Abstract：
The glycans form a unique complex on the surface of cancer cells and play a pivotal role in tumor progression, impacting proliferation, invasion, and metastasis. TRA-1-60 is a glycan that was identified as a critical marker for the establishment of fully reprogrammed inducible pluripotent stem cells. Its expression has been detected in multiple cancer tissues, including embryonal carcinoma, prostate cancer, and pancreatic cancer, but the biological and pathological characterization of TRA-1-60-expressing tumor cells remains unclear within various types of malignancies. Here, we report the biological characteristics of TRA-1-60-expressing gastric cancer cells, especially those with its cell surface expression, and the therapeutic significance of targeting TRA-1-60. The cells with cell membrane expression of TRA-1-60 were mainly observed in the invasive area of patient gastric cancer tissues and correlated with advanced stages of the disease based on histopathological and clinicopathological analyses. In vitro analysis using a scirrhous gastric adenocarcinoma line, HSC-58, which highly expresses TRA-1-60 on its plasma membrane, revealed increased stress-resistant mechanisms, supported by the upregulation of glutathione synthetase and NCF-1 (p47phox) via lipid-ROS regulatory pathways, as detected by RNA-seq analysis followed by oxidative stress gene profiling. Our in vivo therapeutic study using the TRA-1-60-targeting antibody-drug conjugate, namely, Bstrongomab-conjugated monomethyl auristatin E, showed robust efficacy in a mouse model of peritoneal carcinomatosis induced by intraperitoneal xenograft of HSC-58, by markedly reducing massive tumor ascites. Thus, targeting the specific cell surface glycan, TRA-1-60, shows a significant therapeutic impact in advanced-stage gastric cancers.
摘要：
这些聚糖在癌细胞表面形成独特的复合物，并在肿瘤进展中发挥关键作用。影响扩散，入侵,和转移。TRA-1-60是一种聚糖，被鉴定为建立完全重编程的可诱导多能干（iPS）细胞的关键标记。已在多个癌组织中检测到其表达，包括胚胎癌,前列腺癌,和胰腺癌，但是在各种类型的恶性肿瘤中，表达TRA-1-60的肿瘤细胞的生物学和病理学特征仍不清楚。这里,我们报道了表达TRA-1-60的胃癌细胞的生物学特性，尤其是那些具有细胞表面表达的细胞，以及靶向TRA-1-60的治疗意义。根据组织病理学和临床病理分析，主要在患者胃癌组织的浸润区域观察到具有TRA-1-60细胞膜表达的细胞，并且与疾病的晚期阶段相关。使用硬胃腺癌系进行体外分析，HSC-58在其质膜上高度表达TRA-1-60，揭示了增强的抗压机制，通过脂质-ROS调节途径上调谷胱甘肽合成酶（GSS）和NCF-1（p47phox），通过RNA-seq分析和氧化应激基因谱分析检测到。我们使用TRA-1-60靶向抗体-药物偶联物（ADC）进行的体内治疗研究，即Bstrongomab缀合单甲基奥瑞他汀E（MMAE），通过显着减少大量肿瘤腹水，在由HSC-58腹膜内异种移植物诱导的腹膜癌小鼠模型中显示出强大的功效。因此，靶向特定的细胞表面聚糖，TRA-1-60在晚期胃癌中显示出显著的治疗效果。（243字）
