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. 2021 Dec;191(12):2052–2063. doi: 10.1016/j.ajpath.2021.08.011

Figure 1.

Figure 1

Molecular pathways that promote lymphangiogenesis in liver cancers. Under hypoxia, hypoxia-inducible factor-1⍺ (HIF1⍺) increases the transcription of lymphangiogenic factors, such as angiopoietin-1/2 (ANG1/2), vascular endothelial growth factor (VEGF)-C/D, platelet-derived growth factor (PDGF)-B, and PDGF-D. PDGF-D secreted from hepatic cancer cells bind to PDGF receptor (PDGFR)-B expressed on the surface of cancer-associated fibroblast (CAFs), which, in turn, leads to increased transcription of VEGF-C from CAFs. The VEGF-C secreted from CAFs binds to VEGF receptor (VEGFR)-3 on lymphatic endothelial cells (LECs) and induces lymphangiogenesis. In the background of preexisting liver diseases, such as cirrhosis, NF-κB pathway is stimulated in LECs, which increases transcription of Prospero homeobox 1 protein (PROX1) and VEGFR-3, thus up-regulating LEC proliferation and lymphangiogenesis. All these processes lead to a high degree of lymphangiogenesis in the hepatic tumor microenvironment, ultimately aggravating lymph node metastasis. Generated with BioRender.com (Toronto, ON, Canada).