Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2–Jagged1 Interaction in Lung Cancer
Ying-Ming Tsai, Kuan‐Li Wu, Yu‐Wei Liu, Wei‐An Chang, Yung‐Chi Huang, Chao‐Yuan Chang, Pei-Hsun Tsai, Szi-Hui Liao, Jen‐Yu Hung, Ya‐Ling Hsu
Abstract
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: 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.