Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Clin Cancer Res. 2011 Mar 15;17(6):1306-16. doi: 10.1158/1078-0432.CCR-10-1824. Epub 2011 Mar 8.
Carcinoma-associated fibroblasts (CAFs) in tumor stroma play an important role in tumor progression and have been associated with a poor prognosis in oral squamous cell carcinoma (OSCC). However, how CAFs influence OSCC malignancy and whether normalizing CAFs inhibits cancer progression remain unclear.
The relationship between the expression of Galectin-1 (Gal-1) and alpha-smooth muscle actin (α-SMA, a CAF marker) in OSCC patient samples and primary cultured CAFs was examined by quantitative real-time PCR, Western blotting, and immunofluorescence. To examine the effect of Gal-1 on CAF activation and CAF-mediated tumor invasion and migration in vitro, Gal-1 expression was knocked down by small hairpin RNA. Finally, cancer cells and CAFs were coimplanted into SCID mice to evaluate the effect of Gal-1 on CAF-modulated tumor progression in vivo.
Gal-1 expression is positively associated with α-SMA in the stroma of OSCC specimens. Gal-1 knockdown decreases activated CAF characteristics, resulting in a decrease in α-SMA expression and extracellular matrix protein production. Notably, blocking Gal-1 expression significantly inhibits CAF-conditioned medium-induced tumor cell migration and invasion, possibly by reducing the production of monocyte chemotactic protein-1 (MCP-1/CCL2). MCP-1 induces the migration of OSCC cells by binding to the receptor CCR2; adding an MCP-1 antibody to CAF-conditioned medium that inhibits the interaction between MCP-1 and CCR2 abolishes migration. Finally, we found that Gal-1 knockdown in CAFs significantly reduces CAF-augmented tumor growth and metastasis in vivo.
Our findings demonstrate that Gal-1 regulates CAF activation and indicate that targeting Gal-1 in CAFs inhibits OSCC metastasis by modulating MCP-1 expression.
肿瘤基质中的癌相关成纤维细胞（CAFs）在肿瘤进展中发挥重要作用，并与口腔鳞状细胞癌（OSCC）的预后不良相关。然而，CAFs 如何影响 OSCC 的恶性程度以及 CAFs 的正常化是否抑制癌症进展尚不清楚。
通过定量实时 PCR、Western blot 和免疫荧光检测 OSCC 患者样本和原代培养 CAFs 中半乳糖凝集素-1（Gal-1）表达与α-平滑肌肌动蛋白（α-SMA，CAF 标志物）之间的关系。为了研究 Gal-1 对 CAF 激活以及 CAF 介导的肿瘤侵袭和迁移的体外影响，用短发夹 RNA 敲低 Gal-1 表达。最后，将癌细胞和 CAFs 共同植入 SCID 小鼠中，以评估 Gal-1 对体内 CAF 调节肿瘤进展的影响。
Gal-1 表达与 OSCC 标本基质中的α-SMA 呈正相关。Gal-1 敲低可降低激活的 CAF 特征，导致α-SMA 表达和细胞外基质蛋白产生减少。值得注意的是，阻断 Gal-1 表达可显著抑制 CAF 条件培养基诱导的肿瘤细胞迁移和侵袭，这可能是通过减少单核细胞趋化蛋白-1（MCP-1/CCL2）的产生。MCP-1 通过与受体 CCR2 结合诱导 OSCC 细胞迁移；在抑制 MCP-1 和 CCR2 之间相互作用的 CAF 条件培养基中加入 MCP-1 抗体可消除迁移。最后，我们发现 CAFs 中的 Gal-1 敲低可显著减少体内 CAF 增强的肿瘤生长和转移。
我们的研究结果表明 Gal-1 调节 CAF 激活，并表明通过调节 MCP-1 表达，靶向 CAFs 中的 Gal-1 可抑制 OSCC 转移。
