Interestingly, MMP-1/protease-activated receptor-1 (PAR1) signaling axis has been implicated in tumor angiogenesis and intravasation of carcinoma cells by inducing vascular permeability (122), as well as, hypoxia-regulated MMP-1 expression in metastatic bladder cancer cells, which could be associated to a reactive oxygen species (ROS)-related regulation of the spheroid metastatic phenotype and cell spread (123). This evidence concerns the gene F2R and urinary bladder cancer.