Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2014

01-06-2014 | Gastrointestinal Oncology

EpCAM, a Potential Therapeutic Target for Esophageal Squamous Cell Carcinoma

Authors: Tatsuo Matsuda, MD, Hiroya Takeuchi, MD, PhD, Sachiko Matsuda, PhD, Kunihiko Hiraiwa, MD, PhD, Taku Miyasho, PhD, Minoru Okamoto, PhD, Kazufumi Kawasako, PhD, Rieko Nakamura, MD, PhD, Tsunehiro Takahashi, MD, PhD, Norihito Wada, MD, PhD, Hirofumi Kawakubo, MD, PhD, Yoshiro Saikawa, MD, PhD, Tai Omori, MD, Yuko Kitagawa, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 3/2014

Login to get access

Abstract

Background

Molecular-targeted drugs are not available for esophageal squamous cell carcinoma (ESCC), which has a poor prognosis. We investigated the clinicopathological significance of epithelial cell adhesion molecule (EpCAM) expression and the utility of EpCAM as a potential therapeutic target.

Methods

The relationship between EpCAM expression and clinicopathological factors was examined by immunohistochemistry in 74 patients with resectable ESCC. A total of ten ESCC cell lines were analyzed for EpCAM expression. The effects of EpCAM knockdown in TE4, TE10, and TE14 cells were examined with regard to cell proliferation and gene expression in vitro and tumor growth in vivo. The antitumor effect of catumaxomab in ESCC cell lines was examined.

Results

EpCAM overexpression was associated with poor survival in ESCC patients (P = 0.026). Multivariate Cox regression analysis showed that EpCAM overexpression was a significant and independent prognostic factor for surgically treated ESCC (P = 0.004). TE4 and TE10 cells showed high EpCAM expression, in contrast to TE14. EpCAM siRNA knockdown in TE4 and TE10 cells downregulated CCND1 and CCNE2 and suppressed cell proliferation. Low EpCAM expression reduced tumorigenesis; TE4 cells initiated tumorigenesis in seven of the ten mice injected, whereas shRNA knockdown resulted in smaller tumors in two of ten mice at 6 weeks after transplantation. Concentration- and time-dependent antitumor effects of catumaxomab were observed in TE4 and TE10 cells.

Conclusions

EpCAM overexpression is an independent prognostic factor for surgically treated ESCC. EpCAM contributes to cell proliferation and tumorigenesis and may be a useful therapeutic target for ESCC.
Literature
1.
2.
Brenner B, Ilson DH, Minsky BD. Treatment of localized esophageal cancer. Semin Oncol. 2004;31:554–65.PubMedCrossRef
3.
4.
Yamazaki M, Yamashita Y, Kubo N, Yashiro M, Ohira M, Ako E, et al. Concurrent Biological Targeting Therapy of Squamous Cell Carcinoma of the Esophagus with Cetuximab and Trastuzumab. Oncol Rep. 2012;28:49–54.PubMed
5.
Lorenzen S, Schuster T, Porschen R, Al-Batran SE, Hofheinz R, Thuss-Patience P, et al. Cetuximab plus cisplatin-5-fluorouracil versus cisplatin-5-fluorouracil alone in first-line metastatic squamous cell carcinoma of the esophagus: a randomized phase II study of the Arbeitsgemeinschaft Internistische Onkologie. Ann Oncol. 2009;20:1667–73.PubMedCrossRef
6.
Herlyn M, Steplewski Z, Herlyn D, Koprowski H. Colorectal carcinoma-specific antigen: detection by means of monoclonal antibodies. Proc Natl Acad Sci U S A. 1979;76:1438–42.PubMedCentralPubMedCrossRef
7.
Patriarca C, Macchi RM, Marschner AK, Mellstedt H. Epithelial cell adhesion molecule expression (CD326) in cancer: a short review. Cancer Treat Rev. 2012;38:68–75.PubMedCrossRef
8.
9.
Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009;69:5627–9.PubMedCrossRef
10.
Went P, Vasei M, Bubendorf L, Terracciano L, Tornillo L, Riede U, et al. Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers. Br J Cancer. 2006;94:128–35.PubMedCentralPubMedCrossRef
11.
Varga M, Obrist P, Schneeberger S, Muhlmann G, Felgel-Farnholz C, Fong D, et al. Overexpression of epithelial cell adhesion molecule antigen in gallbladder carcinoma is an independent marker for poor survival. Clin Cancer Res. 2004;10:3131–6.PubMedCrossRef
12.
Seligson DB, Pantuck AJ, Liu X, Huang Y, Horvath S, Bui MH, et al. Epithelial cell adhesion molecule (KSA) expression: pathobiology and its role as an independent predictor of survival in renal cell carcinoma. Clin Cancer Res. 2004;10:2659–69.PubMedCrossRef
13.
Spizzo G, Went P, Dirnhofer S, Obrist P, Simon R, Spichtin H, et al. High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat. 2004;86:207–13.PubMedCrossRef
14.
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;43:869–77.PubMedCrossRef
15.
Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer. 2010;127:2209–21.PubMedCentralPubMedCrossRef
16.
Nagrath S, Sequist LV, Maheswaran S, Bell DW, Irimia D, Ulkus L, et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature. 2007;450:1235–9.PubMedCentralPubMedCrossRef
17.
Hiraiwa K, Takeuchi H, Hasegawa H, Saikawa Y, Suda K, Ando T, et al. Clinical significance of circulating tumor cells in blood from patients with gastrointestinal cancers. Ann Surg Oncol. 2008;15:3092–100.PubMedCrossRef
18.
Ruf P, Gires O, Jager M, Fellinger K, Atz J, Lindhofer H. Characterisation of the new EpCAM-specific antibody HO-3: implications for trifunctional antibody immunotherapy of cancer. Br J Cancer. 2007;97:315–21.PubMedCentralPubMedCrossRef
19.
Momburg F, Moldenhauer G, Hammerling GJ, Moller P. Immunohistochemical study of the expression of a Mr 34,000 human epithelium-specific surface glycoprotein in normal and malignant tissues. Cancer Res. 1987;47:2883–91.PubMed
20.
Schmidt M, Hasenclever D, Schaeffer M, Boehm D, Cotarelo C, Steiner E, et al. Prognostic effect of epithelial cell adhesion molecule overexpression in untreated node-negative breast cancer. Clin Cancer Res. 2008;14:5849–55.PubMedCrossRef
21.
Gastl G, Spizzo G, Obrist P, Dunser M, Mikuz G. Ep-CAM overexpression in breast cancer as a predictor of survival. Lancet. 2000;356:1981–2.PubMedCrossRef
22.
Spizzo G, Went P, Dirnhofer S, Obrist P, Moch H, Baeuerle PA, et al. 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;103:483–8.PubMedCrossRef
23.
Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, et al. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res. 2004;64:5818–24.PubMedCrossRef
24.
Litvinov SV, van Driel W, van Rhijn CM, Bakker HA, van Krieken H, Fleuren GJ, et al. Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation. Am J Pathol. 1996;148:865–75.PubMedCentralPubMed
25.
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;23:5748–58.PubMedCrossRef
26.
Munz M, Zeidler R, Gires O. The tumour-associated antigen EpCAM upregulates the fatty acid binding protein E-FABP. Cancer Lett. 2005;225:151–7.PubMedCrossRef
27.
Fujii S, Tominaga O, Nagawa H, Tsuno N, Nita ME, Tsuruo T, et al. Quantitative analysis of the cyclin expression in human esophageal cancer cell lines. J Exp Clin Cancer. 1998;17:491–6.
28.
Shinozaki H, Ozawa S, Ando N, Tsuruta H, Terada M, Ueda M, et al. Cyclin D1 amplification as a new predictive classification for squamous cell carcinoma of the esophagus, adding gene information. Clin Cancer Res. 1996;2:1155–61.PubMed
29.
Takeuchi H, Ozawa S, Ando N, Shih CH, Koyanagi K, Ueda M, et al. Altered p16/MTS1/CDKN2 and cyclin D1/PRAD-1 gene expression is associated with the prognosis of squamous cell carcinoma of the esophagus. Clin Cancer Res. 1997;3:2229–36.PubMed
30.
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Nat Acad Sci U S A. 2007;104:10158–63.CrossRef
31.
Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology. 2009;136:1012–24.PubMedCentralPubMedCrossRef
32.
Marhaba R, Klingbeil P, Nuebel T, Nazarenko I, Buechler MW, Zoeller M. CD44 and EpCAM: cancer-initiating cell markers. Curr Mol Med. 2008;8:784–804.PubMedCrossRef
Metadata
Title
EpCAM, a Potential Therapeutic Target for Esophageal Squamous Cell Carcinoma
Authors
Tatsuo Matsuda, MD
Hiroya Takeuchi, MD, PhD
Sachiko Matsuda, PhD
Kunihiko Hiraiwa, MD, PhD
Taku Miyasho, PhD
Minoru Okamoto, PhD
Kazufumi Kawasako, PhD
Rieko Nakamura, MD, PhD
Tsunehiro Takahashi, MD, PhD
Norihito Wada, MD, PhD
Hirofumi Kawakubo, MD, PhD
Yoshiro Saikawa, MD, PhD
Tai Omori, MD
Yuko Kitagawa, MD, PhD
Publication date
01-06-2014
Publisher
Springer US
Published in
Annals of Surgical Oncology / Issue Special Issue 3/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-014-3579-8

Other articles of this Special Issue 3/2014

Annals of Surgical Oncology 3/2014 Go to the issue

Hepatobiliary Tumors

Expressions of Hypoxia-Inducible Factor-1 and Epithelial Cell Adhesion Molecule are Linked with Aggressive Local Recurrence of Hepatocellular Carcinoma After Radiofrequency Ablation Therapy

Hepatobiliary Tumors

Comparison of the Therapeutic Outcomes Between Surgical Resection and Percutaneous Ablation for Small Hepatocellular Carcinoma

Colorectal Cancer

Quality of Surgery for Stage III Colon Cancer: Comparison Between England, Germany, and Japan

Hepatobiliary Tumors

Long-term Survival of Patients with Cholangiolocellular Carcinoma After Curative Hepatectomy

Pancreatic Tumors

Profiling of Autoantibodies in Sera of Pancreatic Cancer Patients

Thoracic Oncology

Pulmonary Metastasectomy Secondary to Esophageal Carcinoma: Long-Term Survival and Prognostic Factors