Herein we have shown that malignant cells derived from human melanoma and prostate cancer, as well as human embrional kidney 293 cells (HEK-293) transfected with the full-length form (D1D2D3) of the human uPAR, exhibit a uPAR-dependent mesenchymal invasion across a 3D Matrigel substrate, that is proportional to uPAR expression and that may be strongly reduced by preventing uPAR interaction with its ligand uPA, the observed residual mesenchymal Matrigel invasion being surely ascribable to the activity of multiple proteases. Here, PLAU is linked to prostate cancer.