Cancer-associated fibroblast-induced M2-polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor-1 pathway
Cancer-associated fibroblast-induced M2-polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor-1 pathway
复制标题
癌症相关成纤维细胞诱导的m2极化巨噬细胞通过纤溶酶原激活物抑制剂-1途径促进肝癌的进展
DOI：
10.3892/ijo.2021.5239
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发表时间：
2021-08-01
影响因子：
5.2
通讯作者：
Shimada, Mitsuo
中科院分区：
文献类型：
--
作者：
Chen, Shuhai;Morine, Yuji;Shimada, Mitsuo
靶向肿瘤间质是癌症治疗中的重要策略。癌相关成纤维细胞（CAFs）和肿瘤相关巨噬细胞（TAMs）是肝细胞癌（HCC）肿瘤微环境（TME）的两种主要成分，它们可以促进肿瘤的进展。纤溶酶原激活物抑制剂-1（派-1）在HCC中的上调可预测不利的肿瘤行为和预后。然而，癌细胞、TAM和CAF之间的串扰以及派-1在HCC中的功能仍有待充分研究。在本研究中，巨噬细胞极化和关键的旁分泌因子在其与CAFs和癌细胞的相互作用过程中进行了评估。采用细胞增殖、创伤愈合、Transwell和Matrigel等方法研究肝癌细胞的体外恶性行为。结果发现，癌细胞和CAF通过上调巨噬细胞中CD 163和CD 206的mRNA表达水平，下调IL-6 mRNA的表达和分泌，诱导TAM的M2极化。源自癌细胞的TAM和CAF都促进HCC细胞增殖和侵袭。此外，派-1表达上调TAMs后，与CAF条件培养基刺激，并促进肝癌细胞的恶性行为，通过介导上皮间质转化。CAF是TME中C-X-C基序趋化因子配体12（CXCL 12）的主要产生者，CXCL 12参与诱导TAM中派-1的分泌。总之，本研究的结果表明，CAFs促进M2极化的巨噬细胞和诱导派-1分泌通过CXCL 12。此外，还发现TAMs产生的派-1增强了HCC细胞的恶性行为。因此，这些因子可能是抑制肿瘤细胞、CAF和TAM之间串扰的靶点。
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.