Figure 6.

Schema of mechanisms of FGF2-driven acquired resistance to anti-VEGF therapy. (a) VEGF induces tumor angiogenesis by activating the VEGF signaling pathway in endothelial cells. Tumor vessels are abnormal in that they are mixtures of large and small tortuous vessels, have impaired function, and are hardly covered with pericytes. (b) VEGF-dependent vessel formation is suppressed by chronic expression of VEGFR2-Fc. However, the activated FGF2 signaling pathway maintains tumor vessels despite chronic inhibition of the VEGF signaling pathway. Tumor vessels covered by pericytes become resistant to VEGFR2-Fc. c Simultaneous expression of FGFR2-Fc and VEGFR2-Fc inhibits activation of the FGF signaling between pericytes and endothelial cells. This further decreases the number of tumor vessels and enhances tumor growth suppression. Thus, dual inhibition of FGFR and VEGFR, such as in lenvatinib treatment, enhances antitumor activity.