MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor

Yu, Ying; Sato, Junji

doi:10.1002/(sici)1097-4652(199902)178:2<235::aid-jcp13>3.0.co;2-s

Cited by 199 publications

(104 citation statements)

References 70 publications

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“…Nevertheless, clinical trials solely targeting the VEGF/ VEGFR2 pathway (bevacizumab) did thus far not provide convincing evidence for efficacy of such antiangiogenic approach. Importantly, Ras signaling in endothelial cells can be triggered by multiple proangiogenic receptors, including VEGFR2, fibroblast growth factor receptor-2, Tie2 (Tek), integrins (a v h 3 and a v h 5 ), and EDG1 (23,42,43). Therefore, it is not yet clear whether only VEGFR2, Raf, or both kinases are effectively targeted by NVP-AAL881 to achieve the inhibition of angiogenesis.…”

Section: Discussionmentioning

confidence: 59%

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growthinhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.

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Section: Discussionmentioning

confidence: 59%

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Lang¹,

Schachtschneider²,

Moser³

et al. 2008

Molecular Cancer Therapeutics

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“…VEGF has been reported to stimulate the stress-activated p38 MAP kinase (37,38). To determine which VEGF receptor is involved, the phosphorylation status of p38 was analyzed after stimulation with wild type Flt-and KDR-selective VEGF.…”

Section: Resultsmentioning

confidence: 99%

Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)

Gille

Kowalski

Li³

et al. 2001

Journal of Biological Chemistry

537

177

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“…Based on evidence that the mTOR-p70S6K signalling pathway is required for VEGF stimulation of endothelial cells (Yu and Sato, 1999), we verified whether everolimus could inhibit angiogenesis at a second level, where receptor-mediated stimulation of vascular endothelial cells occurs. To investigate this hypothesis, we first evaluated the capability of everolimus to inhibit HUVECs (human umbilical vein endothelial cells) survival: HUVECs are sensitive to everolimus, with a 35% survival inhibition at 0.1 mM ( Figure 3D).…”

Section: Everolimus Inhibits Vascular Endothelial Cells Proliferationmentioning

confidence: 93%

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

et al. 2008

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Inhibition of a single transduction pathway is often inefficient due to activation of alternative signalling. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation, survival and angiogenic pathways and has been implicated in the resistance to EGFR inhibitors. Thus, mTOR blockade is pursued to interfere at multiple levels with tumour growth. We used everolimus (RAD001) to inhibit mTOR, alone or in combination with anti-EGFR drugs gefitinib or cetuximab, on human cancer cell lines sensitive and resistant to EGFR inhibitors, both in vitro and in vivo . We demonstrated that everolimus is active against EGFR-resistant cancer cell lines and partially restores the ability of EGFR inhibitors to inhibit growth and survival. Everolimus reduces the expression of EGFR-related signalling effectors and VEGF production, inhibiting proliferation and capillary tube formation of endothelial cells, both alone and in combination with gefitinib. Finally, combination of everolimus and gefitinib inhibits growth of GEO and GEO-GR (gefitinib resistant) colon cancer xenografts, activation of signalling proteins and VEGF secretion. Targeting mTOR pathway with everolimus overcomes resistance to EGFR inhibitors and produces a cooperative effect with EGFR inhibitors, providing a valid therapeutic strategy to be tested in a clinical setting.

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MAP kinases, phosphatidylinositol 3-kinase, and p70 S6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor

Cited by 199 publications

References 70 publications

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes

Analysis of Biological Effects and Signaling Properties of Flt-1 (VEGFR-1) and KDR (VEGFR-2)

Inhibition of mTOR pathway by everolimus cooperates with EGFR inhibitors in human tumours sensitive and resistant to anti-EGFR drugs

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