Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, Ghent University, Ghent, Belgium.
Exp Cell Res. 2018 Jan 15;362(2):332-342. doi: 10.1016/j.yexcr.2017.11.034. Epub 2017 Nov 28.
Cancer-associated fibroblasts (CAFs) support cancer growth, invasion, and metastasis. Glucocorticoids (GCs), drugs often administered together with chemotherapy, are steroidal ligands of the glucocorticoid receptor (GR), a transcription factor which upon activation regulates expression of multiple genes involved in suppression of inflammation. We have previously shown that in dexamethasone (Dex)-treated CAFs derived from colon cancer, production and secretion of several factors related to cancer progression, such as tenascin C (TNC) and hepatocyte growth factor (HGF), were strongly suppressed. In this study we show that GCs can neutralize the cancer cell-promoting properties of CAFs. Conditioned medium from solvent-treated CAFs (CM) stimulates proliferation, motility and stretched morphotype of GR-deficient HCT8/E11 colon cancer cells. Yet, HCT8/E11 proliferation and stretched morphotype are impaired upon treatment with conditioned medium from Dex-treated CAFs (CM), but HCT8/E11 cell migration is slightly increased under these conditions. Moreover, expression and potential activity of MMP-2 is also reduced in CM compared with CM. These combined in vitro results concur with the results from in vivo chick chorioallantoic membrane assays, where the co-cultures of CAFs with colon cancer cells displayed impaired tumor formation and cancer cell invasion due to Dex administration. Combined, GC treatment influences cancer cell behavior indirectly through effects on CAFs.
癌症相关成纤维细胞（CAFs）支持癌症的生长、侵袭和转移。糖皮质激素（GCs）是与化疗一起经常使用的药物，它们是糖皮质激素受体（GR）的甾体配体，GR 是一种转录因子，激活后可调节参与炎症抑制的多个基因的表达。我们之前已经表明，在来源于结肠癌的地塞米松（Dex）处理的 CAFs 中，几种与癌症进展相关的因子的产生和分泌，如 tenascin C（TNC）和肝细胞生长因子（HGF），被强烈抑制。在这项研究中，我们表明 GCs 可以中和 CAFs 的促进癌细胞的特性。溶剂处理的 CAFs（CM）的条件培养基（CM）刺激 GR 缺陷的 HCT8/E11 结肠癌细胞的增殖、迁移和伸展形态。然而，用 Dex 处理的 CAFs（CM）处理后，HCT8/E11 增殖和伸展形态受到损害，但在这些条件下，HCT8/E11 细胞迁移略有增加。此外，与 CM 相比，MMP-2 的表达和潜在活性也降低。这些体外综合结果与体内鸡胚绒毛尿囊膜测定的结果一致，由于 Dex 给药，CAFs 与结肠癌细胞的共培养显示出肿瘤形成和癌细胞侵袭受损。总之，GC 治疗通过对 CAFs 的影响间接影响癌细胞的行为。
