**5. Conclusion**

activator (uPA) and its high-affinity cellular receptor (uPAR) is critical for fibrinolytic activities including targeted degradation of the basement matrix. Moreover, uPAR is motile within the cellular membrane, which allows its allocation at the cellular front of desired direction for proteolysis [100]. Under normal conditions, the process of active proteolysis is tightly control‐

In cancer, biology activation of uPA/uPAR system is a prerequisite for efficient focal proteol‐ ysis, adhesion, migration and enables penetrating tumor cells to invade and metastasize [101]. Extracellular matrix proteolysis acts at all stages of the metastatic cascade: detachment of tumor cells from primary site, intravasation, hematogeneous dissemination, extravasation, and metastases formation. These processes are executed by proteolytic enzymatic systems, including uPA/uPAR, matrix metalloproteinases, and cysteine proteinases, which interact synergistically and are responsible for the complex proteolytic activity of tumors [102].

The cellular receptor for the urokinase plasminogen activator (uPAR) is a key molecule for efficient pericellular proteolysis. Apart from potentiating proteolytic activity, the complex uPA/uPAR ignites series of intracellular signaling events associated with the processes of proliferation, adhesion, chemotaxis, migration, and angiogenesis. Tissue overexpression of uPA/uPAR is found in various human tumors—breast, prostate, GIT, and lung. It is associated with advanced disease and is independent adverse prognostic factor for survival [103]. Direct involvement of uPAR in processes of tumor biology characterizes it as a hallmark of the malignant invasive phenotype. Overexpression of uPAR cDNA in osteosarcoma cells increases its ability to penetrate the basal membrane [104]. Invasive potential of tumor cells in chorionallantois membrane of chicken embryos correlates with uPAR-associated proteolytic activity [105]. Expression of uPAR gene by tumor cells is required for vascular intravasation, whereas uPAR gene expression decreases invasive potential of transformed fibroblasts in vitro [106]. Experiments with anti-uPAR inhibitory antibodies demonstrate reduction of the matric proteolytic activity [107, 108]. Levels and activity of uPAR are regulated at the transcriptional level by oncogene-controlled promoter activation. uPAR promoter region contains binding motifs for several transcriptional factors that regulate cellular differentiation, migration, and apoptosis: specific protein 1 (SP1), activator protein 1 (AP1) and activator protein 2 (AP2) [109]. uPAR basal expression is regulated proximally from SP1 transcriptional starting point. In tumor models of colorectal cancer, constitutive, and induced uPAR expression is regulated by AP1 binding motif via MAPK and c-JUN NH2-terminal kinase (JNK) signaling [110]. AP2 binding motif is required for constitutive overexpression of uPAR promoter activity in invasive

tumor cells after stimulation by the tumor promoter phorbol acetate.

The role of K-ras and SRC oncogenes in uPAR regulation has been identified. K-ras regulates uPAR mediated proteolysis by transcriptional binding of AP1 to the promoter motif. Down‐ regulation of promoter activity as in deletion of the AP1 binding activity has been observed in tumor clones with K-ras allelic deletion. The knockout effect is accompanied by significant reduction of uPAR expression and tumor-associated proteolysis [111]. Increased uPAR protein expression and laminin degradation parallel to c-SRC activation are observed in SW 480 cells transfected to constitutively overexpress s-SRC. Elevated uPAR expression is due to tran‐ scriptional activation secondary to increased binding of SP1 to the complementary promoter

led by the proteolytic systems.

12 Tumor Metastasis

Identification of hemostatic system as a component of the tumor microenvironment would provide a research scaffold for novel determinants of tumor progression. The role of hemostatic components in the processes of tumor growth, angiogenesis, invasion, and metastasis makes them an accessible potential target for targeted therapy. Analysis of their predictive and prognostic value as surrogate biomarkers for tumor-induced events would yield development of novel tools for monitoring and antitumor strategies.
