Cancer‑associated fibroblast‑induced M2‑polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor‑1 pathway

Int J Oncol. 2021 Aug;59(2):59. doi: 10.3892/ijo.2021.5239. Epub 2021 Jul 1.

Abstract

Targeting the tumor stroma is an important strategy in cancer treatment. Cancer‑associated fibroblasts (CAFs) and tumor‑associated macrophages (TAMs) are two main components in the tumor microenvironment (TME) in hepatocellular carcinoma (HCC), which can promote tumor progression. Plasminogen activator inhibitor‑1 (PAI‑1) upregulation in HCC is predictive of unfavorable tumor behavior and prognosis. However, the crosstalk between cancer cells, TAMs and CAFs, and the functions of PAI‑1 in HCC remain to be fully investigated. In the present study, macrophage polarization and key paracrine factors were assessed during their interactions with CAFs and cancer cells. Cell proliferation, wound healing and Transwell and Matrigel assays were used to investigate the malignant behavior of HCC cells in vitro. It was found that cancer cells and CAFs induced the M2 polarization of TAMs by upregulating the mRNA expression levels of CD163 and CD206, and downregulating IL‑6 mRNA expression and secretion in the macrophages. Both TAMs derived from cancer cells and CAFs promoted HCC cell proliferation and invasion. Furthermore, PAI‑1 expression was upregulated in TAMs after being stimulated with CAF‑conditioned medium and promoted the malignant behavior of the HCC cells by mediating epithelial‑mesenchymal transition. CAFs were the main producer of C‑X‑C motif chemokine ligand 12 (CXCL12) in the TME and CXCL12 contributed to the induction of PAI‑1 secretion in TAMs. In conclusion, the results of the present study suggested that CAFs promoted the M2 polarization of macrophages and induced PAI‑1 secretion via CXCL12. Furthermore, it was found that PAI‑1 produced by the TAMs enhanced the malignant behavior of the HCC cells. Therefore, these factors may be targets for inhibiting the crosstalk between tumor cells, CAFs and TAMs.

Keywords: cancer‑associated fibroblasts; epithelial‑mesenchymal transition; hepatocellular carcinoma; plasminogen activator inhibitor‑1; tumor‑associated macrophages.

MeSH terms

  • Cancer-Associated Fibroblasts / cytology*
  • Cancer-Associated Fibroblasts / metabolism
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Communication
  • Cell Line, Tumor
  • Cell Movement
  • Cell Polarity
  • Cell Proliferation
  • Coculture Techniques
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Liver Neoplasms / metabolism*
  • Macrophage Activation
  • Plasminogen Activator Inhibitor 1 / metabolism*
  • Prognosis
  • Signal Transduction
  • THP-1 Cells
  • Tumor Microenvironment
  • Tumor-Associated Macrophages / cytology*
  • Tumor-Associated Macrophages / metabolism
  • Up-Regulation*

Substances

  • Plasminogen Activator Inhibitor 1
  • SERPINE1 protein, human

Grant support

This study was partly supported by the Research Program on Hepatitis from Japanese Foundation for Multidisciplinary Treatment of Cancer and the Japan Agency for Medical Research and Development (grant nos. JP19fk0210048 and JP20fk0210048), Grant-in-Aid for Scientific Research (grant nos. 20K08957 and 18K02871) and Taiho Pharmaceutical Co., Ltd.