Cancer‑associated fibroblast stimulates cancer cell invasion in an interleukin‑1 receptor (IL‑1R)‑dependent manner

Abstract

Tumor microenvironment serves an important role in tumor growth and metastasis. Cancer cells can promote growth and malignancy by altering the surrounding stroma. Cancer-associated fibroblast (CAF) are an abundant cell type present within the tumor microenvironment and provide tumorigenic features by secreting cytokines. In the current study, the CAF-mediated invasion of oral squamous cell carcinoma (OSCC) was investigated and the associated mechanisms were elucidated. Cancer invasion was estimated using a Matrigel-coated Transwell chamber and FITC-gelatin matrix. To verify the effect of the tumor microenvironment, conditioned media (CM) from normal fibroblast (NF) and CAFs were prepared. An ELISA was performed to estimate the level of IL-1β. A proteome profiler human protease array was performed to verify the proteases affected by stimulation with CM, from CAF. Recombinant IL-1β protein increased the invasion of OSCC cells. IL-1β expression was higher in CAF than NF. CM from CAF (CM-CAF) increased cancer invasion and FITC-gelatin matrix degradation. The invasive capacity provided by CAF was abrogated by an IL-1 receptor (IL-1R) antagonist. Additionally, CM-CAF increased the secretion of ADAM 9 and Kallikrein 11 from OSCC cells. The invasion activity by CM-CAF was partially abrogated by the neutralization of ADAM 9 or Kallikrein 11. In conclusion, by providing stromal factor, CAFs were a critical inducer of OSCC invasion, and CAF secretes the required amount of IL-1β to increase cancer invasion activity. The invasive capacity of CAF was identified to be IL-1R-dependent. ADAM 9 and Kallikrein 11 were influencing factors involved in the increase of CAF-mediated cancer invasion.

Neoadjuvant chemotherapy alters the balance of effector to suppressor immune cells in advanced ovarian cancer

“…In contrast, in breast cancer, a recommended method of evaluation has been published by the international TILs Working Group where both stromal TILs and intra-epithelial TILs have been well defined and assessed as independent parameters, both representing true intra-tumoral TILs. Based on recent studies on breast cancer, stromal TILs have emerged as a stronger, more reproducible prognostic marker than intra-epithelial TILs [ 22 , 40 – 42 ]. We had chosen to use their recommended definitions and method of evaluation in our study to differentiate intra-epithelial from stromal TILs and to evaluate stromal TILs.…”

Cancer-Associated Fibroblasts in Oral Cancer: A Current Perspective on Function and Potential for Therapeutic Targeting

“…CAF also modulate tumour cell invasion via secreted soluble factors. Various CAF-secreted factors, have been implicated in promoting HNSCC invasion and/or proliferation, including IL-1β (interleukin 1β) [ 42 ], activin A [ 43 ], HGF (hepatocyte growth factor) [ 44 ] and EREG (epiregulin) [ 45 ], which has additionally been suggested to play an autocrine role in CAF activation [ 45 ]. In recent years there has also been significant interest in CAF-tumour cell communication via exosomes.…”

Cancer-Associated Fibroblasts Differentiated by Exosomes Isolated from Cancer Cells Promote Cancer Cell Invasion

“…For breast cancer cells, the cluster is composed of many interleukin proteins such as IL-1, IL-6, etc. CAFs provide cancer invasion by secreting cytokines, and these cytokines have been suggested as critical tumor microenvironment factors [56].…”