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

Ying-Ming Tsai,Yung-Chi Huang,Jen-Yu Hung,Kuan-Li Wu,Chao-Yuan Chang,Yu-Wei Liu,Ya-Ling Hsu,Pei-Hsun Tsai,Wei-An Chang,Szi-Hui Liao

doi:10.3389/fonc.2021.696931

Abstract

BackgroundAngiogenesis 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.ObjectivesTo validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer.MethodsIn this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways.ResultsH1299 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.ConclusionThis 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.

Highlights

Lung cancer is the leading cause of cancer-related mortality globally with poorer prognosis compared with that of breast, prostate, and colorectal cancer [1]
human umbilical vein ECs (HUVECs), normal human lung fibroblasts (NHLFs), and human lung cancer cells H1299 were obtained from the American Type Culture Collection (ATCC) and human lung adenocarcinoma CL1-0 cell line was generously provided by Dr Pan-Chyr Yang (Department of Internal Medicine, National Taiwan University Hospital)
We generated cancer-associated fibroblasts (CAFs) by coculturing normal human lung fibroblast with cancer cells for 24 h, and identified a-smooth muscle actin (a-SMA) [23, 24] was increased in fibroblast when they were stimulated by cancer cells (Supplementary Figure 1A)

Summary

Introduction

Lung cancer is the leading cause of cancer-related mortality globally with poorer prognosis compared with that of breast, prostate, and colorectal cancer [1]. Vascular mimicry (VM) is a process in which tumor cells form vascular-like networks that are not lined with endothelial cells (ECs). These networks contribute to tumor blood supply, which fosters cancer progression, metastasis, and chemoresistance to angiostatic compounds [3, 4]. A growing body of evidence has demonstrated that the interaction between the tumor microenvironment (TME) and tumor cells plays a critical role in cancer development and progression [8, 9]. Tumor VM formation with its non-cancer cells as macrophages and fibroblasts is associated with cancer cells invasiveness and metastasis [10, 11] and the interaction of the TME in VM development is not yet understood. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression

Objectives

Methods

Results

Conclusion