transducer 1) Gires O Increased expression of EpCAM is a marker for decreased relapse-free survival (Stoecklein et al., 2006). Oncogenesis EpCAM is strongly overexpressed. Mutations Note: So far, no mutations of the TACSTD1/epcam gene were described. Implicated in Hepatocyte development Colon cancer Note: EpCAM is strongly expressed in differentiation hepatocytes and progenitors thereof (Schmelzer et al., 2007; Schmelzer and Reid, 2008). Oncogenesis EpCAM is strongly overexpressed and was used as a molecular target for monoclonal, therapeutic antibody 17-1A (Panorex©) (RiethMüller et al., 1994). EpCAM, in a complex with claudin-7, CD44 isoforms, and tetraspanins, is involved in colorectal cancer progression (Kuhn et al., 2007). Breakpoints Note: No breakpoints described so far. To be noted Breast cancer Note: The gene name TACSTD1, for TumourAssociated Calcium Signalling Signal Transducer 1, is highly misleading and unappropriate. EpCAM, alias TACSTD1, is in fact a signal-transducing membrane protein (Munz et al., 2004), however it is involved in calcium-independent homophilic cell-to-cell adhesion (Litvinov et al., 1994). We shall therefore propose to use the term epcam for the gene and EpCAM for the protein (Baeuerle and Gires, 2007). The characterisation of the molecular function of EpCAM in carcinoma cells pinpointed a role in signalling and regulation of gene transcription rather than cell-to-cell adhesion (Osta et al., 2004; Munz et al., 2004). With respect to cell adhesion properties of EpCAM literature is even contradictory (Fornaro et al., 1995; Litvinov et al., 1994). More recent work described EpCAM as a marker for tumour-initiating cancer stem cells in a variety of entities including colon (Dalerba et al., 2007), pancreas (Li et al., 2007), and breast carcinomas (Al-Hajj et al., 2003). A symposium on functions and clinical applications of EpCAM was initiated 2006 and will be held every two years. For more details please visit http://www.epcamsymposium.de . Prognosis Increased expression of EpCAM is a marker for poor prognosis and overall survival of patients suffering from node-positive breast cancer (Spizzo et al., 2004). Oncogenesis EpCAM is strongly overexpressed. Ovarian cancer Prognosis Increased expression of EpCAM is a marker for poor prognosis and overall survival of patients suffering from ovarian cancer (Spizzo et al., 2006). Oncogenesis EpCAM is strongly overexpressed. Renal cancer (RCC) Prognosis Increased expression of EpCAM is a marker for improved prognosis in patients suffering from clear cell RCC and might help to discriminate between chromophobe RCC and oncocytomas (Went et al., 2005). Oncogenesis EpCAM is strongly overexpressed in chromophobe RCC but not in oncocytomas. References Linnenbach AJ, Wojcierowski J, Wu SA, Pyrc JJ, Ross AH, Dietzschold B, Speicher D, Koprowski H. Sequence investigation of the major gastrointestinal tumor-associated antigen family, GA733. Proc Natl Acad Sci USA 1989;86 (1):27-31. Head and Neck Squamous Cell carcinomas (HNSCCs) Prognosis Expression of EpCAM is a marker for disseminated tumour cells in HNSCCs (Chaubal et al., 1999). Oncogenesis EpCAM is strongly overexpressed in HNSCCS. Strnad J, Hamilton AE, Beavers LS, Gamboa GC, Apelgren LD, Taber LD, Sportsman JR, Bumol TF, Sharp JD, Gadski RA. Molecular cloning and characterization of a human adenocarcinoma/epithelial cell surface antigen complementary DNA. Cancer Res 1989;49(2):314-317. Elias DJ, Hirschowitz L, Kline LE, Kroener JF, Dillman RO, Walker LE, Robb JA, Timms RM. Phase I clinical comparative study of monoclonal antibody KS1/4 and KS1/4-methotrexate immunoconjugate in patients with non-small cell lung carcinoma. Cancer Res 1990;50(13):4154-4159. Esophagus Squamous Cell carcinomas Prognosis Atlas Genet Cytogenet Oncol Haematol. 2008;12(6) 444 TACSTD1 (tumor-associated calcium signal transducer 1) Gires O Szala S, Froehlich M, Scollon M, Kasai Y, Steplewski Z, Koprowski H, Linnenbach AJ. Molecular cloning of cDNA for the carcinoma-associated antigen GA733-2. Proc Natl Acad Sci USA 1990;87(9):3542-3546. Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillander WE. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 2004;64(16):5818-5824. Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 1994;125(2):437-446. LeNaour F, André M, Greco C, Billard M, Sordat B, Emile JF, Lanza F, Boucheix C, Rubinstein E. Profiling of the tetraspanin web of human colon cancer cells. Mol Cell Proteomics 2006;5(5):845-857. Schön MP, Schön M, Klein CE, Blume U, Bisson S, Orfanos CE. Carcinoma-associated 38-kD membrane glycoprotein MH 99/KS is relatd to proliferation and age of transformed epithelial cell lines. J Invest Dermatol 1994;102(6):987-991. Baeuerle PA, Gires O. EpCAM finding its role in cancer (Review). Brit J Cancer 2007;96(3):417-423. Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoye T, Gurney A, Huang Eh, Simeone DM, Shelton AA, Pamiani G, Castelli C, Clarke MF. Phenotypic characterisation of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007;104(24):10158-10163. Cirulli V, Ricordi C, Hayek A. E-Cadherin, N-CAM, and EpCAM expression in human fetal pancreata. Transpl Proc 1995;27(6):3335. Kasper M, Behrens J, Schuh D, Müller M. Distribution of ECadherin and Ep-CAM in the human lung during development and after injury. Histochem Cell Biol 1995;103(4):281-286. Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, Smith MR, Kwak EL, Digumarthy S, Muzihansky A, Ryan P, Balis UJ, Tompkins Rg, Haber DA, Toner M. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007;450(7173):1235-1239. Kroesen BJ, Helfrich W, Bakker A, Wubbena AS, Bakker H, Kal HB, The TH, de Leij L. Reduction of EGP-2-positive pulmonary metastases by bispecific-antibody-redirected T cells in an immunocompetent rat model. Int J Cancer 1995;61(6):812-818. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R. Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445(7123):111-115. Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn ICH, Prins F, Fleuren GJ, Warnaar SO. Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol 1997;139(5):1337-1348. Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao Hk, Moss N, Melhem A, McClelland R, Turner W, Kulik M, Sherwood S, Tallheden T, Cheng N, Furth ME, Reid LM. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 2007;204(8):1973-1987. Balzar M, Winter MJ, de Boer CJ, Litvinov SV. The Biology of the 17-1A antigen (Ep-CAM) (Review). J Mol Med 1999;77(10):699-712. This article should be referenced as such: Gires O. TACSTD1 (tumor-associated calcium transducer 1). Atlas Genet Cytogenet Haematol.2008;12(6):443-445. Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G. Ep-CAM overexpression in breast cancer as a predictor of survival. Lancet 2000;356(9246):1981-1982. Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 2004;23(34):5748-5758. Atlas Genet Cytogenet Oncol Haematol. 2008;12(6) 445 signal Oncol