Abstract
BackgroundKejinyan decoction, as an experienced formula of Zhou Zhongying (the Master of Traditional Chinese Medicine) has been widely used in clinic for lung cancer treatment in China, while the anti-lung cancer mechanism of it is still remained to be elucidated. Herein, our basic study found that the survival of lung cancer xenograft mice was significantly prolonged after intragastrically administered high dose of Kejinyan decoction (3.8 g per kg BW) for 15 days. More importantly, we found that Kejinyan decoction inhibited the metastasis of lung cancer cells in vivo. Thus in this study, we aim to elucidate the anti-metastasis effects of Kejinyan decoction.MethodsRNA-Seq was used to find out the gene regulation of Kejinyan decoction on the mice, flow cytometry assay was used to detect the immunocytes in the spleen, ELISA assay was used to detect the inflammatory factors in the serum and spleen, and immunofluorescence assay was used to detect the level of immune cells and the expression of glycol-metabolism related enzymes in situ. Also, we established a lung cancer orthotopic xenograft tumor model to assess the influence of Kejinyan decoction on the metastatic ability of lung cancer cells in vivo.ResultsGO analysis of gene sequencing of tumor tissue samples showed that Kejinyan decoction regulated immune response. Further flow cytometry analysis of splenic lymphocyte showed that Kejinyan decoction upregulated M1 macrophages and downregulated M2 macrophages, while the total level of macrophages changed little, which was verified by detection of CD68, F4/80, CD206, and CD86 in tumor tissue section. Moreover, detection of inflammatory cytokines showed that Kejinyan decoction downregulated TNF-α, IFN-γ, IL-6, as well as IL-4, IL-13 in tumor microenvironment. Further studies also showed that Kejinyan decoction had little effect on tumor hypoxia, but downregulated glycolysis in tumor tissues. More importantly, we found that Kejinyan decoction inhibited the metastasis of lung cancer cells in vivo.ConclusionOur findings conclude that Kejinyan decoction inhibited lung cancer cell metastasis through affecting macrophage polarization and energy reprogramming.
Highlights
Kejinyan decoction, as an experienced formula of Zhou Zhongying has been widely used in clinic for lung cancer treatment in China, while the anti-lung cancer mechanism of it is still remained to be elucidated
Kejinyan decoction prolonged the survival of Lewis lung cancer mice In the Lewis lung carcinoma C57BL/6 mice, we found that Kejinyan decoction significantly improved the quality of life of the mice, and prolonged the overall survival of the mice especially at the high dose of Kejinyan decoction (3.8 g/kg) (Fig. 1a)
Overview of the differentially expressed genes between Kejinyan decoction treated group and the mock group To further explore the influence of Kejinyan decoction on biological function of lung cancer, we carried out RNA sequence on tumor tissue isolated from Lewis lung carcinoma C57BL/6 mice treated with or without Kejinyan decoction and 13,343 common genes were identified between the two groups through a Venn diagram (Fig. 2a)
Summary
As an experienced formula of Zhou Zhongying (the Master of Traditional Chinese Medicine) has been widely used in clinic for lung cancer treatment in China, while the anti-lung cancer mechanism of it is still remained to be elucidated. We found that Kejinyan decoction inhibited the metastasis of lung cancer cells in vivo. In China, the incidence of lung cancer increased rapidly, metastasis and recurrence are the main causes of the death of lung cancer. Tumorassociated macrophages (TAMs) are most abundant components in tumor immune microenvironment, which mainly include two polarization subsets M1 (classically activated, pro-inflammatory) and M2 (alternatively activated, immunosuppressive) [7, 8]. Some cytokines and chemokines produced by tumor cells promote M2 macrophages polarization, and result in immunosuppressive microenvironment formation in return [9]. Researchers increasingly realize that improving immunosuppressive TME is beneficial for cancer treatment [11]
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