Department of Medical Oncology, Hospital Universitario Puerta de Hierro de Majadahonda, Majadahonda, Madrid, Spain.
Int J Cancer. 2014 Jun 15;134(12):2984-90. doi: 10.1002/ijc.28613. Epub 2013 Nov 29.
Snail1 is a transcriptional factor that plays an important role in epithelial-mesenchymal transition and in the acquisition of invasive properties by epithelial cells. In colon tumors, Snail1 expression in the stroma correlates with lower specific survival of cancer patients. However, the role(s) of Snail1 expression in stroma and its association with patients' survival have not been determined. We used human primary carcinoma-associated fibroblasts (CAFs) or normal fibroblasts (NFs) and fibroblast cell lines to analyze the effects of Snail1 expression on the protumorigenic capabilities in colon cancer cells. Snail1 expression was higher in CAFs than in NFs and, as well as α-SMA, a classic marker of activated CAFs. Moreover, in tumor samples from 50 colon cancer patients, SNAI1 expression was associated with expression of other CAF markers, such as α-SMA and fibroblast activation protein. Interestingly, coculture of CAFs with colon cells induced a significant increase in epithelial cell migration and proliferation, which was associated with endogenous SNAI1 expression levels. Ectopic manipulation of Snail1 in fibroblasts demonstrated that Snail1 expression controlled migration as well as proliferation of cocultured colon cancer cells in a paracrine manner. Furthermore, expression of Snail1 in fibroblasts was required for the coadjuvant effect of these cells on colon cancer cell growth and invasion when coxenografted in nude mice. Finally, cytokine profile changes, particularly MCP-3 expression, in fibroblasts are put forward as mediators of Snail1-derived effects on colon tumor cell migration. In summary, these studies demonstrate that Snail1 is necessary for the protumorigenic effects of fibroblasts on colon cancer cells.
Snail1 是一种转录因子，在上皮-间质转化和上皮细胞获得侵袭性方面发挥重要作用。在结肠肿瘤中，基质中 Snail1 的表达与癌症患者的生存率降低相关。然而，基质中 Snail1 表达的作用及其与患者生存的关系尚未确定。我们使用人原发性癌相关成纤维细胞 (CAFs) 或正常成纤维细胞 (NFs) 和成纤维细胞系来分析 Snail1 表达对结肠癌细胞致瘤能力的影响。CAFs 中的 Snail1 表达高于 NFs，并且与经典的激活 CAFs 标志物 α-SMA 表达相关。此外，在 50 名结肠癌患者的肿瘤样本中，SNAI1 表达与其他 CAF 标志物（如 α-SMA 和成纤维细胞激活蛋白）的表达相关。有趣的是，CAFs 与结肠细胞共培养可显著诱导上皮细胞迁移和增殖，这与内源性 SNAI1 表达水平相关。成纤维细胞中 Snail1 的异位操纵表明，Snail1 表达以旁分泌方式控制共培养的结肠癌细胞的迁移和增殖。此外，当在裸鼠中共同异种移植时，成纤维细胞中 Snail1 的表达对于这些细胞对结肠癌细胞生长和侵袭的协同作用是必需的。最后，成纤维细胞中细胞因子谱的变化，特别是 MCP-3 的表达，被提出作为 Snail1 对结肠肿瘤细胞迁移的影响的介导物。总之，这些研究表明，Snail1 是成纤维细胞对结肠癌细胞致瘤作用所必需的。
