Ang-2 modulates VEGFR3-induced lymphangiogenesis in peritumoral adipose tissue of metastatic head and neck cancer

Experimental studies have highlighted the connection between tumor-associated lymphatic vessel formation and adipose tissue. However, peritumoral lymphangiogenesis in metastatic head and neck cancer (HNC) remains insufficiently explored. This study contrasts lymphangiogenesis and regulatory factor expression in peritumoral adipose tissue (PTAT) surrounding metastatic head and neck tumors versus primary tumors. Histological, histochemical, and real-time PCR analyses were conducted on perioperatively collected adipose tissue samples from primary and metastatic tumors. Lymphatic Vessel Endothelial Hyaluronan Receptor-1 (LYVE-1) positive lymphatic vessel density significantly increased in peritumoral adipose tissue around metastatic tumors (M-PTAT). In M-PTAT, lymphatic vessels expressing LYVE-1 or VEGFD significantly increased, correlating with inflammatory cell count, elevated angiopoietin-2 (Ang-2) expression, and fibrosis factors. Expression levels of VEGF-D, VEGF receptor-3, and other lymphangiogenesis regulators in M-PTAT significantly surpassed those in peritumoral adipose tissue around primary tumors (P-PTAT). Notably, Ang-2 expression, confirmed histologically and at the mRNA level, was higher in M-PTAT than in P-PTAT. Ang-2 and VEGF-D stimulation promoted sprout formation in human lymphatic endothelial cells. This study underscores that M-PTAT, compared to primary tumors, exhibits more extensive lymphangiogenesis, inflammation, and fibrosis due to overexpression of Ang-2, LYVE-1, and VEGF-D.