Studies on the changes of uPA system in a co-culture model of bone marrow stromal cells–leukemia cells

The core of the tumor microenvironment in the hematological system is formed by bone marrow stromal cells (BMSCs). In the present study, we explored the interaction between the urokinase plasminogen activator (uPA) system and the leukemia bone marrow microenvironment (BMM). We established BMSCs–HL60 and HS-5–K562 co-culture models in direct contact mode to simulate the BMM in leukemia. In BMSCs-HL60 co-culture model, the expression levels of uPA, uPA receptor (uPAR), plasminogen activator inhibitor 1 (PAI-1) and vascular endothelial growth factor (VEGF) in BMSCs were higher than those in mono-cultured BMSCs. Matrix metalloproteinase (MMP)-9 (MMP-9) was up-regulated in co-cultured HL60 cells. In HS-5–K562 co-culture model, only uPA, PAI-1, and VEGF-A were up-regulated in HS-5 cells. The levels of the uPA protein in the co-culture supernatant were significantly higher than that of mono-cultured BMSCs or HS-5 cells. Our findings demonstrate that the co-culture stimulates the production of uPA, uPAR, PAI-1, MMP-9, and VEGF-A by BMSCs. It could further explain how the uPA system in leukemia cells is involved in the growth, development, and prognosis of leukemia.

The Role of Stromal Proteolytic Systems in Cancer Progression (Review)

Oncological diseases belong to life-threatening pathologies being the second most frequent cause of morbidity and mortality after cardiovascular diseases. Clarification of carcinogenesis mechanisms makes it possible to expand the stock of tools available for prevention of critical illness accompanying this pathological condition.Nowadays, proteolytic systems of tumor microenvironment (ТМЕ) are regarded as key regulators of a tumor progression including tumor growth, invasion and metastazing. The review discusses ТМЕ structure and role in cancer progression.Recent data decipher the role of proteolytic systems in the interaction stromal cells with tumor cells in different types of cancer in humans. The most known proteolytic systems contributed to cancer progression are matrix metalloproteinase system (MMP), urokinase-type plasminogen activator system (uPA-system), various cathepsins, granzymes, and elastase. Inhibition of extracellular proteolysis in the course of an oncological process is considered an effective approach to cancer therapy.

Distribution of urokinase-type plasminogen activator and its receptor in malignant tissues of gastric adenocarcinoma.

e15530 Background: Peritoneal metastases are the most common recurrence of gastric cancer, even after radical surgery. Urokinase-type plasminogen activator (uPA) system, including its receptor uPAR, is crucial in the proteolysis activation for the cleavage of the extracellular matrix and basement membrane. The purpose of the study was to determine the antigen form uPA-Ag, active form uPA-act and the uPAR receptor in tissues of adenocarcinoma of the stomach, its perifocal tissues (PT), greater omentum and peritoneum in patients with stomach cancer T3-4аN0-3M1 and T3-4аN0-3M0. Methods: Tissues of patients with gastric adenocarcinoma T3-4аN0-3M1 (n = 21: 10 men, 11 women) and T3-4аN0-3M0 (n = 24: 15 men, 9 women) aged 61.23±4.8 years were studied. Controls: non-cancer patients aged 39.1±3.2 years (n = 17: 6 men, 11 women). Levels of uPA-act, uPA-Ag and uPAR were determined by ELISA using standard test systems. Statistical analysis was performed using the SPSS 11.5 software package for Windows. Results: In T3-4аN0-3M1, the highest uPAR levels were observed in tissues of the tumor, greater omentum and peritoneum, compared to T3-4аN0-3M0 and controls (p < 0.01). In PT of T3-4аN0-3M1, uPAR levels were lower than in tumor (p < 0.01) but higher than in resection line tissues. Tumor levels of uPA-act in T3-4аN0-3M1 and T3-4аN0-3M0 were similar and in both cases higher than in PT. In the greater omentum in T3-4аN0-3M1, uPA-act levels were similar to tumor levels and exceeded the values in T3-4аN0-3M0 (p < 0.01). Peritoneal uPA-act did not differ in T3-4аN0-3M1 and T3-4аN0-3M0 but was higher than in controls (p < 0.05). Tumor levels of uPA-Ag in T3-4аN0-3M1 exceeded the levels in T3-4аN0-3M0 and in both PT (p < 0.05). Levels of uPA-Ag in the greater omentum in T3-4аN0-3M1 were higher than in T3-4аN0-3M0 and lower than in controls (p < 0.01). Comparable uPA-Ag levels in T3-4аN0-3M1 and T3-4аN0-3M0 were lower than in controls (p < 0.01). Conclusions: Gastric adenocarcinoma secretes uPAR and uPA, and uPAR levels in the tumor are associated with omental or peritoneal metastases. Levels of uPAR and uPA-act in the greater omentum and peritoneum in T3-4аN0-3M1 are increased even higher than in T3-4аN0-3M0; uPAR can serve as a marker of a pre-metastatic niche in peritoneal tissues.

HPEFT for Hierarchical Heterogeneous Multi-DAG in a Multigroup Scan UPA System

Multidirected acyclic graph (DAG) workflow scheduling is a key problem in the heterogeneous distributed environment in the distributed computing field. A hierarchical heterogeneous multi-DAG workflow problem (HHMDP) was proposed based on the different signal processing workflows produced by different grouping and scanning modes and their hierarchical processing in specific functional signal processing modules in a multigroup scan ultrasonic phased array (UPA) system. A heterogeneous predecessor earliest finish time (HPEFT) algorithm with predecessor pointer adjustment was proposed based on the improved heterogeneous earliest finish time (HEFT) algorithm. The experimental results denote that HPEFT reduces the makespan, ratio of the idle time slot (RITS), and missed deadline rate (MDR) by 3.87–57.68%, 0–6.53%, and 13–58%, respectively, and increases relative relaxation with respect to the deadline (RLD) by 2.27–8.58%, improving the frame rate and resource utilization and reducing the probability of exceeding the real-time period. The multigroup UPA instrument architecture in multi-DAG signal processing flow was also provided. By simulating and verifying the scheduling algorithm, the architecture and the HPEFT algorithm is proved to coordinate the order of each group of signal processing tasks for improving the instrument performance.

Urokinase-Type Plasminogen Activator System in Norm and in Life-Threatening Processes (Review)

The multifunctional urokinase-type plasminogen activator system (uPA-system) includes serine proteinase — uPA or urokinase, its receptor (uPAR) and two inhibitors (PAI-1 and PAI-2). The review discusses the structural features and involvement of the system components in the development of life-threatening processes including carcinogenesis, inflammation, neurogenesis and fibrinolysis, in regulation of which the destruction of extracellular matrix (ECM), cell mobility and signaling inside and outside the cell play a decisive role. uPA triggers the processes by activating the plasminogen and its convertion into plasmin involved in the activation of matrix metalloproteinases (MMPs) in addition to the regulation of fibrinolysis. MMPs can hydrolyze all the major ECM components and therefore play a key role in invasion, metastasis, and cell mobility. MMPs activates a cassette of biologically active regulatory molecules and release them from ECM. uPAR, PAI-1 and PAI-2 are responsible for regulation of the uPA activity. In addition, being a signaling receptor, uPAR along with MMPs lead to the stimulation of a number of signaling pathways that are associated with the regulation of proliferation, apoptosis, adhesion, growth and migration of cells contributing to tumor progression, inflammation, chemotaxis, and angiogenesis. Effective participation of the uPA system components in ECM destruction and regulation of intracellular and extracellular signaling pathways demonstrates that the system significantly contributes to the regulation of various physiological and pathological processes.

The Urokinase Plasminogen Activator System in Human Cancers: An Overview of Its Prognostic and Predictive Role

Urokinase plasminogen activator (uPA) system regulates extracellular matrix remodelling by activating ubiquitous protease plasmin in many important physiological processes. The system components include uPA, plasminogen activator inhibitors (PAIs) and uPA receptor (uPAR). Besides its role in physiological processes, uPA system is active in most tumour types where its aberrant regulation has been associated with the development of metastatic phenotype. In vitro and in vivo studies have shown that the over-expression of uPA, PAI-1 and uPAR not only enhances tumour cell invasion capacity and metastasis, but also corresponds to a higher risk of disease correlating with traditional clinicopathological features which makes them potential prognostic biomarkers and therapeutic targets in a wide range of human malignancies. This review focuses on uPA system's prognostic and predictive role in several types of human cancers, summarizing its activities in cancer development and highlighting the importance of addressing all unanswered questions before bridging the gap between laboratory findings to clinic use of uPA system's components as cancer biomarkers.