Stromal delivery of long Pentraxin-3 impairsFGF7FGFR-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-derived hPTX3 on tumor growth, vascularization and metastasis. hPTX3 overexpression inhibits angiogenesis in transgenic mice as observed in ex vivo aorta ring and in vivo matrigel plug assays. Next, various syngeneic FGF-dependent tumor cell lines, including TRAMP-C2 prostate carcinoma, B16-F10 melanoma and Lewis Lung carcinoma cells, were injected subcutaneously 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 inhibition of FGFR1 phosphorylation, tumor vascularization and tumor cell proliferation. In addition, 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, when injected intravenously 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.