No abstract

Endothelial progenitor cells (EPC) reportedly differentiate into endothelial cells and participate in angiogenesis, including neovascularization at sites of neoplastic development. Recently, we reported that Flk+/CD31-/CD34- mesenchymal stem cells (MSC) possess the potential of differentiating into both endothelial and hematopoietic cells. We hypothesized that these MSC contribute to tumor angiogenesis. This concept is controversial and this study was undertaken to address this controversy. We show that progeny of human MSC as well as differentiated endothelial cells possess the ability to participate in tumor angiogenesis. When human marrow-derived MSC were injected into tail veins of severe combined immunodeficient (SCID) mice engrafted with human malignant melanoma, human cells incorporated into tumor vessels. Moreover, human-derived endothelial cells were identified in the walls of mouse tumor vessels by immunohistology. We report for the first time that similar results are obtained when mice carrying malignant melanoma are injected with differentiated human endothelial cells. Thus, we demonstrate that both differentiated endothelial cells from tissue peripheral to that of a tumor as well as progeny of human MSC have similar capacities to participate in angiogenesis.

Angiogenesis in solid tumors is divided into two modes: endothelium-dependent vessel (EDV) and vasculogenic mimicry (VM). Sphingosine-1-phosphate receptor 1 (S1PR1) plays a vital role on EDV in a variety of human tumors. However, the relationship between S1PR1 and VM is not clear. The aim of this study is to investigate S1PR1 on the regulation of EDV and mimicry formation in breast cancer. Here we show that S1PR1 phosphorylates the complex of VE-cadherin to regulate the switch of EDV and mimicry formation. Suppression of S1PR1 impairs EDV, but contributes to the generation of VM, invasion, and metastasis in vivo and vitro. By inhibiting RhoA activation, the S1PR1/VE-cadherin signaling is blocked. S1PR1 controls VE-cadherin expression and EDV via RhoA activation. Moreover, the low expression of S1PR1 correlates with VM and poor prognosis in breast cancer patient. The results show that S1PR1 regulated RhoA activation to accelerate VE-cadherin phosphorylation (Y731), leading to increased EDV and reduced VM in breast cancer. S1PR1 may provide a new thinking direction for antiangiogenic therapy for patients with breast cancer.

BackgroundITGA3 is a member of the integrin family, a cell surface adhesion molecule that can interact with extracellular matrix (ECM) proteins. The purpose of this study was to explore the significance of ITGA3 expression in the prognosis and clinical diagnosis of breast cancer patients.MethodsOncomine, the Human Protein Atlas (HPA) and UALCAN were used to analyze the expression of ITGA3 in various cancers. PrognoScan, GEPIA, Kaplan–Meier plotter and Easysurv were utilized to analyze the prognosis of ITGA3 in certain cancers. Based on TCGA data, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of ITGA3 expression. cBio-Portal and MethSurv were used to evaluate the genomic mechanism. LinkedOmics, NetworkAnalyst and Metascape were used to build the signaling network. TIMER is a web server for comprehensive analysis of tumor infiltrating immune cells and tumor infiltrating lymphocytes (TILs).ResultsThe expression of ITGA3 in normal breast tissues was greater than that in breast cancer tissues at both the mRNA and protein levels. High expression of ITGA3 was associated with better prognosis of breast cancer patients. ROC analysis indicated that ITGA3 had significant diagnostic value. Genomic analysis revealed that promoter methylation of ITGA3 leads to transcriptional silencing, which may be one of the mechanisms underlying ITGA3 downregulation in BRCA. Immune infiltration analysis showed that ITGA3 may be involved in the recruitment of immune cells.ConclusionsThis study identified ITGA3 as a novel biomarker to estimate the diagnosis and prognosis of breast cancer. In addition, ITGA3 is involved in ECM regulation and immune cell infiltration.