TROP2和上皮细胞粘附分子表达的缺失与pTa期肿瘤分级进展相关，但与pT2-4期膀胱尿路上皮癌的疾病转归无关。

Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

作者信息

Müller Jan H, Plage Henning, Elezkurtaj Sefer, Mandelkow Tim, Huang Zhihao, Lurati Magalie C J, Raedler Jonas B, Debatin Nicolaus F, Vettorazzi Eik, Samtleben Henrik, Hofbauer Sebastian, Furlano Kira, Neymeyer Jörg, Goranova Irena, Ralla Bernhard, Weinberger Sarah, Horst David, Roßner Florian, Schallenberg Simon, Marx Andreas H, Fisch Margit, Rink Michael, Slojewski Marcin, Kaczmarek Krystian, Ecke Thorsten, Hallmann Steffen, Koch Stefan, Adamini Nico, Lennartz Maximilian, Minner Sarah, Simon Ronald, Sauter Guido, Zecha Henrik, Schlomm Thorsten, Bady Elena

机构信息

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Department of Urology, Charité Berlin, Berlin, Germany.

出版信息

Front Oncol. 2024 Jan 12;13:1342367. doi: 10.3389/fonc.2023.1342367. eCollection 2023.

DOI:10.3389/fonc.2023.1342367

PMID:38282671

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10811247/

Abstract

INTRODUCTION

Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status.

METHODS

To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format.

RESULTS

The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis.

CONCLUSION

Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

摘要

引言

滋养层细胞表面抗原2（TROP2；EpCAM2）是一种跨膜糖蛋白，与EpCAM（EpCAM；EpCAM1）密切相关。这两种蛋白在上皮发育和EpCAM表达中具有部分重叠功能，但尚未在膀胱癌中进行共同的比较分析。TROP2是抗体药物偶联物赛托珠单抗戈维汀（SG；TrodelvyTM）的靶点，美国食品药品监督管理局（FDA）已批准其用于治疗转移性尿路上皮癌，无论其TROP2表达状态如何。

方法

为了评估尿路上皮膀胱癌中TROP2和EpCAM表达细微差异的潜在临床意义，通过多重荧光免疫组织化学结合基于深度学习的自动细胞检测算法，对组织微阵列（TMA）形式的2700多例尿路上皮膀胱癌中的这两种蛋白进行了分析。

结果

TROP2和EpCAM的染色模式高度相似。对于这两种蛋白，染色强度从pTa G2低级别（TROP2：68.8±36.1；EpCAM：21.5±11.7）逐渐降低到pTa G2高级别（64.6±38.0；19.3±12.2）和pTa G3（52.1±38.7；16.0±13.0，各p<0.001）。在pT2-4期癌中，TROP2和EpCAM的平均染色强度为中等（61.8±40.9；18.3±12.3）。对于这两种蛋白，这均显著低于pTa G2低级别（各p<0.001），但也高于pTa G3肿瘤（TROP2为p=0.022，EpCAM为p=0.071）。在pT2-4期癌中，TROP2和EpCAM的染色水平与pT、分级、国际抗癌联盟（UICC）分类以及患者总生存期或肿瘤特异性生存期无关。TROP2/EpCAM比值与恶性表型和患者预后无关。