Effects Of PDGF - B And VEGF On Tumor Peripheral Cells And Mouse Tissues

The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Tumor vasculature is irregular and exhibits primitive architecture in association with improper recruitment of pericytes (PCs)/vascular smooth muscle cells (VSMCs). However, mechanisms underlying regulation of vascular PC recruitment and repelling in association with tumor cell dissemination remain poorly understood. Here we show our surprising findings that tumor cell-derived platelet-derived growth factor-B (PDGF-B) induces PC loss, vascular disorganization and leakiness in a dose-dependent manner. Consistent with premature and leaky vascular features, a significantly increased number of circulating tumor cells found in tumor-bearing animals, leading to extensive metastases. PDGFR-β blockades substantially prevented PC loss, vascular permeability and tumor cell dissemination in high PDGF-B-producing tumors. Conversely, inhibition of the PDGFR-β signaling pathway resulted in significant loss of PCs in PDGF-B low producing or negative tumors. Our data suggest a paradoxical novel mechanism of tumor-derived PDGF-B in PC coverage and anti-PDGF drugs may lead to opposing effects on vascular remodeling and cancer metastasis depending on PDGF-B expression levels in tumors.We also show PDGF-B markedly induces erythropoietin (EPO) mRNA and protein expression by targeting the PDGFR-β+stromal and perivascular compartments. In mouse tumor models, PDGF-B-induced EPO promotes tumor growth via two mechanisms:1) paracrine stimulation of tumor angiogenesis by directly inducing endothelial cell proliferation, migration, spouting and tube formation; and2) endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia. Similarly, delivery of an adenovirus-PDGF-B to tumor-free mice markedly increases EPO production and hematopoietic parameters. An EPO blockade specifically attenuates PDGF-B-induced tumor growth, angiogenesis and hematopoiesis. At the molecular level, we show that the PDGF-B-PDGFR-P signaling system activates EPO promoter via in part transcriptional regulation of ATF3in a possible association with JUN and SP1. These findings uncover a novel mechanism of PDGF-B-induced tumor growth, angiogenesis and hematopoiesis.Vascular endothelial growth factor-A (VEGF-A) is a key target for new antiangiogenic drugs for the treatment of both malignant and nonmalignant human diseases. Vascular effects of VEGF family members are mainly mediated by VEGF receptor1(VEGFR1), VEGF receptor2(VEGFR2) and VEGF receptor3(VEGFR3). VEGF-A promotes angiogenesis and vascular permeability main via VEGFR2. Conversely, the function and signaling of VEGFR1, which is present on endothelial and nonendothelial cells, are poorly understood. Anti-VEGF, anti-VEGFR1, anti-VEGFR2and anti-VEGFR3are compared within different kinds of healthy tissue and organs in mouse. Blood vessel and lymphatic vessel vasculature were checked. VEGF signaling blockade experiment in different tissue will improve the understanding of VEGFRs’ relationship and the therapeutic potential of targeting these particular vascular factors.Magnetic resonance spectroscopy (MRS) is a unique non-invasive method of detecting cardiac metabolism. Taurine (Tau) is a sulfur-containing β-amino acid, and is the most abundant (almost60%) free amino acid in myocardium. We hypothesized change of taurine level in myocardial tissue could be a potential indicator of myocardial ischemia and early infarction. Adult Sprague-Dawley (SD) rats were divided into7groups after myocardial ischemia, which was induced by the left anterior descending coronary artery (LAD) ligation. Infarcted myocardial tissue was obtained for high-resolution magic angle spinning1H NMR (HRMAS1H NMR) analysis. The data were computed via principal components analysis (PCA), and the results were validated through High Performance Liquid Chromatography (HPLC). Both HRMAS and HPLC results showed that taurine in ischemic myocardial tissue dropped significantly within5min compared to the baseline level, and was maintained within6hours postischemia. Taurine in the myocardial tissue declined more noticeably than creatine at the time point of5min after LAD ligation.The result indicate taurine could be used as an indicator for detecting early myocardial ischemia by1H MRS.