MAPK and PI3K signalling differentially regulate angiogenic and lymphangiogenic cytokine secretion in squamous cell carcinoma of the head and neck

Abstract

Vascular endothelial growth factors (VEGF-C and VEGF-A) play important roles in tumour-induced lymphangiogenesis and angiogenesis, respectively, key processes implicated in promoting tumour growth and metastatic spread. Previous work from our laboratory has shown that EGFR overexpression in squamous carcinomas of the head and neck (SCCHN) is linked to high levels of VEGF-A and VEGF-C (but low levels of VEGF-D) and is associated with poor prognosis. The present study explored the signalling pathways regulating the induction of VEGF-C and VEGF-A in the SCCHN cell lines CAL 27 and Detroit 562. The addition of exogenous EGF induced the expression of VEGF-C and VEGF-A in a concentration-dependent manner and this was blocked by a selective EGFR inhibitor, gefitinib. In both cell lines stimulated with endogenous or exogenous ligand, inhibition of MEK1/2 (with U0126 or PD98059) or PI3K (with PI-103 or LY294002) resulted in a marked reduction of EGFR-induced VEGF-A expression, whereas exogenous EGF-induced VEGF-C upregulation was blocked by inhibitors of MEK but not PI3K. Inhibition of p38 MAPK suppressed EGF-induced VEGF-C upregulation in CAL 27 cells, but inhibited EGF-induced VEGF-A upregulation in Detroit 562. Taken together, our evidence suggests that both endogenous and exogenous EGFR activation induces VEGF-A expression requiring both PI3K and MAPK signalling whereas VEGF-C expression is dependent on MAPK, but not the PI3K or mTOR pathways in SCCHN cell lines. p38 MAPK appears to be differentially linked to either VEGF-A or VEGF-C regulation in different cellular contexts.