Figure 7.

Summary and schematic illustration of key pathways and regulators identified as up- or downregulated in metastatic versus non-metastatic tumors or SES in this study. The urokinase plasminogen activator system (uPAS) plays a central role in remodeling the extracellular matrix (ECM) promoting metastasis. The uPAS exerts its activity by enhanced uPA-mediated conversion of co-localized plasminogen to plasmin and subsequent activation of matrix metalloproteases (MMP). PAI-1 (SERPINE1) can inhibit uPA activity but is also upregulated and contributes to cell signaling. MMPs and plasmin cleave and remodel the ECM leading to the release of latent growth factors (GFs) such as EGF, VEGF-A, TGF-β, and HGF (hepatocyte growth factor). By binding to their cognate receptors, EGFR and VEGFR (encoded by FLT1), and c-MET, these growth factors in turn act as important upregulators of the uPAS (via uPAR) and other downstream effectors, which induce large-scale cellular changes that further promote ECM remodeling, cellular migration, and invasion and, ultimately, metastasis. A few of these growth factor receptors are themselves overexpressed (i.e., MET, FLT1) and can drive invasion and metastasis regardless of growth factor activation. Aberrant miRNA expression, such as downregulated has-miR-340-5p, is also associated with upregulated uPAR expression. Direct and indirect downstream effectors of the uPAS include vitronectin, focal adhesions via integrins and focal adhesion kinase (FAK), the proliferation, and survival pathways MAPK/ERK PI3K/Akt/mTOR and VEGF-A, which facilitate increased protection against apoptosis/anoikis, increased cell proliferation, and EMT and angiogenesis; these are also important for invasion and metastasis. Created with BioRender.com.