Vascular related pathologies in cardiovascular disease and cancer

Cardiovascular disease (CVD) and cancer are the leading causes of death worldwide. A damaged endothelium is one of the factors contributing towards these diseases. This thesis focused on understanding the implications of alterations to the physiological endothelium resulting in pathologies related to vascular disease and cancer metastasis. Functional healing response occurs in the diseased vessel wall aimed at restoring the vessel after an injury. Existing studies state that vascular progenitor cells contribute to the injured vasculature and aid in the repair process. Yet the mechanisms underlying the amalgamation of the cells to the endothelium, their origin and functions have not been clear. Through Study 1 using animal models of arterial injury, we examined the role of bone marrow derived cells in arterial repair and the mechanisms behind it. We observed that bone marrow-derived cells, helped in the initial stages of arterial injury and were subsequently eliminated from the artery wall. They localized in the arterial intima and most them were of endothelial phenotype. Additionally, bone marrow-derived cells did not fuse with the intima but could differentiate into vascular cells. This helped them adjust in the vessel wall and meet the needs of their new microenvironment. Fascinatingly, local delivery of bone marrow-derived endothelial cells to the sites of arterial injury caused a 1.4-fold decrease of the intimal lesion area. These results define the role of BM derived endothelial cells in the development of intimal lesions post vascular injury and this information contributes to the existing understanding of the pathogenesis of intimal hyperplasia. Hemodynamic forces are a cause of a dysfunctional endothelium. A turbulent blood flow could result in vascular disease. Studies have shown that red blood cell distribution (RDW) width as a risk factor for death in cancer and CVD. RDW is one of the haematological parameters commonly reported as part of a complete blood count An RDW higher than normal is termed as anisocytosis. Anisocytosis has been traditionally used, in combination with the red blood cell corpuscular volume, to diagnose chronic inflammatory status in the body. It has been never studied before if anisocytosis is just factor that reflects chronic inflammation in the body, or is factor that directly affects it. Hence in Study 2, we hypothesized that anisocytosis leads to changes in blood flow affecting interaction between blood and vascular endothelium at the bifurcation of arteries. We found that a high RDW is a predictive factor for the interaction between cellular components of blood and vascular wall. These interactions can lead to increased inflammation in the vessels and initiation of thrombosis. Put together, we suggest that anisocytosis measured by RDW is a predictive factor of vascular diseases. Cancer metastasis is one of the major causes of mortality and arises also due to a damaged endothelium. In Study 3 we investigated the role of murine cytomegalovirus(MCMV) in colon cancer progression using MCMV infected and non-infected animal models. Our results indicate that MCMV did not affect tumor growth but increases the incidence of metastasis to the lungs. Additionally, using microarray analysis we found cytokeratins 1, 2 and 14 to be upregulated 100 times in the infected models compared to the non-infected. We speculate that in our case metastasis is mediated possibly through a cytokeratin mediated pathway. The mechanism for dissemination is under investigation. In Study 4, we investigated the effect of C/EBPβ on metastasis and the relationship between C/EBPβ expression and overall survival of breast cancer patients. We found that decrease in C/EBPβ expression was related to shorter overall survival of breast cancer patients. Loss of C/EBPβ also, affected tumor growth, morphology and lung metastasis in murine 4T1 breast cancer model. Furthermore, inhibition of C/EBPβ resulted in an augmented expression of MHCII and CD45+, CD3+ and CD4+ lymphocytes accumulation in the tumors. Additional experiments established the role of inflammation in C/EBPβ-mediated metastasis formation

Patologia naczyń krwionośnych w chorobach układu krążenia i chorobach nowotworowych

Cancer and Cardiovascular diseases (CVD) are the two most prominent causes of death worldwide. Emerging evidence indicates shared risk factors and a common biology between these diseases. For instance, chronic inflammation has a significant role in contributing to both diseases. An alteration of the vasculature and the endothelial cells plays a key role in pathogenesis of CVD and cancer. The widespread overlap regarding disease prevention and risk factors for these diseases suggest a common mechanism in terms of molecular pathways. The goal of this tutorial is to present common problems and mechanism of these two mayor diseases.Choroby nowotworowe i sercowo-naczyniowe (CVD) to dwie najczęstsze przyczyny śmierci na całym świecie. Pojawiające się dowody wskazują na wspólne czynniki ryzyka i wspólną biologię między tymi chorobami. Na przykład przewlekły stan zapalny ma znaczącą rolę w przyczynianiu się do obu chorób. Zmiana układu naczyniowego i komórek śródbłonka odgrywa kluczową rolę w patogenezie CVD i raka. Czynniki ryzyka tych chorób sugerują wspólny mechanizm pod względem szlaków molekularnych. Celem tego artykulu jest przedstawienie typowych problemów i mechanizmów tych dwóch chorób

Effect of Chemokine (C-C Motif) Ligand 7 (CCL7) and Its Receptor (CCR2) Expression on Colorectal Cancer Behaviors

Colorectal cancer is the source of one of the most common cancer-related deaths worldwide, where the main cause of patient mortality remains metastasis. The aim of this study was to determine the role of CCL7 (chemokine (C-C motif) ligand 7) in tumor progression and finding whether it could predict survival of colorectal cancer patients. Initially, our study focused on the crosstalk between mesenchymal stem cells (MSCs) and CT26 colon carcinoma cells and resulted in identifying CCL7 as a chemokine upregulated in CT26 colon cancer cells cocultured with MSCs, compared with CT26 in monoculture in vitro. Moreover, we showed that MSCs enhance CT26 tumor cell proliferation and migration. We analyzed the effect of CCL7 overexpression on tumor progression in a murine CT26 model, where cells overexpressing CCL7 accelerated the early phase of tumor growth and caused higher lung metastasis rates compared with control mice. Microarray analysis revealed that tumors overexpressing CCL7 had lower expression of immunoglobulins produced by B lymphocytes. Additionally, using Jh mutant mice, we confirmed that in the CT26 model, CCL7 has an immunoglobulin-, and thereby, B-cell-dependent effect on metastasis formation. Finally, higher expression of CCL7 receptor CCR2 (C-C chemokine receptor type 2) was associated with shorter overall survival of colorectal cancer patients. Altogether, we showed that CCL7 is essentially involved in the progression of colorectal cancer in a CT26 mouse model and that the expression of its receptor CCR2 could be related to a different outcome pattern of patients with colorectal carcinoma

Red blood cell distribution width is associated with increased interactions of blood cells with vascular wall

The mechanism underlying the association between elevated red cell distribution width (RDW) and poor prognosis in variety of diseases is unknown although many researchers consider RDW a marker of inflammation. We hypothesized that RDW directly affects intravascular hemodynamics, interactions between circulating cells and vessel wall, inducing local changes predisposing to atherothrombosis. We applied different human and animal models to verify our hypothesis. Carotid plaques harvested from patients with high RDW had increased expression of genes and proteins associated with accelerated atherosclerosis as compared to subjects with low RDW. In microfluidic channels samples of blood from high RDW subjects showed flow pattern facilitating direct interaction with vessel wall. Flow pattern was also dependent on RDW value in mouse carotid arteries analyzed with Magnetic Resonance Imaging. In different mouse models of elevated RDW accelerated development of atherosclerotic lesions in aortas was observed. Therefore, comprehensive biological, fluid physics and optics studies showed that variation of red blood cells size measured by RDW results in increased interactions between vascular wall and circulating morphotic elements which contribute to vascular pathology

Overexpression of endothelin B receptor in glioblastoma: a prognostic marker and therapeutic target?

Background: Glioblastoma (GBM) is the most common malignant brain tumor with median survival of 12-15 months. Owing to uncertainty in clinical outcome, additional prognostic marker(s) apart from existing markers are needed. Since overexpression of endothelin B receptor (ETBR) has been demonstrated in gliomas, we aimed to test whether ETBR is a useful prognostic marker in GBM and examine if the clinically available endothelin receptor antagonists (ERA) could be useful in the disease treatment. Methods: Data from The Cancer Genome Atlas and the Gene Expression Omnibus database were analyzed to assess ETBR expression. For survival analysis, glioblastoma samples from 25 Swedish patients were immunostained for ETBR, and the findings were correlated with clinical history. The druggability of ETBR was assessed by protein-protein interaction network analysis. ERAs were analyzed for toxicity in in vitro assays with GBM and breast cancer cells. Results: By bioinformatics analysis, ETBR was found to be upregulated in glioblastoma patients, and its expression levels were correlated with reduced survival. ETBR interacts with key proteins involved in cancer pathogenesis, suggesting it as a druggable target. In vitro viability assays showed that ERAs may hold promise to treat glioblastoma and breast cancer. Conclusions: ETBR is overexpressed in glioblastoma and other cancers and may be a prognostic marker in glioblastoma. ERAs may be useful for treating cancer patients