Mesenchymal stem cells in vascular structure and remodeling in cancer

Mesenchymal stem cells (MSCs) are present in vascular structure and play an important role in vessel remodeling in normal, as well as pathological conditions, such as transplant arteriosclerosis or tumor angiogenesis. Moreover, MSCs affect tumor growth and metastasis by production of chemokines, such as (C-C motif) ligand 7 (CCL7). Similar effect on tumor biology exert multiple other factors, such as CCAAT-enhancer binding protein β (C/EBPβ), which is a transcription factor playing an essential role in mammary gland development and breast cancer progression. In study I, presence of MSCs in vascular structure, as well as their role in vascular remodeling in transplant arteriosclerosis was analyzed. Specifically, rat allograft model was used to identify the predominant cell types associated with this process and to find factors crucial for their recruitment into the graft. This study identified adventitia as a potentially important source of mesenchymal stem cells that contribute to formation of intimal hyperplasia. Furthermore, monocyte chemoattractant protein-1 (MCP-1) was found as a potent chemokine for the recruitment of adventitial vascular progenitor cells to intimal lesions. Study II and III focus on the role of C/EBPβ transcription factor in breast cancer progression. Namely, in study II C/EBPβ was associated with epithelial-to-mesenchymal transition (EMT) features in triple-negative human breast cancer and invasive areas of mammary tumors in MMTV-PyMT mice. In vitro studies showed that C/EBPβ was repressed during EMT by miR-155, a breast cancer oncomiR. Moreover, C/EBPβ depletion enhanced TGFβ response towards EMT and contributed to evasion of growth inhibitory response to TGFβ. C/EBPβ loss caused potentiated invasion and metastasis of breast cancer cells to the lungs in mouse 4T1 model. In addition, C/EBPβ was shown to transcriptionally activate genes encoding epithelial junction proteins E-cadherin and coxsackie virus and adenovirus receptor (CAR). Study III was focused on explaining the mechanism of C/EBPβ effect on metastasis, as well as determining the relationship between C/EBPβ expression and survival of breast cancer patients. Firstly, study showed that decrease in C/EBPβ expression was associated with shorter overall survival of breast cancer patients. Next, loss of C/EBPβ affected tumor growth, morphology and lung metastasis in murine 4T1 breast cancer model. Moreover, inhibition of C/EBPβ caused enhanced histocompatibility complex II (MHCII) expression and accumulation of CD45+, CD3+ and CD4+ lymphocytes in the tumors. Additional experiments confirmed the role of inflammation in C/EBPβ-mediated metastasis formation. Study IV involved analysis of crosstalk between MSCs and colon cancer. Results demonstrated that MSCs affect CT26 tumor cell proliferation, migration and expression of different chemokines in coculture with CT26 cells in vitro, such as (C-C motif) ligand 7 (CCL7). The next goal of the study was to analyze the effect of CCL7 overexpression on tumor progression in mouse CT26 colon cancer model. Cells overexpressing CCL7 accelerated early phase of tumor growth and led to higher lung metastasis rate in tumor-bearing mice. Lastly, higher CCR2 expression, which is a CCL7 receptor, was associated with shorter overall survival of colorectal cancer patients

A High Red Blood Cell Distribution Width Predicts Failure of Arteriovenous Fistula

In hemodialysis patients, a native arteriovenous fistula (AVF) is the preferred form of permanent vascular access. Despite recent improvements, vascular access dysfunction remains an important cause of morbidity in these patients. In this prospective observational cohort study, we evaluated potential risk factors for native AVF dysfunction. We included 68 patients with chronic renal disease stage 5 eligible for AVF construction at the Department of General and Vascular Surgery, Central Clinical Hospital Ministry of Internal Affairs, Warsaw, Poland. Patient characteristics and biochemical parameters associated with increased risk for AVF failure were identified using Cox proportional hazards models. Vessel biopsies were analyzed for inflammatory cells and potential associations with biochemical parameters. In multivariable analysis, independent predictors of AVF dysfunction were the number of white blood cells (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.24 to 2.25; p<0.001), monocyte number (HR 0.02; 95% CI 0.00 to 0.21; p = 0.001), and red blood cell distribution width (RDW) (HR 1.44; 95% CI 1.17 to 1.78; p<0.001). RDW was the only significant factor in receiver operating characteristic curve analysis (area under the curve 0.644; CI 0.51 to 0.76; p = 0.046). RDW>16.2% was associated with a significantly reduced AVF patency frequency 24 months after surgery. Immunohistochemical analysis revealed CD45-positive cells in the artery/vein of 39% of patients and CD68-positive cells in 37%. Patients with CD68-positive cells in the vessels had significantly higher white blood cell count. We conclude that RDW, a readily available laboratory value, is a novel prognostic marker for AVF failure. Further studies are warranted to establish the mechanistic link between high RDW and AVF failure

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

Mouse CCL9 Chemokine Acts as Tumor Suppressor in a Murine Model of Colon Cancer

Colorectal cancer is the third most frequently diagnosed cancer in the world. Despite extensive studies and apparent progress in modern strategies for disease control, the treatment options are still not sufficient and effective, mostly due to frequently encountered resistance to immunotherapy of colon cancer patients in common clinical practice. In our study, we aimed to uncover the CCL9 chemokine action employing the murine model of colon cancer to seek new, potential molecular targets that could be promising in the development of colon cancer therapy. Mouse CT26.CL25 colon cancer cell line was used for introducing lentivirus-mediated CCL9 overexpression. The blank control cell line contained an empty vector, while the cell line marked as CCL9+ carried the CCL9-overexpressing vector. Next, cancer cells with empty vector (control) or CCL9-overexpressing cells were injected subcutaneously, and the growing tumors were measured within 2 weeks. Surprisingly, CCL9 contributed to a decline in tumor growth in vivo but had no effect on CT26.CL25 cell proliferation or migration in vitro. Microarray analysis of the collected tumor tissues revealed upregulation of the immune system-related genes in the CCL9 group. Obtained results suggest that CCL9 reveals its anti-proliferative functions by interplay with host immune cells and mediators that were absent in the isolated, in vitro system. Under specific study conditions, we determined unknown features of the murine CCL9 that have so far bee reported to be predominantly pro-oncogenic

Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer

Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein (CLEC)14A as a potential downstream target of ACVRL1. Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer

RDW is a predictor of AVF patency.

<p>Receiver operating characteristic curve analysis for RDW showed an area under the curve of 0.644 (CI 0.51 to 0.76; <i>p</i> = 0.046) (A). RDW values in the highest quartile (>16.2%) were associated with a significantly reduced AVF patency rate at 24 months after surgery (<i>p</i> = 0.036). The Kaplan-Meier curves were compared with the log-rank test (B).</p

Inflammatory cells are present in the arterial and venous vessel wall.

<p>Leukocytes, defined as CD45-positive cells, were found in the radial artery or cephalic vein or both in 39% of the patients. Monocytes/macrophages, defined as CD68-positive cells, were found in the vessel wall in 37% of the patients. Both cell types were most frequently located in the arterial and venous intima and media. The larger squares are magnifications of the smaller ones.</p