Vascular PPARb/d Promotes Tumor Angiogenesis and Progression
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ABSTRACT:
PROVIDER: PRJNA590054 | ENA |
REPOSITORIES: ENA
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Project description:PPARβ/δ has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now it is not clear to what extent the expression of PPARβ/δ in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPARβ/δ. Following specific over-expression of PPARβ/δ in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPARβ/δ. In order to identify molecular downstream targets of PPARβ/δ in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing.We show here that PPARβ/δ activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation.
2019-12-12 | GSE140513 | GEO
Project description:Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which function as transcription factors. Among them, PPARβ/δ is highly expressed in endothelial cells. Pharmacological activation with PPARβ/δ agonists had been shown to increase their angiogenic properties. PPARβ/δ has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now, it is not clear to what extent the expression of PPARβ/δ in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPARβ/δ. Following specific over-expression of PPARβ/δ in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPARβ/δ. In order to identify molecular downstream targets of PPARβ/δ in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing. We identified platelet-derived growth factor receptor beta (Pdgfrb), platelet-derived growth factor subunit B (Pdgfb), and the tyrosinkinase KIT (c-Kit) as new PPARβ/δ -dependent molecules. We show here that PPARβ/δ activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation.
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Project description:NOTCH3 promotes vascular smooth muscle cells progression by targeting RANBP1
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Project description:Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* has been shown to suppress anti-tumor immunity which promotes tumor metastasis. Here, we show that the protumor actions of KRAS* extend to the adipogenic transformation of fibroblasts into lipid-laden cancer-associated fibroblasts (CAFs), which spur angiogenesis. Mechanistically, KRAS*-mediated activation of the transcription factor CP2 (TFCP2) resulted in TFCP2-mediated transcriptional upregulation of pro-adipogenic factors BMP4 and WNT5B to drive lipid-rich CAF transformation. Functionally, these lipid-rich CAFs promoted tumor growth via their production of vascular endothelial growth factor A (VEGFA). Correspondingly, genetic and pharmacological neutralization of TFCP2 decreased the abundance of lipid-rich CAFs, reduced tumor angiogenesis, and increased survival in an autochthonous KRAS*–driven CRC mouse model. These murine findings mirror translational profiles in human CRC. Thus, KRAS* transforms the stromal cell state to promote tumor angiogenesis and disease progression, providing an actionable therapeutic intervention for KRAS*–driven CRC.
2023-09-15 | GSE229559 | GEO
Project description:Impaired histone inheritance promotes tumor progression
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Project description:In the tumor microenvironment the extracellular matrix molecule tenascin-C is highly expressed which correlates with worsened survival prognosis. Tenascin-C promotes multiple steps in cancer progression. In particular, tenascin-C promotes the tumor angiogenic switch and the formation of more but poorly functional blood vessels by ill defined mechanisms. Here, we studied tenascin-C angio-modulatory functions by tumor and stromal cells. Unexpectedly, we observed that direct contact of endothelial cells with tenascin-C impairs angiogenesis through disruption of actin polymerization. This resulted in cytoplasmic retention of the F-actin sensor and co-transcription factor YAP and led to downregulation of YAP pro-angiogenic target genes. Conversely, tumor cells and carcinoma associated fibroblasts exposed to tenascin-C secreted pro-angiogenic factors that promoted endothelial cell survival and tubulogenesis. We identified and functionally validated CXCL12 and Ephrin- B2 as important pro-angiogenic effectors of tenascin-C. Proteomic analysis of the secretome of tumor cells exposed to tenascin-C revealed a signature that predicts shorter survival of patients with low grade glioma and glioblastoma with a particular significance for a combined expression of tenascin-C and Ephrin-B2. Altogether, we demonstrated a dual mechanism of action of tenascin-C in tumor angiogenesis where direct contact of endothelial cells with tenascin-C impairs angiogenesis, and paracrine signals derived from contact of tumor cells and carcinoma associated fibroblasts with tenascin-C promotes angiogenesis. These opposing effects provide for the first time an explanation of divergent mechanisms controlled by tenascin-C which can result in a denser but less functional tumor blood vasculature and might unveil new targeting and prediction opportunities.
2016-11-07 | PXD005217 | Pride
Project description:The initial factor in the occurrence, development, and prognosis of cerebral ischemia is vascular dysfunction in the brain, and vascular remodeling of the brain is the key therapeutic target and strategy for ischemic tissue repair. Limb remote ischemic preconditioning exhibits potential pleiotropic protective effects in many brain-related diseases, including stroke.Whether limb remote ischemic preconditioning has other effects such as vascular protective effects and the detailed mechanism by which limb remote ischemic preconditioning improves pathology and angiogenesis in cerebral ischemia remains to be further elucidated. The present study was designed to investigate whether limb remote ischemic preconditioning protects vascular structure and promotes angiogenesis in cerebral ischemic rats.
2024-06-05 | PXD052843 |
Project description:Background and aims: There are considerable evidences demonstrating that angiogenesis and chronic inflammation are mutually dependent. However, although cirrhosis progression is characterized with a chronic hepatic inflammatory process, this connection is not sufficiently explored as a therapeutic strategy. Therefore, this study was aimed to assess the potential benefits of targeting angiogenesis in cirrhotic livers to modulate inflammation and fibrosis. For this purpose, we evaluate the therapeutic utility of angiogenesis inhibitors. Methods: The in vivo effects of angiogenesis inhibitors were monitored in liver of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, a-smooth muscle actin (a-SMA) accumulation, differential gene expression (by microarrays), and portal pressure. Results: Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1, angiopoietin-2 and placental growth factor (PlGF) in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Interestingly, the expression of these adhesion molecules correlated well with local inflammatory infiltrate. Livers of cirrhotic rats treated with angiogenesis inhibitors presented a significant decrease in hepatic vascular density, inflammatory infiltrate, a-SMA abundance, collagen expression and portal pressure. Conclusion: Angiogenesis inhibitors may offer a potential novel therapy for cirrhosis due to its multiple mechanisms of action against angiogenesis, inflammation and fibrosis in cirrhotic livers. Experiment Overall Design: RNA from liver of 4 non-treated cirrhotic rats or 4 rats treated with angiogenesis inhibitors was hybridized to 8 high-density oligonucleotide microarray (Rat2302, Affymetrix, Santa Clara, CA)
2008-06-15 | E-GEOD-6929 | biostudies-arrayexpress
Project description:Purpose: Metastasis remains the primary cause of prostate cancer (CaP) related death. Here, we investigate the molecular, pathologic, and clinical outcome associations of EphA6 expression and its role in CaP progression and metastasis.Experimental Design: The gene expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in CaP cell lines by real-time RT-PCR. Metastatic potential of EphA6 gene was analyzed by RNAi approaches in a spontaneous CaP mouse model. The mRNA expression of EphA6 was measured in 58 benign prostate hyperplasia (BPH) and 112 CaP samples. Results: Among the tested Ephs and ligands, EphA6 is the only consistently overexpressed member in CaP lymph node metastatic cells. EphA6 knock-down (KD) in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, KD of EphA6 decreases tube formation in vitro and angiogenesis in vivo. Studies on the clinical samples demonstrate that EphA6 is overexpressed in the CaP tumor tissues compared with those from BPH patients. The correlation was identified between EphA6 expression and vascular invasion (P=0.004), neural invasion (P=0.002), PSA level (P=0.013), and TNM staging (P=0.021) in 112 CaP cases.Further, genome-wide gene expression analysis in KD of EphA6 cells identified a panel of genes, such as PIK3IPA, AKT1, and EIF5A2, which could be associated with EphA6-regulated cancer progression. Conclusions: These findings identify EphA6 as a potentially novel metastasis gene, and increased EphA6 mRNA expression positively correlates with CaP progression. The mechanisms to inhibit EphA6 expression might suppress CaP metastatic aggressiveness. Knock-down of EphA6 induced gene expression in human prostate cell:PC-3M/shEphA6-1, PC3M/shControl, CWR22rv1/shEphA6-1, and CWR22rv1/shControl cell line.
2015-02-27 | E-GEOD-66335 | biostudies-arrayexpress
Project description:The platelet-derived growth factor (PDGF) signaling system contributes to tumor angiogenesis and vascular remodeling. Here, we show PDGF-BB markedly induces erythropoietin (EPO) mRNA and protein expression by targeting the PDGFR-beta+ stromal and perivascular compartments. In mouse tumor models, PDGF-BB-induced EPO promotes tumor growth via two mechanisms: 1) paracrine stimulation of tumor angiogenesis by directly inducing endothelial cell proliferation, migration, sprouting and tube formation; and 2) endocrine stimulation of extramedullary hematopoiesis leading to increased oxygen perfusion and protection against tumor-associated anemia. Similarly, delivery of an adenovirus-PDGF-BB to tumor-free mice markedly increases EPO production and hematopoietic parameters. An EPO blockade specifically attenuates PDGF-BB-induced tumor growth, angiogenesis and hematopoiesis. At the molecular level, we show that the PDGF-BB-PDGFR-beta signaling system activates EPO promoter via in part transcriptional regulation of ATF3 by possible association with c-Jun and SP1. These findings uncover a novel mechanism of PDGF-BB-induced tumor growth, angiogenesis and hematopoiesis. Comparison of S17 stromal cells treated with PDGF-BB for 72h to control
2011-12-04 | E-GEOD-33717 | biostudies-arrayexpress