The Complex Role of Thrombin in Cancer and Metastasis: Focus on Interactions with the Immune System.

Thrombin, a pleiotropic enzyme involved in coagulation, plays a crucial role in both procoagulant and anticoagulant pathways. Thrombin converts fibrinogen into fibrin, initiates platelet activation, and promotes clot formation. Thrombin also activates anticoagulant pathways, indirectly inhibiting factors involved in coagulation. Tissue factor triggers thrombin generation, and the overexpression of thrombin in various cancers suggests that it is involved in tumor growth, angiogenesis, and metastasis. Increased thrombin generation has been observed in cancer patients, especially those with metastases. Thrombin exerts its effects through protease-activated receptors (PARs), particularly PAR-1 and PAR-2, which are involved in cancer progression, angiogenesis, and immunological responses. Thrombin-mediated signaling promotes angiogenesis by activating endothelial cells and platelets, thereby releasing proangiogenic factors. These functions of thrombin are well recognized and have been widely described. However, in recent years, intriguing new findings concerning the association between thrombin activity and cancer development have come to light, which justifies a review of this research. In particular, there is evidence that thrombin-mediated events interact with the immune system, and may regulate its response to tumor growth. It is also worth reevaluating the impact of thrombin on thrombocytes in conjunction with its multifaceted influence on tumor progression. Understanding the role of thrombin/PAR-mediated signaling in cancer and immunological responses is crucial, particularly in the context of developing immunotherapies. In this systematic review, we focus on the impact of the thrombin-related immune system response on cancer progression.

Actual, Personalized Approaches to Preserve Cognitive Functions in Brain Metastases Breast Cancer Patients.

Breast cancer (BC) is the most often diagnosed cancer among women worldwide and second most common cause of brain metastases (BMs) among solid malignancies being responsible for 10-16% of all BMs in oncological patients. Moreover, BMs are associated with worse prognosis than systemic metastases. The quality of life (QoL) among brain metastases breast cancer (BMBC) patients is significantly influenced by cognitive functions. Cancer-related cognitive deficits and the underlying neural deficits in BMBC patients can be caused via BMs per se, chemotherapy administration, brain irradiation, postmenopausal status, or comorbidities. Brain RT often leads to cognitive function impairment by damage of neural progenitor cells of the hippocampus and hence decreased QoL. Sparing the hippocampal region of the brain during RT provides protective covering of the centrally located hippocampi according to the patient's clinical requirements. This article discusses the personalized strategies for treatment options to protect cognitive functions in BMBC patients, with special emphasis on the innovative techniques of radiation therapy.

The Learning Curve and Inter-Observer Variability in Contouring the Hippocampus under the Hippocampal Sparing Guidelines of Radiation Therapy Oncology Group 0933.

Hippocampal-sparing brain radiotherapy (HS-BRT) in cancer patients results in preservation of neurocognitive function after brain RT which can contribute to patients' quality of life (QoL). The crucial element in HS-BRT treatment planning is appropriate contouring of the hippocampus. Ten doctors delineated the left and right hippocampus (LH and RH, respectively) on 10 patients' virtual axial images of brain CT fused with T1-enhanced MRI (1 mm) according to the RTOG 0933 atlas recommendations. Variations in the spatial localization of the structure were described in three directions: right-left (X), cranio-caudal (Y), and forward-backward (Z). Discrepancies concerned three-dimensional localization, shape, volume and size of the hippocampus. The largest differences were observed in the first three delineated cases which were characterized by larger hippocampal volumes than the remaining seven cases. The volumes of LH of more than half of hippocampus contours were marginally bigger than those of RH. Most differences in delineation of the hippocampus were observed in the area of the posterior horn of the lateral ventricle. Conversely, a large number of hippocampal contours overlapped near the brainstem and the anterior horn of the lateral ventricle. The most problematic area of hippocampal contouring is the posterior horn of the lateral ventricle. Training in the manual contouring of the hippocampus during HS-BRT treatment planning under the supervision of experienced radiation oncologists is necessary to achieve optimal outcomes. This would result in superior outcomes of HS-BRT treatment and improvement in QoL of patients compared to without HS-BRT procedure. Correct delineation of the hippocampus is problematic. This study demonstrates difficulties in HS-BRT treatment planning and highlights critical points during hippocampus delineation.

Personalized Radiation Therapy in Cancer Pain Management.

The majority of advanced cancer patients suffer from pain, which severely deteriorates their quality of life. Apart from analgesics, bisphosphonates, and invasive methods of analgesic treatment (e.g., intraspinal and epidural analgesics or neurolytic blockades), radiation therapy plays an important role in pain alleviation. It is delivered to a growing primary tumour, lymph nodes, or distant metastatic sites, producing pain of various intensity. Currently, different regiments of radiation therapy methods and techniques and various radiation dose fractionations are incorporated into the clinical practice. These include palliative radiation therapy, conventional external beam radiation therapy, as well as modern techniques of intensity modulated radiation therapy, volumetrically modulated arch therapy, stereotactic radiosurgery or stereotactic body radiation therapy, and brachytherapy or radionuclide treatment (e.g., radium-223, strontium-89 for multiple painful osseous metastases). The review describes the possibilities and effectiveness of individual patient-tailored conventional and innovative radiation therapy approaches aiming at pain relief in cancer patients.

Endothelial Protein C Receptor (EPCR), Protease Activated Receptor-1 (PAR-1) and Their Interplay in Cancer Growth and Metastatic Dissemination.

Endothelial protein C receptor (EPCR) and protease activated receptor 1 (PAR-1) by themselves play important role in cancer growth and dissemination. Moreover, interactions between the two receptors are essential for tumor progression. EPCR is a cell surface transmembrane glycoprotein localized predominantly on endothelial cells (ECs). It is a vital component of the activated protein C (APC)-mediated anticoagulant and cytoprotective signaling cascade. PAR-1, which belongs to a family of G protein⁻coupled cell surface receptors, is also widely distributed on endothelial and blood cells, where it plays a critical role in hemostasis. Both EPCR and PAR-1, generally considered coagulation-related receptors, are implicated in carcinogenesis and dissemination of diverse tumor types, and their expression correlates with clinical outcome of cancer patients. Existing data explain some mechanisms by which EPCR/PAR-1 affects cancer growth and metastasis; however, the exact molecular basis of cancer invasion associated with the signaling is still obscure. Here, we discuss the role of EPCR and PAR-1 reciprocal interactions in cancer progression as well as potential therapeutic options targeted specifically to interact with EPCR/PAR-1-induced signaling in cancer patients.

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.

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.

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.

Protease-activated receptors - biology and role in cancer.

The fact that blood coagulation disorders may accompany malignant disease is well established. However, many studies have shown that components of the haemostatic system may also elicit signaling leading to cancer developement and progression. The potential mechanism by which coagulation factors play a role in cancer invasion is not completely understood, but one hypothesis is that protease-activated receptors (PARs) play a prominent role. PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They have important functions in haemostasis and inflammation but may also be implicated in cancer cell progression. Thrombin, tissue factor (TF) and matrix metalloproteinases (MMPs) are the main activators of these receptors. The mechanism of persistent activation of PARs was also described in cancer cells. Here, we discuss the physiological and pathological role of PARs with a particular focus on PARs' contribution to cancer biology. We also present therapeutic options tailored specifically to inhibition of PAR-induced signalling in cancer patients.

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.

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.

Erythropoietin receptor and tissue factor are coexpressed in human breast cancer cells.

PURPOSE: Erythropoiesis-stimulating agents (ESAs) are recommended for treating chemotherapy-induced anemia in breast cancer patients. Reduced survival rates in ESAs-treated patients have been reported, possibly due to thromboembolic complications, however the exact mechanism remains obscure. The principal activator of blood coagulation in cancer is tissue factor (TF). There are data that erythropoietin receptor (EPO-R) is expressed in tumor cells. The purpose of this study was to evaluate the expression of EPO-R and TF in loco in breast cancer. METHODS: The expression of EPO-R and TF was investigated in 24 invasive breast carcinoma specimens. Immunohistochemical (IHC) methodologies according to ABC technique and double-staining IHC procedure were employed utilizing antibodies against EPO-R and TF. RESULTS: Expression of EPO-R and TF was demonstrated in the tumor cells in all breast cancer specimens. No staining for EPO-R and TF was visualized in normal breast tissue. Double staining studies revealed co-expression of both EPO-R and TF in breast cancer cells and endothelial cells. CONCLUSIONS: EPO-R and TF expression and their coexpression in breast cancer cells suggest a possibility that EPO-R might be responsible for some adverse effects and reduced survival observed in ESAs-treated breast cancer patients with anemia, possibly due to the interaction with TF. Further experimental studies are warranted to determine the role of both EPO-R and TF in the treatment with ESAs of breast cancer patients with chemotherapy-induced anemia.

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.

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.