Fig. 7: Survival correlation and schematic diagram of underlying mechanisms of synergistic anti-FGF-2⁺ tumor activity by combination therapy.

a Kaplan–Meier survival of FGF-2-high vs. FGF-2-low breast cancer (BRCA, n = 246 vs. 267; P = 0.0458); b ovarian cancer (OV, n = 131 vs. 129; P = 0.0097); c bladder carcinoma (BLCA, n = 261 vs. 141; P = 0.007); d and pancreatic adenocarcinoma (PAAD, n = 57 vs. 120; P = 0.003). The log-rank test was used for statistical analysis at the endpoint. Source data are provided as a Source Data file. e Tumors often produce FGF-2 and VEGF to stimulate tumor angiogenesis. While VEGF stimulates endothelial cell proliferation, migration, and endothelial cell tip formation, FGF-2 primarily induces endothelial cell proliferation. In FGF-2 positive tumors, blocking FGF-2-triggered signaling such as inhibition of FGFR inhibits endothelial cell proliferation and angiogenesis. However, the impact of anti-FGF agents on tumor angiogenesis may be modest because tumors employ VEGF to stimulate neovascularization. Thus, VEGF plays a compensatory role in circumventing the antiangiogenic effect by FGF-2. Similarly, blocking VEGF alone in FGF-2 positive tumors may also produce a limited antitumor effect because of the compensatory effect of FGF-2. In addition, FGF-2 is a potent perivascular factor to stimulate pericyte proliferation and vascular coverage through an intimate collaboration with the PDGF-B-PDGFRβ signaling pathway. Blocking PDGFRβ alone would lead to ablation of perivascular cells from tumor vessels, permitting exposure of endothelial cells to vascular stimuli such as FGF-2 and VEGF. In supporting this view, we show that anti-PDGFRβ increases rather than reduces vascular density in FGF-2 positive tumors. Simultaneous blocking VEGF and PDGFRβ signaling pathways inhibits vascular sprouting and vascular stability, leading to vascular regression in FGF-2 positive tumors.