Role of prostaglandin E2-dependent angiogenic switch in cyclooxygenase 2-induced breast cancer progression.
Proc Natl Acad Sci U S A
; 101(2): 591-6, 2004 Jan 13.
Article
em En
| MEDLINE
| ID: mdl-14688410
ABSTRACT
Overexpression of human cyclooxygenase 2 (COX-2) in the mammary glands of transgenic mice induces tissue-specific tumorigenic transformation. However, the molecular mechanisms involved are not yet defined. Here we show that COX-2 expressed in the epithelial cell compartment regulates angiogenesis in the stromal tissues of the mammary gland. Microvessel density increased before visible tumor growth and exponentially during tumor progression. Inhibition of prostanoid synthesis with indomethacin strongly decreased microvessel density and inhibited tumor progression. Up-regulation of angiogenic regulatory genes in COX-2 transgenic mammary tissue was also potently inhibited by indomethacin treatment, suggesting that prostanoids released from COX-2-expressing mammary epithelial cells induce angiogenesis. G protein-coupled receptors for the major product, prostaglandin E(2) (PGE(2)) EP(1-4), are expressed during mammary gland development, and EP(1,2,4) receptors were up-regulated in tumor tissue. PGE(2) stimulated the expression angiogenic regulatory genes in mammary tumor cells isolated from COX-2 transgenic mice. Such cells are tumorigenic in nude mice; however, treatment with Celecoxib, a COX-2-specific inhibitor, reduced tumor growth and microvessel density. These results define COX-2-derived PGE(2) as a potent inducer of angiogenic switch during mammary cancer progression.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Dinoprostona
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Prostaglandina-Endoperóxido Sintases
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Isoenzimas
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Neoplasias Mamárias Experimentais
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Neovascularização Patológica
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2004
Tipo de documento:
Article
País de afiliação:
Estados Unidos