Journal of Gastric Cancer

The Korean Gastric Cancer Association (대한위암학회)
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Clinicopathologic Characteristics of Trop Family Proteins (Trop-2 and EpCAM) in Gastric Carcinoma

  • Hye Sung Kim (Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine) ;
  • Younghoon Kim (Department of Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Hye Seung Lee (Department of Pathology, Cancer Research Institute, Seoul National University College of Medicine)
  • Received : 2024.04.15
  • Accepted : 2024.07.18
  • Published : 2024.10.01
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Abstract

Purpose: Trop family proteins, including epithelial cell adhesion molecule (EpCAM) and Trop-2, have garnered attention as potential therapeutic and diagnostic targets for various malignancies. This study aimed to elucidate the clinicopathological significance of these proteins in gastric carcinoma (GC) and to reinforce their potential as biomarkers for patient stratification in targeted therapies. Materials and Methods: Immunohistochemical (IHC) analyses of EpCAM and Trop-2 were performed on GC and precancerous lesions, following rigorous orthogonal validation of the antibodies to ensure specificity and sensitivity. Results: Strong membranous staining (3+) for Trop-2 was observed in 49.3% of the GC cases, whereas EpCAM was strongly expressed in almost all cases (93.2%), indicating its widespread expression in GC. A high Trop-2 expression level, characterized by an elevated H-score, was significantly associated with intestinal type by Lauren classification, gastric mucin type, presence of lymph node metastasis, human epidermal growth factor receptor 2-positivity, and Epstein-Barr virus (EBV)-positivity. Patients with a high Trop-2 expression level exhibited poorer survival outcomes on univariate and multivariate analyses. High EpCAM expression levels were prevalent in differentiated histologic type, microsatellite instability-high, and EBV-negative cancer, and were correlated with high densities of CD3 and CD8 T cells and elevated combined positive score for programmed death-ligand 1. Conclusions: These results highlight the differential expression of Trop-2 and EpCAM and their prognostic implications in GC. The use of meticulously validated antibodies ensured the reliability of our IHC data, thereby offering a robust foundation for future therapeutic strategies targeting Trop family members in GC.

Keywords

References

  1. Nakatsukasa M, Kawasaki S, Yamasaki K, Fukuoka H, Matsuda A, Tsujikawa M, et al. Tumor-associated calcium signal transducer 2 is required for the proper subcellular localization of claudin 1 and 7: implications in the pathogenesis of gelatinous drop-like corneal dystrophy. Am J Pathol 2010;177:1344-1355.
  2. Toyoshima K, Hayashi A, Kashiwagi M, Hayashi N, Iwatsuki M, Ishimoto T, et al. Analysis of circulating tumor cells derived from advanced gastric cancer. Int J Cancer 2015;137:991-998.
  3. Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, et al. Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol 2009;27:1941-1947.
  4. Goel S, Bauer RJ, Desai K, Bulgaru A, Iqbal T, Strachan BK, et al. Pharmacokinetic and safety study of subcutaneously administered weekly ING-1, a human engineere monoclonal antibody targeting human EpCAM, in patients with advanced solid tumors. Ann Oncol 2007;18:1704-1707.
  5. Wu CJ, Lu M, Feng X, Nakato G, Udey MC. Matriptase cleaves EpCAM and TROP2 in keratinocytes, destabilizing both proteins and associated claudins. Cells 2020;9:9.
  6. Cubas R, Zhang S, Li M, Chen C, Yao Q. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer 2010;9:253.
  7. Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther 2019;12:1781-1790.
  8. Guerra E, Trerotola M, Aloisi AL, Tripaldi R, Vacca G, La Sorda R, et al. The Trop-2 signalling network in cancer growth. Oncogene 2013;32:1594-1600.
  9. Cardillo TM, Govindan SV, Sharkey RM, Trisal P, Arrojo R, Liu D, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate: characterization and efficacy in pancreatic, gastric, and other cancers. Bioconjug Chem 2015;26:919-931.
  10. Gehring A, Huebner K, Rani H, Erlenbach-Wuensch K, Merkel S, Mahadevan V, et al. DNA demethylation and tri-methylation of H3K4 at the TACSTD2 promoter are complementary players for TROP2 regulation in colorectal cancer cells. Sci Rep 2024;14:2683.
  11. Deng Y, Li M, Zhuo M, Guo P, Chen Q, Mo P, et al. Histone demethylase JMJD2D promotes the self-renewal of liver cancer stem-like cells by enhancing EpCAM and Sox9 expression. J Biol Chem 2021;296:100121.
  12. Zhao W, Zhu H, Zhang S, Yong H, Wang W, Zhou Y, et al. Trop2 is overexpressed in gastric cancer and predicts poor prognosis. Oncotarget 2016;7:6136-6145.
  13. Muhlmann G, Spizzo G, Gostner J, Zitt M, Maier H, Moser P, et al. TROP2 expression as prognostic marker for gastric carcinoma. J Clin Pathol 2009;62:152-158.
  14. Zhao W, Ding G, Wen J, Tang Q, Yong H, Zhu H, et al. Correlation between Trop2 and amphiregulin coexpression and overall survival in gastric cancer. Cancer Med 2017;6:994-1001.
  15. Songun I, Litvinov SV, van de Velde CJ, Pals ST, Hermans J, van Krieken JH. Loss of Ep-CAM (CO17-1A) expression predicts survival in patients with gastric cancer. Br J Cancer 2005;92:1767-1772.
  16. Du W, Ji H, Cao S, Wang L, Bai F, Liu J, et al. EpCAM: a potential antimetastatic target for gastric cancer. Dig Dis Sci 2010;55:2165-2171.
  17. Wang YY, Li L, Zhao ZS, Wang YX, Ye ZY, Tao HQ. L1 and epithelial cell adhesion molecules associated with gastric cancer progression and prognosis in examination of specimens from 601 patients. J Exp Clin Cancer Res 2013;32:66.
  18. Kroepil F, Dulian A, Vallbohmer D, Geddert H, Krieg A, Vay C, et al. High EpCAM expression is linked to proliferation and lauren classification in gastric cancer. BMC Res Notes 2013;6:253.
  19. Warneke VS, Behrens HM, Haag J, Kruger S, Simon E, Mathiak M, et al. Members of the EpCAM signalling pathway are expressed in gastric cancer tissue and are correlated with patient prognosis. Br J Cancer 2013;109:2217-2227.
  20. Lee HS, Lee HK, Kim HS, Yang HK, Kim YI, Kim WH. MUC1, MUC2, MUC5AC, and MUC6 expressions in gastric carcinomas: their roles as prognostic indicators. Cancer 2001;92:1427-1434.
  21. Sivertsson A, Lindstrom E, Oksvold P, Katona B, Hikmet F, Vuu J, et al. Enhanced validation of antibodies enables the discovery of missing proteins. J Proteome Res 2020;19:4766-4781.
  22. Karlsson M, Zhang C, Mear L, Zhong W, Digre A, Katona B, et al. A single-cell type transcriptomics map of human tissues. Sci Adv 2021;7:eabh2169.
  23. Binder JX, Pletscher-Frankild S, Tsafou K, Stolte C, O'Donoghue SI, Schneider R, et al. COMPARTMENTS: unification and visualization of protein subcellular localization evidence. Database (Oxford) 2014;2014:bau012.
  24. Jiang L, Wang M, Lin S, Jian R, Li X, Chan J, et al. A quantitative proteome map of the human body. Cell 2020;183:269-283.e19.
  25. Bankhead P, Loughrey MB, Fernandez JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep 2017;7:16878.
  26. Yun S, Koh J, Nam SK, Kwak Y, Ahn SH, Do Park J, et al. Immunoscore is a strong predictor of survival in the prognosis of stage II/III gastric cancer patients following 5-FU-based adjuvant chemotherapy. Cancer Immunol Immunother 2021;70:431-441.
  27. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-567.
  28. Pyo JS, Ko YS, Kang G, Kim DH, Kim WH, Lee BL, et al. Bile acid induces MUC2 expression and inhibits tumor invasion in gastric carcinomas. J Cancer Res Clin Oncol 2015;141:1181-1188.
  29. Kim MA, Lee HJ, Yang HK, Bang YJ, Kim WH. Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma. Histopathology 2011;59:822-831.
  30. Hofmann M, Stoss O, Shi D, Buttner R, van de Vijver M, Kim W, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology 2008;52:797-805.
  31. Kim HS, Choi SI, Min HL, Kim MA, Kim WH. Mutation at intronic repeats of the ataxia-telangiectasia mutated (ATM) gene and ATM protein loss in primary gastric cancer with microsatellite instability. PLoS One 2013;8:e82769.
  32. Chang MS, Kim WH. Epstein-Barr virus in human malignancy: a special reference to Epstein-Barr virus associated gastric carcinoma. Cancer Res Treat 2005;37:257-267.
  33. Choi J, Lee HE, Kim MA, Jang BG, Lee HS, Kim WH. Analysis of MET mRNA expression in gastric cancers using RNA in situ hybridization assay: its clinical implication and comparison with immunohistochemistry and silver in situ hybridization. PLoS One 2014;9:e111658.
  34. Wang J, Day R, Dong Y, Weintraub SJ, Michel L. Identification of Trop-2 as an oncogene and an attractive therapeutic target in colon cancers. Mol Cancer Ther 2008;7:280-285.
  35. Zeng P, Chen MB, Zhou LN, Tang M, Liu CY, Lu PH. Impact of TROP2 expression on prognosis in solid tumors: a systematic review and meta-analysis. Sci Rep 2016;6:33658.