Tsukuda Kazuhiko, Ishida Masaharu, Miura Takayuki, Maeda Shimpei, Ohtsuka Hideo, Mizuma Masamichi, Nakagawa Kei, Unno Michiaki
Department of Surgery, Tohoku University Graduate School of Medicine.
Tohoku J Exp Med. 2025 Jul 17;266(3):279-293. doi: 10.1620/tjem.2024.J126. Epub 2024 Nov 7.
The importance of the microenvironment in cancer progression is widely recognized, and interactions between cancer cells and stromal cells play an important role in the progression of the disease. A major component of stromal cells are fibroblasts, known as cancer-associated fibroblasts (CAFs). CAFs are thought to enhance the malignant properties of cancer cells through various secreted proteins. It is also known that CAFs function as a leading cell in cancer invasion, and their migratory ability is involved in local cancer invasion. The aim of this study was to elucidate the function of CAF in gallbladder cancer, which is one of the gastrointestinal malignancies with the worst prognosis.CAFs were primarily cultured from surgical specimens of gallbladder cancer patients. We investigated the migration ability of established CAFs and the effects of conditioned medium obtained from CAFs on the growth and invasion ability of gallbladder cancer cell lines. Functional analysis showed that the migration ability of certain CAFs was enhanced compared to control, and that conditioned medium enhanced the migration and invasion of gallbladder cancer cell lines. Gene expression analysis of CAFs revealed that tenascin-C (TNC) and podoplanin (PDPN) were highly expressed in CAFs with the enhancing functions. Immunohistochemical staining of TNC and PDPN on surgical specimens was performed to investigate the relationship with the prognosis. Disease-free survival and overall survival were found to be reduced in patients with high expression of those genes. The results of this study indicate that CAFs expressing TNC and PDPN promote cancer progression in gallbladder cancer.
微环境在癌症进展中的重要性已得到广泛认可，癌细胞与基质细胞之间的相互作用在疾病进展中起着重要作用。基质细胞的一个主要成分是成纤维细胞，即癌症相关成纤维细胞（CAFs）。人们认为CAFs通过各种分泌蛋白增强癌细胞的恶性特性。还已知CAFs在癌症侵袭中起主导细胞的作用，其迁移能力与局部癌症侵袭有关。本研究的目的是阐明CAF在胆囊癌中的功能，胆囊癌是预后最差的胃肠道恶性肿瘤之一。CAFs主要从胆囊癌患者的手术标本中培养。我们研究了已建立的CAFs的迁移能力以及从CAFs获得的条件培养基对胆囊癌细胞系生长和侵袭能力的影响。功能分析表明，与对照组相比，某些CAFs的迁移能力增强，并且条件培养基增强了胆囊癌细胞系的迁移和侵袭。CAFs的基因表达分析显示，腱生蛋白-C（TNC）和血小板反应蛋白-1（PDPN）在具有增强功能的CAFs中高表达。对手术标本进行TNC和PDPN的免疫组织化学染色以研究与预后的关系。发现那些基因高表达的患者无病生存期和总生存期缩短。本研究结果表明，表达TNC和PDPN的CAFs促进胆囊癌的癌症进展。
