Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2-Jagged1 Interaction in Lung Cancer

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. & nbsp; Objectives To validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer. & nbsp; 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. & nbsp; 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 gamma-secretase inhibitor enforced the anticancer effect of anti-vascular endothelial growth factor antibodies in a mouse model. & nbsp; 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.

Automated summary

This study verified the role of cancer-associated fibroblasts (CAFs) in inducing lung cancer to create vascular-like networks, facilitating tumor development and metastasis. Disruption of the connections between cancer cells and CAFs can enhance the anti-tumor effect of anti-vascular endothelial growth factor antibodies.