CAF-INDUCED TAMs PROMOTE HCC PROGRESSION VIA PAI-1
Chen, Shuhai Tokushima University
森根, 裕二 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
徳田, 和憲 Tokushima University
山田, 眞一郎 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
齋藤, 裕 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
西, 正暁 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
池本, 哲也 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
島田, 光生 Tokushima University 徳島大学 教育研究者総覧 KAKEN研究者をさがす
plasminogen activator inhibitor‑1
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.
International Journal of Oncology
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
ijo_59_2_59.pdf 1.43 MB