PEDF inhibits lymphatic metastasis of nasopharyngeal carcinoma as a new lymphangiogenesis inhibitor

Chuanghua Luo,Danrui Zhang,Xi Wang,Zhonghan Yang,Guoquan Gao,Caiqi Ma,Xia Yang,Weiwei Qi,Haofan Yin,Ting Zhang,Junxi Liu,Tianxiao Gao,Zumin Xu,Ti Zhou

doi:10.1038/s41419-021-03583-1

Abstract

Nasopharyngeal carcinoma (NPC) is one of the most malignant tumors in southern China and Asia, and lymph node metastasis is an important cause for treatment failure. Lymphangiogenesis is a crucial step in lymphatic metastasis of NPC, while little is known about lymphangiogenesis in NPC. Similar to angiogenesis, lymphangitic neovascularization is a process of balance between pro-lymphangiogenesis and anti-lymphangiogenesis factors, but there are few studies on endogenous lymphangiogenesis inhibitors. Pigment epithelium-derived factor (PEDF) is a well-known effective endogenous angiogenesis inhibitor. However, the relationship between PEDF and lymphangiogenesis remains unknown. Our present study reveals that PEDF is lowly expressed in human NPC tissues with poor prognosis and is negatively correlated with lymphatic vessel density (LVD). Consistently, PEDF inhibits lymphangiogenesis and lymphatic metastasis of NPC in vivo experiments. Mechanistically, PEDF inhibits the proliferation, migration, and tube formation of lymphatic endothelial cells and promotes cell apoptosis. On the other hand, PEDF reduces the expression and secretion of vascular endothelial growth factor C (VEGF-C) of NPC cells through the nuclear factor-κB (NF-κB) signaling pathway. Our findings indicate that PEDF plays a vital role in lymphatic metastasis by targeting both lymphatic endothelial cells and NPC cells, and PEDF may represent a novel therapeutic target for NPC.

Highlights

Nasopharyngeal carcinoma (NPC) is an upper respiratory tract tumor arising from nasopharynx epithelium, which is common in southern China and Asia
Low expression of Pigment epithelium-derived factor (PEDF) is correlated with poor prognosis and negatively with lymphatic vessel density (LVD) in human NPC tissues To find the relationship between PEDF and LVD in NPC, we detected the PEDF expression and LVD by immunohistochemistry (IHC) in a NPC tissue microarray, which contains human nasopharyngeal cancer (22 cases), papilloma (15 cases), polyp (6 cases), hyperplasia, and inflammation (6 cases)
These findings indicated that PEDF was negatively correlated with LVD, and downregulation of PEDF was correlated with poor prognosis in human NPC tissues

Summary

Introduction

Nasopharyngeal carcinoma (NPC) is an upper respiratory tract tumor arising from nasopharynx epithelium, which is common in southern China and Asia. Lymphangiogenesis is the outgrowth of new lymphatics from the preexisting lymphatic vessels, which gains wide attention recently for its involvement in lymphatic metastasis[8,9,10]. Lymphangiogenesis is mainly induced by vascular endothelial growth factor C (VEGF-C), VEGF-D, and their receptor VEGFR3, and their interactions will lead to the proliferation and migration of lymphatic endothelial cells. Luo et al Cell Death and Disease (2021)12:295 and, the formation of lymphatic vessels[11,12,13]. Except for VEGF-C/D, many factors were reported to promote tumor lymphangiogenesis, such as VEGF-A14,15, hepatocyte growth factor (HGF)[16], fibroblast growth factor(FGF)[17], epidermal growth factor(EGF)[18], plateletderived growth factor-A(PDGF-A)[19], and insulin-like growth factor(IGF)[20]. It is necessary to find a better and more effective endogenous lymphangiogenesis inhibitor, and the role and mechanism of these inhibitors still need to be further elucidated

Methods

Results

Conclusion