Author:

Keywords:

Glucocorticoids, Cancer-associated fibroblasts (CAFs), Cancer cell invasion, Cancer cell proliferation, Colon cancer, Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, TUMOR MICROENVIRONMENT, RECEPTOR, MECHANISMS, MYOFIBROBLASTS, RESISTANCE, TRANSITION, MIGRATION, COMPOUND, PATHWAYS, BIOLOGY, Animals, Cancer-Associated Fibroblasts, Cell Line, Tumor, Cell Movement, Cell Proliferation, Coculture Techniques, Colonic Neoplasms, Dexamethasone, Gene Expression Regulation, Neoplastic, Hepatocyte Growth Factor, Humans, Matrix Metalloproteinase 2, Neoplasm Invasiveness, Tenascin, 0601 Biochemistry and Cell Biology, 1103 Clinical Sciences, Biochemistry & Molecular Biology, 3101 Biochemistry and cell biology

Abstract:

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 (CMCTRL) stimulates proliferation, motility and stretched morphotype of GRdeficient HCT8/E11 colon cancer cells. Yet, HCT8/E11 proliferation and stretched morphotype are impaired upon treatment with conditioned medium from Dex-treated CAFs (CMDEX), but HCT8/E11 cell migration is slightly increased under these conditions. Moreover, expression and potential activity of MMP-2 is also reduced in CMDEX compared with CMCTRL. 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.