Tumor-associated astrocytes inhibit tumor cell apoptosis through TNF- α-TNF receptor 2-NF-κB pathway in lung cancer brain metastasis

Abstract Lung cancer is the most common cause of death among all human cancers with up to 50% of the cancers eventually developing into brain metastasis. The treatment methods of brain metastasis are very limited and the prognosis is poor. Studies have shown that the invasion of tumor cells into brain is related to the local activation of astrocytes, and these tumor-associated astrocytes (TAAs) exert either promoting or resisting effects during this process. However, whether astrocytes play a role after tumor cell colonization remains obscure. In the current study, by using of the lung cancer brain metastasis murine model and in vitro. co-culture system, we found the existence of astrocytes in the tumor microenvironment of both clinical patient and murine model with lung cancer brain metastasis. And in the in vitro. co-culture system, astrocytes promoted the survival but not the proliferation of tumor cells through inhibiting their apoptosis. The mechanistic study showed that astrocytes inhibit the apoptosis of tumor cells by secreting TNF-α, and the NF-κB signaling pathway in tumor cells was activated. Knocking down TNF receptor 2 (TNFR2) gene on tumor cells, as well as the inhibitor of NF-κB pathway counteracted the effect of astrocytes. Further, knockdown of TNFR2 increased the intracranial apoptosis of tumor cells and prolonged the survival of mice in lung cancer brain metastasis model. In conclusion, our research indicates that TAAs in lung cancer brain metastasis inhibit the apoptosis of tumor cells by secreting TNF-α dependent on TNFR2-NF-κB signaling pathway.