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

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:

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.

• Authors: 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
• Journal: Frontiers in oncology (Front Oncol) Vol. 11 Pg. 696931 ( 2021) ISSN: 2234-943X [Print] Switzerland
• PMID: 34485133 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Tsai, Wu, Liu, Chang, Huang, Chang, Tsai, Liao, Hung and Hsu.