Background: Angiogenesis is required for tumor development and metastasis, which is a major part in a pro-tumor microenvironment. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression.
Objectives: To validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer.
Methods: In this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways.
Results: H1299 and CL1-0 lung cancer cells were unable to form capillary-like structures. VM formation was induced by cancer-associated fibroblast (CAFs) in both in vitro and in vivo experiments. Notch2-Jagged1 cell-cell contact between cancer cells and CAFs contributes to the formation of VM networks, supported by Notch intracellular domain (NICD) 2 nuclear translocation and N2ICD target gene upregulated in lung cancer cells mixed with CAFs. The polarization of tumor-promoting N2-type neutrophil was increased by VM networks consisting of CAF and cancer cells. The intravasation of cancer cells and N2-type neutrophils were increased because of the loose junctions of VM. Disruption of cancer cell-CAF connections by a γ-secretase inhibitor enforced the anticancer effect of anti-vascular endothelial growth factor antibodies in a mouse model.
Conclusion: This study provides the first evidence that CAFs induce lung cancer to create vascular-like networks. These findings suggest a therapeutic opportunity for improving antiangiogenesis therapy in lung cancer.
Keywords: Jagged1; Notch2; cancer-associated fibroblasts; lung cancer; vascular mimicry.
Copyright © 2021 Tsai, Wu, Liu, Chang, Huang, Chang, Tsai, Liao, Hung and Hsu.