Stromal delivery of long Pentraxin-3 impairs FGF/FGFR-dependent tumor growth and metastasis

The FGF/FGFR system contributes to cancer progression by inducing tumor growth and neovascularization, thus representing an emerging therapeutic target. Long Pentraxin-3 (PTX3) is a soluble pattern recognition receptor expressed by endothelial and immune cells in inflammatory contexts. Among various ligands, PTX3 binds different members of the FGF family, acting as a natural FGF ligand trap. Here, we generated transgenic mice expressing human (h)PTX3 under the control of endothelial specific Tie2/Tek transcription regulatory sequences (Tie2-hPTX3 mice). These animals accumulate significant levels of hPTX3 in perivascular stroma and in the blood stream. On this basis, Tie2-hPTX3 mice were used to investigate the impact of stroma delivery of hPTX3 on tumor growth, vascularization and metastasis. The anti-angiogenic activity of endothelium-derived hPTX3 was confirmed by ex vivo aorta ring and in vivo matrigel plug assays. Next, different syngeneic FGF-dependent tumor cell lines, including TRAMP-C2 prostate carcinoma, B16-F10 melanoma and Lewis Lung carcinoma cells, were subcutaneously injected in Tie2-hPTX3 mice. Notably, the growth of all tumor grafts was significantly reduced in Tie2-hPTX3 mice when compared to wild type animals and was accompanied by a significant reduction of FGFR1 phosphorylation, decrease of tumor vascularity and tumor cell proliferation. Also, B16-F10 melanoma and M5076 ovarian sarcoma cells showed a dramatic decrease of their capacity to form experimental metastases in the lung and liver, respectively, after intravenous injection in Tie2-hPTX3 mice. Also, the orthotopic growth of syngeneic pancreatic and mammary tumor cells was significantly reduced after injection in Tie2-hPTX3 mice and led to increased survival compared to control mice. Finally, double transgenic TRAMP/Tie2-hPTX3 mice showed a significant delay of multistage prostate tumor onset and progression in respect to TRAMP mice. Our findings demonstrate for the first time that in vivo delivery of PTX3 exerts a dramatic impact on tumor growth, vascularization and metastasis. These results have set the basis for the identification of a low molecular weight PTX3-derived molecule that recapitulates the FGF-trap activities of PTX3 and exhibits promising therapeutic potential for FGF-dependent tumors.