Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

Yen, Lily; You, Xiaoli; Moustafa, Ala‐Eddin Al; Batist, Gerald; Hynes, Nancy E.; Mader, Sylvie; Meloche, Sylvain; Alaoui‐Jamali, Moulay A.

doi:10.1038/sj.onc.1203685

Cited by 214 publications

(127 citation statements)

References 68 publications

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“…Transfection of the Her-2/neu gene enhances VEGF expression in breast cancer experimental models (Yen et al, 2000). In this study, the intratumoral concentrations of Her-2/neu were significantly correlated with those of VEGF.…”

Section: Discussionsupporting

confidence: 48%

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

et al. 2005

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Vascular endothelial growth factor (VEGF) receptors consist of three cell-membrane type receptors (VEGFR-1, VEGFR-2 and VEGFR-3), and soluble form of VEGFR-1 (sVEGFR-1), an intrinsic negative counterpart of the VEGF. In this study, we measured intratumoral protein levels of free and total VEGF, VEGFR-2 and sVEGFR-1 from 202 primary breast cancer tissues and examined their prognostic values. A significant inverse correlation was found between free or total VEGF and oestrogen receptor (ER) status ( P =0.042 and 0.032, respectively). A univariate analysis showed that low sVEGFR-1 and high total VEGF were significantly associated with poor prognosis in disease-free survival (DFS) and overall survival (OS). The ratio of sVEGFR-1 to total VEGF was a strong prognostic indicator (DFS: P =0.008; OS: P =0.0002). A multivariate analysis confirmed the independent prognostic values of total VEGF and the ratio of sVEGFR-1 to total VEGF. In subgroup analysis, total VEGF was a significant prognostic indicator for ER-positive tumours but not for ER-negative tumours, whereas sVEGFR-1 was significant for ER-negative tumours but not for ER-positive tumours. In conclusion, the intratumoral sVEGFR-1 level, VEGF level and the ratio of sVEGFR-1 to total VEGF are potent prognostic indicators of primary breast cancer, and might be relevant to ER status.

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Section: Discussionsupporting

confidence: 48%

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

et al. 2005

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“…In addition, bFGF expression has shown a positive correlation with the mytotic activity index (De Jong et al, 1998b). Furthermore, the overexpression of ErbB-2/HER-2, an important predictive factor in breast cancer, is also closely associated with increased angiogenesis (Yen et al, 2000). Thus, the anti-HER-2 blocking antibody trastuzumab (herceptin) acts as an antiangiogenic 'cocktail' controlling the expression of various proangiogenic factors including VEGF, TGF-a, Ang-1 and PAI (Kumar and YarmandBagheri, 2001;Izumi et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

et al. 2004

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The overexpression of angiogenic factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and insulin-like growth factors (IGFs) plays a role in the migration and proliferation of endothelial cells in many cancers. Consequently, we investigated the effects of bombesin/gastrin-releasing peptide (GRP) antagonists on the expression of these angiogenic factors, the activities of matrix metalloproteinases (MMPs)-2 and -9, as well as the vascular density in MDA-MB-435 human oestrogenindependent breast cancers. Nude mice bearing orthotopic xenografts of MDA-MB-435 breast cancers were treated with bombesin/ GRP antagonists for 6 weeks. Daily administration of 20 mg of RC-3095 or 10 mg of RC-3940-II significantly decreased the weight of MDA-MB-435 cancers by 44 and 53%, respectively. The inhibition of tumour growth was associated with a substantial reduction in the expression of mRNA and protein levels of basic fibroblast growth factor (bFGF), IGF-II and VEGF-A in the tumours. Both bombesin/GRP antagonists significantly decreased the vessel density of the tumours by about 37%, as shown by immunohistochemical detection of vessels on tumour slides. Gelatinolytic activities, detected by zymography, revealed a 33 -46% reduction in MMP-9 activity after the treatment with either antagonist. In vitro studies revealed that MDA-MB-435 cells secrete bFGF, IGF-II and VEGF-A, and the secretion of these factors is inhibited by RC-3095 and RC-3940-II. This study demonstrates the antiangiogenic effect of bombesin/GRP antagonists RC-3095 and RC-3940-II, and underscores their possible therapeutic application for treatment of breast cancers.

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“…Vascular endothelial growth factor (VEGF), a potent and specific mitogen for vascular endothelial cells, is a critical mediator of angiogenesis. Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways (Mukhopadhyay et al, 1995;Arbiser et al, 1997;Petit et al, 1997;Akagi et al, 1998;Ellis et al, 1998;Yen et al, 2000). Based on the analysis of melanoma and breast cancer cells recently reported by our group Iervolino et al, 2002;Del Bufalo et al, 2003;Trisciuoglio et al, 2004), this list can now be extended to include the increased VEGF expression resulting from bcl-2 overexpression.…”

Section: Introductionmentioning

confidence: 99%

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

Trisciuoglio¹,

Iervolino²,

Zupi³

et al. 2005

MBoC

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We have previously demonstrated that bcl-2 overexpression in tumor cells exposed to hypoxia increases the expression of vascular endothelial growth factor (VEGF) gene through the hypoxia-inducible factor-1 (HIF-1). In this article, we demonstrate that exposure of bcl-2 overexpressing melanoma cells to hypoxia induced phosphorylation of AKT and extracellular signal-regulated kinase (ERK)1/2 proteins. On the contrary, no modulation of these pathways by bcl-2 was observed under normoxic conditions. When HIF-1␣ expression was reduced by RNA interference, AKT and ERK1/2 phosphorylation were still induced by bcl-2. Pharmacological inhibition of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways reduced the induction of VEGF and HIF-1 in response to bcl-2 overexpression in hypoxia. No differences were observed between control and bcl-2-overexpressing cells in normoxia, in terms of VEGF protein secretion and in response to PI3K and MAPK inhibitors. We also demonstrated that RNA interference-mediated down-regulation of bcl-2 expression resulted in a decrease in the ERK1/2 phosphorylation and VEGF secretion only in bcl-2-overexpressing cell exposed to hypoxia but not in control cells. In conclusion, our results indicate, for the first time, that bcl-2 synergizes with hypoxia to promote expression of angiogenesis factors in melanoma cells through both PI3K-and MAPK-dependent pathways. INTRODUCTIONAngiogenesis is a complex and multilevel process of new capillary formation on the basis of already existing blood vessels. Physiologically, it is a very strictly regulated process, which results in a balance between stimulatory (angiogenic) and inhibitory (angiostatic) factors to control the correct development of blood vessels. Angiogenesis is a rate-limiting step in tumor growth and progression, and many tumors develop a severely hypoxic microenvironment and secrete angiogenesis-stimulating factors (Folkman et al., 1971;Talks et al., 2000). Vascular endothelial growth factor (VEGF), a potent and specific mitogen for vascular endothelial cells, is a critical mediator of angiogenesis. Its expression is induced in cancer cells as a result of hypoxia and multiple genetic alterations, including p53 and PTEN loss-of-function, RAS and SRC gain-of-function, and autocrine tyrosine kinase signaling pathways (Mukhopadhyay et al., 1995;Arbiser et al., 1997;Petit et al., 1997;Akagi et al., 1998;Ellis et al., 1998;Yen et al., 2000). Based on the analysis of melanoma and breast cancer cells recently reported by our group Iervolino et al., 2002;Del Bufalo et al., 2003;Trisciuoglio et al., 2004), this list can now be extended to include the increased VEGF expression resulting from bcl-2 overexpression. Hypoxia-and growth factor-induced VEGF expression in tumor cells is regulated by the hypoxia inducible factor 1 (HIF-1) (Jiang et al., 1997;Mazure et al., 1997;Ravi et al., 2000;Zhong et al., 2000;Zundel et al., 2000;Laughner et al., 2001;Fukuda et al., 2002), a transcription factor that is compose...

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Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

Cited by 214 publications

References 68 publications

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

Association between intratumoral free and total VEGF, soluble VEGFR-1, VEGFR-2 and prognosis in breast cancer

Bombesin antagonists inhibit proangiogenic factors in human experimental breast cancers

Involvement of PI3K and MAPK Signaling in bcl-2-induced Vascular Endothelial Growth Factor Expression in Melanoma Cells

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