Tumorigenesis and the angiogenic switch

Bergers, Gabriele; Benjamin, Laura E.

doi:10.1038/nrc1093

Cited by 3,113 publications

(2,533 citation statements)

References 86 publications

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“…This supports our conclusion that angiogenesis is a primary response to the activation of FGFR1 in the epithelium. Interestingly, vascular branching and MVD analysis did not show a statistically significant increase in vasculature until at least 2 weeks of CID treatment, consistent with observations that vessel dilation can precede sprouting during the angiogenic switch (Bergers and Benjamin, 2003). This underscores how our quantitative measurement of vascular volume in three dimensions allowed a more sensitive detection of the earliest stages of angiogenesis than more conventional two-dimensional MVD.…”

Section: Discussionsupporting

confidence: 82%

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

et al. 2007

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The expression of fibroblast growth factor receptor (FGFR)-1 correlates with angiogenesis and is associated with prostate cancer (CaP) progression. To more precisely define the molecular mechanisms whereby FGFR1 causes angiogenesis in the prostate we exploited a transgenic mouse model, JOCK-1, in which activation of a conditional FGFR1 allele in the prostate epithelium caused rapid angiogenesis and progressive hyperplasia. By labeling the vasculature in vivo and applying a novel method to measure the vasculature in three dimensions, we were able to observe a significant increase in vascular volume 1 week after FGFR1 activation. Although vessel volume and branching both continued to increase throughout a 6-week period of FGFR1 activation, importantly, we discovered that continued activation of FGFR1 was not required to maintain the new vasculature. Exploring the molecular mediators of the angiogenic phenotype, we observed consistent upregulation of HIF-1a, vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2), whereas expression of Ang-1 was lost. Further analysis revealed that loss of Ang-1 expression occurred in the basal epithelium, whereas the increase in Ang-2 expression occurred in the luminal epithelium. Reporter assays confirmed that the Ang-2 promoter was regulated by FGFR1 signaling and a small molecule inhibitor of FGFR activity, PD173074, could abrogate this response. These findings establish a method to follow spontaneous angiogenesis in a conditional autochthonous system, implicate the angiopoietins as downstream effectors of FGFR1 activation in vivo, and suggest that therapies targeting FGFR1 could be used to inhibit neovascularization during initiation and progression of CaP.

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Section: Discussionsupporting

confidence: 82%

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

et al. 2007

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“…MMP9 , a member of the MMP family, is known to induce cancer32 and is highly correlated with liver cancer and metastasis in patients with HCC 33. To investigate how MAN1A1 and MAN1C1 affect cell migration, the mRNA levels of MMP9 were measured in MAN1A1 ‐overexpressing 293T stable cells and MAN1C1 ‐overexpressing Hep3B stable cells.…”

Section: Resultsmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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“…The main player in angiogenesis is the endothelial cell (EC), and numerous activators of EC proliferation and migration have been described. Most of these activators are receptor kinase ligands, such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and epidermal growth factor (EGF), but they can also be of different origin, such as lysophosphatic acid or interleukin-8 (IL8), tumour necrosis factor-a (TNF-a) (Konig et al, 1999;Ruoslahti, 2002;Bergers and Benjamin, 2003). Naturally occurring angiogenic inhibitors include statins (e.g.…”

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confidence: 99%

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

et al. 2007

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Clear cell renal cell carcinoma (CC-RCC) is a highly vascularised tumour and is therefore an attractive disease to study angiogenesis and to test novel angiogenesis inhibitors in early clinical development. Endothelial cell proliferation plays a pivotal role in the process of angiogenesis. The aim of this study was to compare angiogenesis parameters in low nuclear grade (n ¼ 87) vs high nuclear grade CC-RCC (n ¼ 63). A panel of antibodies was used for immunohistochemistry: CD34/Ki-67, carbonic anhydrase IX, hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF). Vessel density (MVD -microvessel density), endothelial cell proliferation fraction (ECP%) and tumour cell proliferation fraction (TCP%) were assessed. mRNA expression levels of angiogenesis stimulators and inhibitors were determined by quantitative RT -PCR. High-grade CC-RCC showed a higher ECP% (P ¼ 0.049), a higher TCP% (P ¼ 0.009), a higher VEGF protein expression (Po0.001), a lower MVD (Po 0.001) and a lower HIF-1a protein expression (P ¼ 0.002) than low-grade CC-RCC. Growth factor mRNA expression analyses revealed a higher expression of angiopoietin 2 in low-grade CC-RCC. Microvessel density and ECP% were inversely correlated (Rho ¼ À0.26, P ¼ 0.001). Because of the imperfect association of nuclear grade and ECP% or MVD, CC-RCC was also grouped based on low/high MVD and ECP%. This analysis revealed a higher expression of vessel maturation and stabilisation factors (placental growth factor, PDGFB1, angiopoietin 1) in CC-RCC with high MVD, a group of CC-RCC highly enriched in low nuclear grade CC-RCC, with low ECP%. Our results suggest heterogeneity in angiogenic activity and vessel maturation of CC-RCC, to a large extent linked to nuclear grade, and, with probable therapeutic implications.

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Tumorigenesis and the angiogenic switch

Cited by 3,113 publications

References 86 publications

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

Conditional activation of FGFR1 in the prostate epithelium induces angiogenesis with concomitant differential regulation of Ang-1 and Ang-2

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile

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