Two Birds, One Stone: Double Hits on Tumor Growth and Lymphangiogenesis by Targeting Vascular Endothelial Growth Factor Receptor 3.

Ming-Chuan Hsu,Mei-Ren Pan,Wen-Chun Hung

doi:10.3390/cells8030270

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR3) has been known for its involvement in tumor-associated lymphangiogenesis and lymphatic metastasis. The VEGFR3 signaling is stimulated by its main cognate ligand, vascular endothelial growth factor C (VEGF-C), which in turn promotes tumor progression. Activation of VEGF-C/VEGFR3 signaling in lymphatic endothelial cells (LECs) was shown to enhance the proliferation of LECs and the formation of lymphatic vessels, leading to increased lymphatic metastasis of tumor cells. In the past decade, the expression and pathological roles of VEGFR3 in tumor cells have been described. Moreover, the VEGF-C/VEGFR3 axis has been implicated in regulating immune tolerance and suppression. Therefore, the inhibition of the VEGF-C/VEGFR3 axis has emerged as an important therapeutic strategy for the treatment of cancer. In this review, we discuss the current findings related to VEGF-C/VEGFR3 signaling in cancer progression and recent advances in the development of therapeutic drugs targeting VEGF-C/VEGFR3.

Highlights

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are critical regulators in the development and maintenance of blood and lymphatic vascular systems
The vascular endothelial growth factor C (VEGF-C)/Vascular endothelial growth factor receptor 3 (VEGFR3) axis has been implicated in cancer progression by directly affecting tumor cells or modulating lymphangiogenesis and immune response
High expression of vascular endothelial growth factors (VEGFs)-C/VEGFR3 has been demonstrated to be correlated with increased lymphatic metastasis and poor prognosis in numerous types of cancers (Table 1)

Summary

Introduction

Vascular endothelial growth factor receptor (VEGFR) tyrosine kinases are critical regulators in the development and maintenance of blood and lymphatic vascular systems. VEGF-C binding induces VEGFR3 dimerization and enhances the phosphorylation of tyrosine kinases in the cytoplasmic tail, resulting in the increase of downstream signaling These phosphotyrosine residues serve as docking sites for recruiting cytoplasmic signaling mediators that elicit diverse cellular responses such as cell proliferation, migration, and survival. VEGFR3 phosphorylation triggers phosphoinositide-3 kinase (PI3K)-dependent activation of AKT and protein kinase C (PKC)-dependent activation of ERK1/2 pathways Stimulation of both signaling pathways promotes the proliferation of lymphatic endothelial cells [32] (Figure 1). The mechanism of NRP2-mediated lymphangiogenesis remains unclear, increasing evidence suggests that NRP2 binds to VEGF-C/D and forms a complex with VEGFR3, thereby activating the VEGFR3 signaling which enhances the proliferation of lymphatic endothelial cells and lymphangiogenesis [40,41,42]. +, the expression of VEGFR3 is correlated with angiogenesis or lymph node metastasis; −, the expression of VEGFR3 is not correlated with angiogenesis or lymph node metastasis

Functional Roles of VEGFR3 in Lymphatic Endothelial Cells

Expression and Function of VEGFR3 in Immune Cells

Small Molecule TKIs of VEGFR3

Findings

Conclusions