Matrine suppresses lung cancer metastasis via targeting M2-like tumour-associated-macrophages polarization

Metastasis is the primary cause of death in lung Cancer, one of the most prevalent and deadly neoplasms. The tumour-associated macrophages (TAMs) are crucial mediators to induce epithelial-mesenchymal transition (EMT) and promote lung metastasis via release of the cytokines. Matrine, a naturally occurring alkaloid, has been found with a variety of pharmacological effects, such as anti-cancer. In this study, an in vitro co-culture cell systems and a Lewis-bearing mouse model were employed to assay the potential effects of matrine on macrophages polarization, and its regulatory effects on EMT of Lewis lung Cancer cells (LLCs). Our results clearly demonstrated that matrine inhibited M2-like RAW264.7 polarization, reducing the production of anti-inflammatory cytokines (IL-4, IL-10, and Arg-1), and M2 surface markers (CD206) were induced by LLCs via mTOR/PI3K/Akt signaling pathway, while it had no significant effect on M1 macrophages polarization. In vitro assays suggested that matrine partially blocked the metastasis of LLCs, and inhibited EMT induced by M2-like macrophages, which was evidenced by up-regulating the expression of E-cadherin and down-regulating the expression of N-Cadherin, vimentin, and Snail. In vivo studies revealed that matrine decreased the ratio of CD206⁺/F4/80⁺, promoted the expression of CD4⁺ and CD8⁺ T cells, and inhibited the expression of Th2 in tumor and spleen tissues. Cell co-culture experiments revealed that Matrine promoted T-cell proliferation, which was impaired by tumour-derived CD11b⁺ myeloid cells. Collectively, our findings suggest that suppression of M2-like macrophages polarization of TAMs is a potential mechanism underlying the anti-metastasis effects of matrine in lung Cancer.