Capillary associated macrophages regulate vascular permeability through VEGF / PI3K / Akt pathway to affect the effect of lung cancer chemotherapy
Description
Background : Lung cancer is the leading cause of cancer-related death worldwide. Chemotherapy is still the core treatment for advanced lung cancer, but the treatment failure caused by chemotherapy resistance is an urgent clinical problem to be solved. Insufficient delivery of chemotherapeutic drugs caused by abnormal vascular permeability in the tumor microenvironment is one of the key mechanisms of drug resistance. However, the regulatory effect of capillary-associated macrophages ( CAMs ) specifically localized around blood vessels on the vascular permeability and chemotherapeutic effect of lung cancer has not been elucidated. Methods : A mouse transplantation model of four lung cancer cell lines A549, H1975, H1299 and LLC was constructed, and a lung cancer cell-human umbilical vein endothelial cell microvascular co-culture system was established. Immunohistochemistry, Evans blue leakage assay, Western blot and RNA-seq were used to systematically detect CAMs infiltration density, vascular permeability and related molecular expression. Results : The abundance of CAMs infiltration in lung cancer tissues was positively correlated with tumor vascular permeability, and negatively correlated with chemotherapy response. Specific depletion of CAMs can reduce vascular permeability and significantly enhance the tumor inhibition of cisplatin without affecting microvessel density. Mechanism studies have shown that CAMs activate the VEGFR2 / PI3K / Akt signaling pathway in endothelial cells by secreting VEGF and TNFα, and induce VE-cadherin endocytosis to destroy endothelial tight junctions. Blocking this pathway can reverse the increase of vascular permeability and synergistically enhance the efficacy of chemotherapy. Conclusion : This study is the first to clarify that CAMs is a key regulator of the ' vascular permeability-chemotherapy drug delivery ' axis of lung cancer, and clarify its core molecular mechanism of regulating vascular permeability, which provides a new theoretical basis for targeting CAMs combined with chemotherapy to overcome chemotherapy resistance of lung cancer.