VEGF upregulates BCL-2 expression and is associated with decreased apoptosis in neuroblastoma cells

Beierle, Elizabeth A.; Strande, Louise; Chen, Mike K.

doi:10.1053/jpsu.2002.30868

Cited by 49 publications

(45 citation statements)

References 35 publications

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“…VEGF protects haematopoietic cells and some leukemic cell lines from chemotherapy-induced apoptosis, an effect that involves the induction of Mcl-1, an anti-apoptotic member of the Bcl-2 family (29). The role of VEGF as a tumour cell survival factor via induction of Bcl-2 and inhibition of apoptosis has been reported in a number of tumour types such as neuroblastoma (30), leukaemia (17) and breast carcinoma cells (18,19).…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Barr

Bouchier‐Hayes²,

Harmey³

2008

Int J Oncol

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Abstract. Vascular endothelial growth factor (VEGF) is produced by most tumour types and stimulates the growth of new blood vessels in the tumour. The expansion of a solid tumour ultimately leads to the development of hypoxic regions, which increases VEGF production and further angiogenesis. In this study, we examined the role of VEGF in the survival of breast tumour cells under hypoxia. Murine 4T1 and human MDA-MB-231 tumour cells were cultured under normoxic and hypoxic growth conditions in the presence or absence of VEGF neutralising antibodies. Apoptosis was assessed in addition to changes in expression of the anti-and pro-apoptotic proteins, Bcl-2 and Bad, respectively. The effect of hypoxia on the novel VEGF receptor, NP1 (neuropilin-1) and the role of the PI3K (phosphatidylinositol-3-kinase) signalling pathway in response to VEGF were examined. VEGF blockade resulted in direct tumour cell apoptosis of both tumour cell lines under normoxia and hypoxia. While blocking VEGF resulted in a downregulation of hypoxia-induced Bcl-2 expression, there was a significant increase in the pro-apoptotic protein Bad relative to cells cultured under hypoxia alone. Both hypoxia and VEGF phosphorylated Akt. Neutralising antibodies to VEGF abrogated this effect, implicating the PI3K pathway in VEGF-mediated cell survival of mammary adenocarcinoma cells. This study demonstrates that VEGF acts as a survival factor not only for endothelial cells as previously thought, but also for some breast tumour cells, protecting them from apoptosis, particularly under hypoxic stress. The data presented provide an additional rationale for combining anti-VEGF strategies with conventional anti-cancer therapies such as chemotherapy and radiotherapy.

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Section: Discussionmentioning

confidence: 99%

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Barr

Bouchier‐Hayes²,

Harmey³

2008

Int J Oncol

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“…14 VEGF, on the other side, is known to exert antiapoptotic and proliferative activities in the liver by stimulating endothelial cell-derived paracrine mediators. 30 VEGF is also produced by tumoral tissue as an angiogenic and antiapoptotic factor 25,31,32 ; the VEGF 188 isoform is the one associated with the most manifest proliferative and invasive phenotype of digestive carcinomas. 27 Our data indicate that COX-2 activation and production of PGs soon after PH are essential requirements for hepatocyte proliferation and for the correct induction of both CT-1 and VEGF.…”

Section: Discussionmentioning

confidence: 99%

“…24,25 After liver resection, this cytokine is first expressed in periportal hepatocytes starting at 24 hours after PH and is involved in proliferation of parenchymal cells. 16 Because in other tissues PGs influence the production of VEGF, 12,13,26 we analyzed the expression of VEGF in the livers of rats treated with NS-398.…”

Section: Effects Of Cox-2 Inhibitor On Liver Regenerationmentioning

confidence: 99%

Interplay among cardiotrophin‐1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration†

et al. 2005

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Prostaglandins are hepatoprotective molecules generated in liver regeneration by the rapid induction of cyclooxygenase-2 (COX-2). Cardiotrophin-1 (CT-1) and vascular endothelial growth factor (VEGF) are other hepatoprotective mediators upregulated at 24 hours after partial hepatectomy. The interactions among these molecules during liver regeneration have not yet been defined. Here we show that rats subjected to partial hepatectomy treated with NS-398, a specific COX-2 inhibitor, exhibited cell cycle arrest, increased hepatocyte apoptosis, persistent extracellular signal-regulated kinase (ERK) 1/2 activation, and increased interleukin-6 production. These changes were associated with downregulation of CT-1 and COX-1 and altered pattern of VEGF expression. Administration of an adenovirus encoding CT-1 to NS-398-treated rats restituted normal levels of COX-1, prostaglandins, and VEGF in the liver after partial hepatectomy and restored normal liver regeneration. Furthermore, the stimulation of isolated rat hepatocytes with CT-1 increased COX-1, COX-2, and VEGF messenger RNAs and prostaglandin synthesis. Conversely, the addition of prostaglandin E1 to the culture increased CT-1 and VEGF production. In conclusion, COX-2 activation and production of prostaglandins soon after partial hepatectomy are essential requirements for hepatocyte proliferation and for the correct induction of both CT-1 and VEGF. CT-1 can restore liver regeneration after COX-2 inhibition by increasing VEGF, COX-1 expression, and prostaglandin synthesis. (HEPATOLOGY 2005;41:460-469.)

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“…Therapeutic blockade of VEGF has been shown to inhibit primary and metastatic tumour growth in animal models (Kim et al, 1993;Asano et al, 1995;Benjamin and Keshet 1997), which has been attributed to an antiangiogenic effect. We and others have recently shown that VEGF can also act as a survival factor for tumour cells, protecting them from apoptosis (Pidgeon et al, 2001;Beierle et al, 2002;Harmey and Bouchier-Hayes, 2002a).…”

mentioning

confidence: 99%

Antimetastatic activity of a cyclooxygenase-2 inhibitor

et al. 2004

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Cyclooxygenase-2 (COX-2) expression is increased in breast cancer and surgery has been shown to increase the growth of metastatic tumours. We investigated the effect of selective COX-2 inhibition on the growth of metastases in either an experimental metastasis model or following excision of a murine primary breast tumour. 50 000 4T1 mammary carcinoma cells were injected into the mammary fat pad of female BALB/c mice. When the mean TD reached 870.4 mm, tumours were excised and the mice were randomised into two groups (n ¼ 12 per group) to receive daily intraperitoneal injections of the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days. Alternatively, experimental metastases were established by tail-vein injection of 50 000 4T1 cells. Mice received either the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days (n ¼ 12 per group). SC-236 treatment significantly reduced tumour burden, the number and size of spontaneous metastases following primary tumour excision. SC-236 treatment also reduced tumour burden, the number and size of experimental metastases. Immunohistochemical staining demonstrated that COX-2 inhibition reduced microvessel density and increased apoptosis within both spontaneous and experimental metastases. These data clearly demonstrate that the selective COX-2 inhibitor, SC-236, has potent antimetastatic activity against both spontaneous metastases arising following primary tumour excision and experimental metastases.

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VEGF upregulates BCL-2 expression and is associated with decreased apoptosis in neuroblastoma cells

Cited by 49 publications

References 35 publications

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Vascular endothelial growth factor is an autocrine survival factor for breast tumour cells under hypoxia

Interplay among cardiotrophin‐1, prostaglandins, and vascular endothelial growth factor in rat liver regeneration†

Antimetastatic activity of a cyclooxygenase-2 inhibitor

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