68 research outputs found
Intussusceptive angiogenesis: pillars against the blood flow
No full textAdaptation of vascular networks to functional demands needs vessel growth, vessel regression and vascular remodelling. Biomechanical forces resulting from blood flow play a key role in these processes. It is well-known that metabolic stimuli, mechanical forces and flow patterns can affect gene expression and remodelling of vascular networks in different ways. For instance, in the sprouting type of angiogenesis related to hypoxia, there is no blood flow in the rising capillary sprout. In contrast, it has been shown that an increase of wall shear stress initiates the splitting type of angiogenesis in skeletal muscle. Otherwise, during development, both sprouting and intussusception act in parallel in building the vascular network, although with differences in spatiotemporal distribution. Thereby, in addition to regulatory molecules, flow dynamics support the patterning and remodelling of the rising vascular tree. Herewith, we present an overview of angiogenic processes with respect to intussusceptive angiogenesis as related to local haemodynamics
Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma.
No full textThe phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6
Decrease in VEGF expression induces intussusceptive vascular pruning
No full textDiminution of VEGF level induces vascular tree regression by intussusceptive vascular pruning. This observation may allude to the mechanism underlying the "normalization" of tumor vasculature if treated with antiangiogenic drugs. The mechanism described here gives new insights into the understanding of the processes of vasculature regression and hence provides new and potentially viable targets for antiangiogenic and/or angio-modulating therapies during various pathological processes
Increasing science, technology, engineering, and mathematics skills using Project Lead the Way
No full textIncludes bibliographical references
Light micrographs showing cell proliferation (a, c, e) and apoptosis (b, d, f) in the developing CAM.
No full texta, c, e: Cell proliferation in the chorionic epithelium at E11 but mainly in the subepithelial layer. By E14 the proliferation is now preponderant within the chorion and subchorionic rare and by E17; only occasional proliferating cells are encountered in the basal layer. b, d, f: Cell apoptosis is more pronounced in the allantois from E13 but mild in the chorion, and shifts to chorion by E17 and is quite pronounced by E18.</p
RNA interference screening identifies a novel role for autocrine fibroblast growth factor signaling in neuroblastoma chemoresistance
No full textChemotherapeutic drug resistance is one of the major causes for treatment failure in high-risk neuroblastoma (NB), the most common extra cranial solid tumor in children. Poor prognosis is typically associated with MYCN amplification. Here, we utilized a loss-of-function kinome-wide RNA interference screen to identify genes that cause cisplatin sensitization. We identified fibroblast growth factor receptor 2 (FGFR2) as an important determinant of cisplatin resistance. Pharmacological inhibition of FGFR2 confirmed the importance of this kinase in NB chemoresistance. Silencing of FGFR2 sensitized NB cells to cisplatin-induced apoptosis, which was regulated by the downregulation of the anti-apoptotic proteins BCL2 and BCLX(L). Mechanistically, FGFR2 was shown to activate protein kinase C-δ to induce BCL2 expression. FGFR2, as well as the ligand fibroblast growth factor-2, were consistently expressed in primary NB and NB cell lines, indicating the presence of an autocrine loop. Expression analysis revealed that FGFR2 correlates with MYCN amplification and with advanced stage disease, demonstrating the clinical relevance of FGFR2 in NB. These findings suggest a novel role for FGFR2 in chemoresistance and provide a rational to combine pharmacological inhibitors against FGFR2 with chemotherapeutic agents for the treatment of NB.Oncogene advance online publication, 1 October 2012; doi:10.1038/onc.2012.416
Logarithmic line graphs showing growth rates of CAM (a) and the various coarse components of the CAM (B).
No full texta: The CAM grew rapidly in phase I (E8-E13), moderately at phase II (E13-18) and was undergoing regression in phase III (E18-E20). CAM volume was significantly correlated to body mass (P = 0.01). CAM growth was strongly positively related to body mass increase up to E18, but it had a strong negative correlation until time of hatching. b: Logarithmic line graphs showing growth regression analysis of the coarse CAM components. The mesoderm was the fastest growing component while the large vessels were the slowest. Both the chorion and allantois grew at the same rate. When viewed on individual basis at various growth phases, all components were growing fastest in phase I and except the mesoderm, they were regressing in phase III. All components were significantly correlated to body mass during the entire period (P ≤ 0.05). The chorion, allantois and vessels were regressing in phase III (showed a strong negative correlation with body mass).</p
Bar graphs showing the proportions (a) and absolute volumes (b) of the CAM components.
No full texta: The mesoderm remained the largest component during the entire growth period at about 70%, declining slightly at E18. The chorion was between 10–18%, being highest at E18 and decreasing to about 10% at E20. The allantois remained at around 10%, peaked at E18 to above this value and then declined to about 8% by E20. The proportion of the large vessels appeared to remain steady at about 4–5% of the CAM. b: In absolute terms, the values of the components followed closely the trend of the proportions. The highest value for the mesoderm was at E15 while the chorion and allantois peaked at E18. Volume of chorion at E8 was significantly lower than all the other time points except E11. The volume at E11 was lower than at E15 and E18. Similarly, chorionic volume was significantly lower at E13 and E20 than at E18. Allantoic volume at E15 and E18 was significantly higher than at both E8 an E11while mesenchymal volume remained significantly higher in the ages E13-E20 than at E8 and E11. Large vessels at E15 and E18 had significantly greater volumes than at E8 and E11.</p
Bar graphs showing the proportions of the capillary and non-capillary components of the chorion (a) as well as the respective absolute volumes (b).
No full texta: Between E8 and E11, the chorionic capillaries take over 50% of the chorionic volume, but are overtaken by chorionic cells as from E13. By the end of incubation, the capillaries take only about 25% of the chorionic volume. b: In absolute terms, the values of both the capillary and non-capillary components reach a peak at E18 and then begin to decline. The volume of the capillaries remains the greater component up to E11. Volumes of the chorionic capillaries were significantly greater (P≤ 0.05) at E15 and E18 than at E8. Chorionic cell volumes were significantly greater (P≤ 0.05) at all subsequent time points than at E8 and were greater also than those at E11 except at E13. Volume was significantly greater at E18 than at E13.</p
Relative expression levels of selected angiogenesis related molecules during the course of CAM development.
No full textThe expression levels, however, did not show any statistically significant differences among various time points (single factor ANOVA). a: Vascular endothelial growth factor receptor 2 (VEGFR2), the vessel endothelial marker, reaches a peak at E11, and then decreases steadily, being least at E20. b: There is an increase in the expression levels of HIF1α at E11, a sharp decrease towards E15 with a peak at E20. c: VEGFA peaks at E11 and again at E20. Its lowest expression levels are at E15 d: The stromal derived factor 1 (SDF-1) expression levels reach a peak at E11 and decline towards E15.</p
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