Department of Periodontology, School of Stomatology, Shandong University, Jinan, China.
Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Shandong University, Jinan, China.
Oral Dis. 2020 Oct;26(7):1375-1383. doi: 10.1111/odi.13306. Epub 2020 Aug 10.
Cancer-associated fibroblasts (CAFs) are "activated" fibroblasts in the tumor microenvironment (TME) and play a vital role in all steps of cancer development. Increasing evidence focusing on the function of CAFs suggests that CAFs are candidate therapeutic targets and that drugs targeting the modification of CAFs would suppress tumor progression and be beneficial to tumor treatment and prevention. In the present study, we found that curcumin reversed the phenotype of CAFs to that of peri-tumor fibroblast (PTF)-like cells by downregulating the expression of α-SMA (a special marker for CAFs) and inhibiting the secretion of pro-carcinogenic cytokines, including transforming growth factor-β1 (TGF-β1), matrix metalloproteinases 2 (MMP2), and stromal cell-derived factor-1 (SDF-1). We further demonstrated that the conditioned medium (CM) derived from CAFs promoted the proliferation of Cal27, and this effect was confirmed by the xenograft model. More importantly, we found that curcumin blocked the CAF-mediated enhancement of Cal27 proliferation in vitro and in vivo. In conclusion, our data suggest that curcumin reverses cell phenotype from CAF to PTF-like cells and suppresses the CAF-mediated proliferation and tumorigenicity of Cal27 by inhibiting TSCC CAFs.
癌症相关成纤维细胞（CAFs）是肿瘤微环境（TME）中的“激活”成纤维细胞，在癌症发展的所有阶段都发挥着重要作用。越来越多的证据集中在 CAFs 的功能上，表明 CAFs 是候选治疗靶点，靶向 CAFs 修饰的药物将抑制肿瘤进展，有利于肿瘤的治疗和预防。在本研究中，我们发现姜黄素通过下调α-SMA（CAFs 的特殊标志物）的表达并抑制致癌细胞因子（包括转化生长因子-β1（TGF-β1）、基质金属蛋白酶 2（MMP2）和基质细胞衍生因子-1（SDF-1）的分泌，将 CAFs 的表型逆转成肿瘤周围成纤维细胞（PTF）样细胞。我们进一步证明，CAFs 衍生的条件培养基（CM）促进了 Cal27 的增殖，这一效应在异种移植模型中得到了证实。更重要的是，我们发现姜黄素阻断了 CAF 介导的 Cal27 体外和体内增殖的增强。总之，我们的数据表明，姜黄素通过抑制 TSCC CAFs 将细胞表型从 CAF 逆转成 PTF 样细胞，并抑制 CAF 介导的 Cal27 增殖和致瘤性。
