Dominika Hempel

Protease-activated receptors (PARs)—biology and role in cancer invasion and metastasis

Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.

Assessment of circulating proteasome chymotrypsin-like activity in plasma of patients with acute and chronic leukemias.

OBJECTIVE We evaluated whether the proteasomal chymotrypsin-like (ChT-L) activity is increased in plasma of patients with acute lymphoblastic (ALL), acute myeloblastic (AML) and chronic lymphocytic (CLL) leukemias. METHODS The activity was assayed using the fluorogenic peptide substrate in the presence of an artificial activator sodium dodecyl sulfate (SDS) in the plasma of healthy donors (n=15) and ALL (n=15), AML (n=28) and CLL (n=22) patients. RESULTS The activity was significantly (P<0.001) higher in the plasma of ALL and AML patients at the diagnosis than in healthy subjects and decreased after therapy or remained unchanged or rose during relapse. By contrast, in CLL patients at the diagnosis, the activity did not differ significantly from the healthy controls. In each group, the activity positively correlated with the serum lactic dehydrogenase activity. CONCLUSIONS Plasma proteasome ChT-L activity can be a useful bio-marker for patients with acute leukemia at the blast stage.

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.

Increased plasma proteasome chymotrypsin-like activity in patients with advanced solid tumors

The chymotrypsin-like (ChT-L) activity is one of the key regulators of intracellular protein degradation. Elevated proteasome ChT-L activity has recently been reported in plasma of patients with leukemia and myelodysplastic syndrome and suggested to have a prognostic significance. The aim of the present study was to evaluate plasma proteasome ChT-L activity in patients with newly diagnosed solid tumors at early and advanced stages of the disease. The activity was assayed using the fluorogenic peptide substrate, Suc-Leu-Leu-Val-Tyr-AMC, in a cohort of 155 patients with early/advanced rectal (n = 43/29), gastric (n = 6/13), and breast (n = 37/27) cancer and compared with that in normal individuals (n = 55). The median plasma proteasome ChT-L activity was elevated by 20–32% in patients with advanced stage of rectal, gastric, and breast cancer compared with healthy donors. The difference turned out to be statistically significant (P < 0.001). By contrast, values in patients with early stage of malignancies were not significantly different from those observed in normal individuals. We also found that plasma proteasome activity correlated with serum carcinoembryonic antigen levels in the group of patients with rectal cancer (r = 0.433, P < 0.05). Elevated plasma proteasome ChT-L activity is indicative of advanced stage of rectal, gastric, and breast cancer. However, the activity does not seem to be a parameter with clinically relevant potential in terms of early detection of cancer in this subset of patients.

Platelets and cancer angiogenesis nexus

There has been remarkable insight into the importance of platelets in a wide range of pathophysiologic events, including inflammation and cancer progression. Thrombocytosis in cancer patients is a common finding. Tumor cells induce platelet activation and subsequent aggregation through direct and indirect mechanisms. Platelets are recognized to contribute to metastatic dissemination. There is plenty of evidence that components of the hemostatic system contribute to the process of angiogenesis. Furthermore, there are accumulated data on the substantial influence of blood platelets in the process of blood vessel formation during malignancy. Platelets appear to be the main physiologic transporters of proangiogenic and antiangiogenic factors. Moreover, they influence the process of angiogenesis through platelet-derived microparticles, microRNA, lipids, and variety of surface receptors. Platelets contribute to early and late stages of angiogenesis. Available data support the overall stimulatory effect of platelets on tumor angiogenesis. It raises the possibility that interfering with platelet function may be an effective antineoplastic treatment strategy.

Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past?

The association between coagulation and cancer development has been observed for centuries. However, the connection between inflammation and malignancy is also well-recognized. The plethora of evidence indicates that among multiple hemostasis components, platelets play major roles in cancer progression by providing surface and granular contents for several interactions as well as behaving like immune cells. Therefore, the anticancer potential of anti-platelet therapy has been intensively investigated for many years. Anti-platelet agents may prevent cancer, decrease tumor growth, and metastatic potential, as well as improve survival of cancer patients. On the other hand, there are suggestions that antiplatelet treatment may promote solid tumor development in a phenomenon described as “cancers follow bleeding.” The controversies around antiplatelet agents justify insight into the subject to establish what, if any, role platelet-directed therapy has in the continuum of anticancer management.

A case of B-cell lymphoma of the uterus

Primary malignant lymphoma occurs rarely in the female reproductive tract. A case of a 64-year-old female patient diagnosed with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma (B-UCL) of the uterus is presented. The patient underwent three cycles of chemotherapy based on R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with rituximab), radiation therapy to the pelvis, and extended hysterectomy. The follow-up has been conducted for three years. No sign of disease recurrence has been observed in physical examination and on images.

Awareness of head and neck cancer - a multicentre survey among young respondents in Poland

PURPOSE Head and neck cancer (HNC) is frequently diagnosed at an advanced stage of the disease, which results in suboptimal treatment outcomes, and leads to aesthetic and functional side-effects. Many risky behaviours associated with this type of cancer start at a young age. The aim of the study was to evaluate the level of HNC awareness in the young population in Poland. MATERIALS AND METHODS An anonymous online survey on HNC was conducted among 1903 people between the ages of 18 and 35 years. Closed-ended questions concerned HNC risk factors, symptoms and prognosis. RESULTS 85.1% of respondents were familiar with HNC. The main source of information was the Internet (57.3%); 78.2% of participants associated HNC occurrence with smoking, 43.4% with alcohol consumption and 37.2% with the human papillomavirus infection. The main risk factors mentioned by students of non-medical educational institutions included smoking, stress and excessive sunbathing. A quarter of respondents (37.7%, if medical students are excluded) were unaware of any early symptoms of HNC. The symptoms mentioned most frequently included chronic hoarseness (55.3%), a lump in the neck (51.8%) and chronic sore throat (51.4%). Over three-quarters of medical students and half of the remaining respondents connected early diagnosis with a better chance of being cured; 4.6% of medical students and 9.6% of students of other educational institutions would seek medical advice only when symptoms made everyday functioning impossible. CONCLUSIONS The level of HNC cancer awareness in the young population is alarmingly low. A large number of non-medical students are unaware of risk factors and early symptoms. Educational campaigns aimed at effective prophylaxis, earlier diagnosis and treatment of HNC are needed.