Department of Surgical Pathology, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan.
Department of Pathology, First People's Hospital of Foshan, Foshan City, Guangdong 528000, China.
Exp Mol Pathol. 2024 Oct;139:104922. doi: 10.1016/j.yexmp.2024.104922. Epub 2024 Aug 2.
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.
胃肠道间质瘤（GIST）是最常见的消化道间叶性肿瘤。其预后取决于原发部位，小肠 GIST 的预后较胃 GIST 差。针对 KIT 酪氨酸激酶活性的分子靶向药物被用于不可切除或复发性 GIST。然而，药物的继发性耐药经常发生，需要基于其他机制的治疗方法。先前，我们报道细胞黏附分子 1（CADM1）在大多数小肠 GIST 中高表达，但在大多数胃 GIST 中不表达。在本研究中，我们研究了针对 CADM1 表达的人 GIST 细胞的抗体药物偶联物（ADC）与抗 CADM1 抗体和单甲基奥瑞他汀 E（抗 CAD-ADC）是否具有抗肿瘤作用。本研究中使用的 ADC 先前用于表达 CADM1 的人间皮瘤细胞，并在体外对其显示出抗肿瘤作用。使用了源自胃的 GIST-T1 细胞系（很少表达 CADM1）和转染 CADM1 cDNA 的 GIST-T1 细胞（GIST-T1-CAD 细胞，高表达 CADM1，代表小肠 GIST）。在体外，抗 CAD-ADC 对 GIST-T1-CAD 细胞显示出显著的细胞毒性作用，而对照 ADC 则没有。原始 GIST-T1 细胞对抗 CAD-ADC 和对照 ADC 均无抗肿瘤作用。当 GIST-T1-CAD 细胞被皮下注射到裸鼠中时，静脉内给予抗 CAD-ADC 显示出抑制肿瘤增大的作用。即使在注射抗 CAD-ADC 后，GIST-T1 细胞的肿瘤仍在生长。当 GIST-T1-CAD 细胞被注射到 SCID 小鼠的腹腔中时，腹腔内给予抗 CAD-ADC 显示出减少腹腔肿瘤的作用。另一方面，在给予对照 ADC 后，腹腔肿瘤生长。在小鼠中，通过宏观和组织学检查未明显发现抗 CAD-ADC 给药引起的组织和器官损伤。这些结果表明，抗 CAD-ADC 对体外和体内小鼠模型中的表达 CADM1 的人 GIST 细胞均具有明显的抗肿瘤作用。
