Panax notoginseng saponins normalises tumour blood vessels by inhibiting EphA2 gene expression to modulate the tumour microenvironment of breast cancer

• Published in: Phytomedicine (Stuttgart) 2023-06, Vol.114, p.154787-154787, Article 154787
• Main Authors: Xia, Linying, Liu, XianLi, Mao, Weiye, Guo, Yingxue, Huang, Jie, Hu, Yingnan, Jin, Lu, Liu, Xia, Fu, Huiying, Du, Yueguang, Shou, Qiyang
• Format: Article
• Language: English
• Subjects: Animals; Breast cancer; Endothelial Cells; EphA2; Gene Expression; Lung metastasis; Mice; Neoplasms - drug therapy; Panax notoginseng - chemistry; Panax notoginseng saponins; Receptor, EphA2 - metabolism; Saponins - pharmacology; Tumor Microenvironment; Vascular normalization
• ISSN: 0944-7113; 1618-095X
• DOI: 10.1016/j.phymed.2023.154787

Panax notoginseng saponins (PNS), the main active component of Panax notoginseng, can promote vascular microcirculation. PNS exhibits antitumor effects in various cancers. However, the molecular basis of the relationship between PNS and tumor blood vessels remains unclear. To study the relationship between PNS inhibiting the growth and metastasis of breast cancer and promoting the normalization of blood vessels. We performed laser speckle imaging of tumor microvessels and observed the effects of PNS on tumor growth and metastasis of MMTV-PyMT (FVB) spontaneous breast cancer in a transgenic mouse model. Immunohistochemical staining of Ki67 and CD31 was performed for tumors, scanning electron microscopy was used to observe tumor vascular morphology, and flow cytometry was used to detect tumor tissue immune microenvironment (TME). RNA-seq analysis was performed using the main vessels of the tumor tissues of the mice. HUVECs were cultured in tumor supernatant in vitro to simulate tumor microenvironment and verify the sequencing differential key genes. After treatment with PNS, we observed that tumor growth was suppressed, the blood perfusion of the systemic tumor microvessels in the mice increased, and the number of lung metastases decreased. Moreover, the vascular density of the primary tumor increased, and the vascular epidermis was smoother and flatter. Moreover, the number of tumor-associated macrophages in the tumor microenvironment was reduced, and the expression levels of IL-6, IL-10, and TNF-α were reduced in the tumor tissues. PNS downregulated the expression of multiple genes associated with tumor angiogenesis, migration, and adhesion. In vitro tubule formation experiments revealed that PNS promoted the formation and connection of tumor blood vessels and normalized the vessel morphology primarily by inhibiting EphA2 expression. In addition, PNS inhibited the expression of tumor vascular marker proteins and vascular migration adhesion-related proteins in vivo. In this study, we found that PNS promoted the generation and connection of tumor vascular endothelial cells, revealing the key role of EphA2 in endothelial cell adhesion and tumor blood vessel morphology. PNS can inhibit the proliferation and metastasis of breast cancer by inhibiting EphA2, improving the immune microenvironment of breast cancer and promoting the normalization of tumor blood vessels. [Display omitted]