Figure 3.

The components of the primary tumor microenvironment and lymphangiogenic factors involved in tumor progression. (A) Tumor cells are surrounded by an abundance of cell types, such as immune cells, macrophages, dendritic cells, fibroblasts, and endothelial cells. Blood and lymphatic capillaries are required to support the growth of the tumor, while serving as a conduit for the dissemination of tumor cells to distant organs. (B) Lymphangiogenesis occurs during tumor progression with lymphangiogenic factors released by tumor cells, namely VEGF-C/D, VEGF-A, NRP-2, ANGPT-2, and HGH/FGF. Tumor cells that expressed chemokine receptors CXCR4 are attracted to inflammatory chemokines CCL21/CXCL21 released by LECs, and thus stimulate lymphangiogenesis. The interaction of LECs with lymphangiogenic factors results in an increase of lymphatic permeability by changing the adhesion properties of LECs, accompanied by the dilation of collecting lymphatic vessels to facilitate the spread of tumor cells through intratumoral and peritumoral lymphangiogenesis, finally leading to lymphatic metastasis. A number of different ncRNAs are expressed throughout the process. ncRNAs exert their pro- (blue) or anti-lymphangiogenic (red) effect by regulating primary lymphangiogenic components. (C) Regulation of tumor-associated lymphangiogenesis by ncRNAs also occurs on LEC transcription factors, such as protocadherin Fat4 (FAT4), vasohibin-1 (VASH1), Ets proto-oncogene 1 and 2 (ETS1 and ETS2), and Zinc finger protein 1 (ZIC1). Keywords: Vascular endothelial growth factor (VEGF-C and VEGF-A); vascular endothelial growth factor receptor (VEGFR-3/2); neuropilin-2 (NRP-2); angiopoietin-2 (ANGPT-2); fibroblast growth factor (FGF); hepatocyte growth factor (HGF); C-C chemokine receptor (CCR); C-C chemokine ligand (CCL); and C-X-C motif chemokine (CXCL).