RESUMO
The sera of patients with breast cancer have higher levels of des[Arg(9)]bradykinin, a kinin B1 receptor (B1R) agonist, than that from healthy individuals. Stimulation of breast cancer cells with the analog Lys-des[Arg(9)]bradykinin causes release of metalloproteinases-2 and -9 and increases cell proliferation. We examined the possibility that breast cancer cells, in addition to B1R, express the kinin-forming protease true tissue kallikrein (KLK1) and the endogenous proteins termed kininogens from which kinins are enzymatically released. Furthermore, we investigated whether stimulation of breast cancer cells with a B1R agonist would modify the cellular levels of KLK6, KLK10 and KLK11, three kallikrein-related peptidases with a still poorly-understood biological role in breast cancer. We found that breast cancer cells expressed KLK1 and kininogens, and that stimulation of estrogen-sensitive breast cancer cells with the B1R agonist produced down-regulation of KLK10 (a protease associated with growth suppression) but up-regulation of KLK11 and KLK6 (peptidases related to increased cell proliferation and invasiveness, respectively). Furthermore, we showed that the B1R agonist acts as a functional stimulus for the secretion of KLK1 and KLK6, an event relevant for kinin production and cell invasion, respectively.
Assuntos
Neoplasias da Mama/metabolismo , Calicreínas/biossíntese , Receptor B1 da Bradicinina/agonistas , Serina Endopeptidases/biossíntese , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , Feminino , Humanos , Calidina/análogos & derivados , Calidina/farmacologia , Calicreínas/sangue , Calicreínas/genética , Cininogênios/biossíntese , Células MCF-7 , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Interferência de RNA , RNA Interferente Pequeno , Serina Endopeptidases/sangue , Calicreínas Teciduais/biossíntese , Calicreínas Teciduais/genética , Regulação para CimaRESUMO
AIMS: The actin-binding protein fascin appears to potentiate the migratory capacity of both normal and neoplastic cells. It has been suggested that microcystic, elongated and fragmented (MELF) glands might represent areas of active invasion within uterine low-grade endometrioid adenocarcinomas. Therefore, fascin immunoreactivity was investigated in a series of endometrial carcinomas specifically comparing expression in conventional tumour areas, foci of MELF-type invasion and in stromal elements. METHODS AND RESULTS: Fascin expression was assessed in 28 uterine endometrioid adenocarcinomas and the results compared with cytokeratin (CK) 7 expression and with tumour morphology and distribution. The conventional glandular component of most tumours showed only focal fascin reactivity (<10% cells positive), but staining was more prominent within the peripheral epithelial cells. Foci of squamous/morular type differentiation were also positive. The neoplastic epithelium in MELF-type invasion usually showed strong fascin immunoreactivity, often contrasting with the adjacent negative or more weakly stained conventional tumour glands. There was also staining of reactive stromal cells surrounding MELF foci. CONCLUSIONS: There are distinct micro-anatomical variations in fascin immunoreactivity within endometrial carcinoma. The localized increase in fascin expression in MELF-type epithelium supports the proposal that MELF changes represent areas of active tumour invasion.
