2006
DOI: 10.1158/0008-5472.can-05-2560
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Characterization of a von Hippel Lindau Pathway Involved in Extracellular Matrix Remodeling, Cell Invasion, and Angiogenesis

Abstract: Inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene results in highly vascularized tumors, making the VHL tumor syndrome an ideal system to study the mechanisms of angiogenesis. VHL operates along two pathways with the first involving hypoxia-inducible factor-A degradation and downregulation of its proangiogenic target genes vascular endothelial growth factor and platelet-derived growth factor-B, and the second pathway promoting extracellular matrix (ECM) assembly. Secretion of proangiogenic fact… Show more

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Cited by 114 publications
(110 citation statements)
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References 39 publications
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“…Smaller studies by others have shown variable associations between clinical outcome and microvessel density. 10,20 Kurban et al 6 showed that VHL mutations resulting in upregulation of HIF1a are associated with decreased microvessel density and low invasive potential, consistent with our results.…”
Section: Discussionsupporting
confidence: 92%
See 1 more Smart Citation
“…Smaller studies by others have shown variable associations between clinical outcome and microvessel density. 10,20 Kurban et al 6 showed that VHL mutations resulting in upregulation of HIF1a are associated with decreased microvessel density and low invasive potential, consistent with our results.…”
Section: Discussionsupporting
confidence: 92%
“…[3][4][5] Additional steps are required for vessel formation, including loss of integrity of the extracellular matrix. 6 Thus, inhibition of tumor angiogenesis is likely to require agents that target both the vessels and the malignant cells, as is evident by the lack of efficacy of monotherapy that directly targets VEGF. 1 Coupled with the clinical development of VEGF-Rtargeting therapies, there is an urgent need to develop biomarkers that predict response to these agents, as clearly only a subset of patients derive benefit from the drugs.…”
mentioning
confidence: 99%
“…Aside from mediating HIF-a proteolysis, pVHL is involved in extracellular matrix (ECM) assembly matrix turnover, [42][43][44][45][46][47] the regulation of intracellular junctions, 48 NF-kB signaling, 49 the regulation of c-Met receptor responsiveness to hepatocyte growth factor (HGF) involving b-catenin 45,50 and the regulation of p53 transcriptional activity by suppressing Mdm2-mediated ubiquitination and nuclear export. 51 Furthermore, pVHL has been shown to regulate microtubule stability and cilia maintenance [52][53][54][55] and controls the activity of plant homeodomain protein Jade-1, 56,57 and atypical protein kinase C isoforms.…”
Section: Biological Functions Not Involving Hifmentioning
confidence: 99%
“…Similarly, Evans et al 107 demonstrated that knockdown of pVHL resulted in E-cadherin suppression via HIF-dependent induction of E2 box-dependent transcriptional repressors Snail and SIP1, and Krishnamachary et al 108 reported that HIF-1 activation in VHL-deficient cells downregulated Ecadherin, led to the loss of cell-cell adhesion and promoted epithelial to mesenchymal transition through the induction of transcriptional repressors TCF3, ZFHX1A and ZFHX1B/SIP1. Therefore, cellular changes, such as loss of intercellular junctions and epithelial de-differentiation involving HIFdependent as well as HIF-independent molecular pathways 48,[106][107][108] in addition to HIF-dependent and -independent alterations in p53 or NF-kB activity, 34,35,49,51 HGF signaling, 45,50,109 and modifications in ECM turnover and re-modeling [42][43][44][45][46][47] create the molecular environment for the development CC-RCC, which most likely requires additional genetic events. The importance of HIF activation in CC-RCC pathogenesis and growth is furthermore underscored by experimental and clinical studies, which demonstrated that inhibition of HIF-a translation by pharmacological targeting of mTOR correlated with reduced tumor growth, 110 and that increased expression of certain HIF target genes, such as CXCR4, as well as E-cadherin suppression was associated with disease progression.…”
Section: Pvhl and Renal Cell Cancermentioning
confidence: 99%
“…Transwell filter assay was done as previously described (64). Cells (HEK-293 and ACHN) were seeded on 8-μm polycarbon filters with serum-free medium.…”
Section: Cell Migration Assaymentioning
confidence: 99%