VEGF Prevents Apoptosis of Human Microvascular Endothelial Cells via Opposing Effects on MAPK/ERK and SAPK/JNK Signaling

Gupta, Kalpna; Kshirsagar, Smita; Li, Wei; Gui, Lizhen; Ramakrishnan, Sundaram; Gupta, Pankaj; Law, Ping Yee; Hebbel, Robert P.

doi:10.1006/excr.1998.4359

Cited by 337 publications

(261 citation statements)

References 33 publications

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“…[1][2][3][4] This protein induces the proliferation, differentiation, and migration of vascular endothelial cells, 4,35 increases the permeability of the capillaries, 1,35 and also enhances the survival of endothelial cells by preventing their apoptosis. 36 However, it is quite possible that its action is not limited in the paracrine, endothelial dependent, angiogenic pathway, but also extends towards a potential autocrine action between cancer cells in various malignancies. [19][20][21][22][23][24] VEGF activities are mediated via two tyrosine kinase receptors VEGFR-1 (also known as flt-1) and VEGFR-2 (also known as Flk-1/KDR).…”

Section: Discussionmentioning

confidence: 99%

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Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

et al. 2005

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Vascular endothelial growth factor is a peptide with well-defined actions on the vasculature and fundamental role in tumor angiogenesis. Its action in vascular endothelium is exerted in a paracrine manner. The immunohistochemical expression of this protein by cancer cells in head and neck squamous cell carcinoma was correlated with increased tumor aggressiveness and poor survival in previous studies. In the past years, an increasing amount of studies demonstrated potential autocrine action of vascular endothelial growth factor in various neoplasms. However, the existence and the impact of such autocrine action in head and neck cancer have not been demonstrated yet. In this retrospective study, we evaluated the expression of vascular endothelial growth factor and its receptors in neoplastic cells, in a cohort of patients with head and neck squamous cell carcinoma, and compared this expression with tumor aggressiveness, clinicopathologic parameters and outcome. High expression of vascular endothelial growth factor was strongly correlated with high expression of vascular endothelial growth factor receptor-2 (but not vascular endothelial growth factor receptor-1) on the cancer cells (Po0.001). The co-overexpression of both the protein and vascular endothelial growth factor receptor-2 was associated with higher tumor proliferation rate (Po0.001). The above cooverexpression also correlated with worse survival (log rank Po0.05) in patients with oral-larynx squamous cell carcinoma. Our results suggest that an autocrine vascular endothelial growth factor loop, mediated via vascular endothelial growth factor receptor-2, probably exists in head and neck squamous cell carcinoma. These observations support the hypothesis that the use of vascular endothelial growth factor receptor-2 inhibitors as adjuvant antiangiogenic therapy might have beneficial effects for these patients, by disrupting both paracrine (endothelial-dependent) and autocrine actions of vascular endothelial growth factor.

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Section: Discussionmentioning

confidence: 99%

“…9 These aspects are mainly due to the different signal transduction cascades induced by VEGFR-1 and VEGFR-2; and specifically, for cell proliferation, to the activation of mitogen-activated protein kinase (MAPK) only by VEGFR-2. 36 It is therefore conceivable that the potential autocrine action of VEGF is mediated via VEGFR-2.…”

Section: Discussionmentioning

confidence: 99%

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

et al. 2005

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“…These responses, likely enhance oxygen delivery and ATP production by glycolytic pathway (Rempel et al, 1996;Dang and Semenza 1999). It was also reported that rhVEGF prevents serum deprivation-induced apoptosis of human microvascular endothelial cells via activation of the MAPK/ERK signaling pathway (Kroll and Waltenberger, 1997;Gupta et al, 1999). Based on these reports, we expected that hypoxia-induced growth factors might exert a protective e ect on the apoptosis in solid tumors.…”

Section: Discussionmentioning

confidence: 80%

“…As reported recently, a member of the MAP kinase superfamily, ERK 1 and 2 have also been reported to be involved in VEGF-induced anti-apoptosis in serumdeprived endothelial cells (Gupta et al, 1999). To discern the involvement of MAPK/ERK pathway in anti-apoptosis of hypoxia and rhVEGF, we used a speci®c inhibitor of MAPK/ERK, PD98059 on serumdeprived HepG2 cells.…”

Section: Effects Of Rhvegf and Hypoxia On Mapk/erk Pathway In Serum-dmentioning

confidence: 97%

“…Recent reports show that anti-apoptotic agents prevent apoptosis by blocking the activation of apoptosisinducing factors (Gotz et al, 1999). For example, VEGF protects endothelial cells from serum deprivation-or ceramide-induced apoptosis, and activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is involved in the anti-apoptotic process (Mukhopadhyay et al, 1998;Gupta et al, 1999). These reports strongly imply that factors involved in tumorigenesis can modulate apoptosis independently.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis

et al. 2000

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Low oxygen and nutrient depletion play critical roles in tumorigenesis, but little is known about how they interact to produce tumor survival and tumor malignancy. In the present study, we investigated the mechanism underlying hypoxia-modulated apoptosis of serum-deprived HepG2 cells. Our results showed that hypoxia blocked the apoptosis, which was accompanied with decreased Bax/ Bcl-2 ratio, inhibited cytochrome c release, and reduced caspase-3 activity. More importantly, increased expressions of VEGF and its receptor-2 (KDR) under hypoxic/ serum-deprived condition suggest that VEGF may act as a survival factor in a self-promoting manner. Data were further supported by results that recombinant human VEGF (rhVEGF) suppressed the serum deprivationinduced apoptosis, and anti-VEGF neutralizing antibody block anti-apoptotic activity of hypoxia. In addition, inhibitors of receptor tyrosine kinase blocked antiapoptosis of hypoxia. Our study further showed that rhVEGF or hypoxia induced ERK phosphorylation in serum-deprived cells, and that a speci®c inhibitor of MAPK/ERK, PD98059 eliminated the anti-apoptotic activity of rhVEGF or hypoxia by increasing Bax/Bcl-2 ratio and caspase-3 activity. Our data led us to conclude that induction of ERK phosphorylation and decrease of Bax/Bcl-2 ratio by rhVEGF implies that hypoxiainduced VEGF prevents apoptosis of serum-deprived cells by activating the MAPK/ERK pathway. Taken together, we propose that hypoxia enhances survival of nutrient-depleted tumor cells by reducing susceptibility to apoptosis, which consequently leads to tumor malignancy. Oncogene (2000) 19, 4621 ± 4631.

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Implication of vascular endothelial growth factor and p53 status for angiogenesis in noninvasive colorectal carcinoma

Kondo

Arii

Furutani

et al. 2000

Cancer

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VEGF Prevents Apoptosis of Human Microvascular Endothelial Cells via Opposing Effects on MAPK/ERK and SAPK/JNK Signaling

Cited by 337 publications

References 33 publications

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis

Implication of vascular endothelial growth factor and p53 status for angiogenesis in noninvasive colorectal carcinoma

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