RESUMO
Ovarian cancer is a highly metastatic disease. Lysophosphatidic acid (LPA) levels are elevated in ascites from ovarian cancer patients, but its potential role in ovarian cancer metastasis has just begun to be revealed. In this work, we show that LPA stimulates invasion of primary ovarian cancer cells, but not ovarian epithelial or borderline ovarian tumor cells, although these benign cells indeed respond to LPA in cell migration. We have found that LPA downregulates tissue inhibitor of metalloproteinases (TIMPs). TIMP2 and TIMP3 play functional role in LPA-induced invasion as negative regulators. G(i) protein, phosphatidylinositol-3 kinase (PI3K), p38 mitogen-activated protein kinase (MAPK), cytosolic phospholipase A(2) and urokinase type plasminogen activator (uPA) are required for LPA-induced cells invasion. TIMP3 may affect two independent downstream targets, vascular endothelial growth factor receptor and p38 MAPK. In vivo, LPA stimulates tumor metastasis in an orthotopic ovarian tumor model, which can be inhibited by a PI3K inhibitor, LY294002. In summary, LPA is likely a key component for promoting ovarian metastasis in vivo. LPA downregulates TIMP3, which may have targets other than metalloproteinases. Our in vivo metastasis mouse model is useful for studying the efficacy of therapeutic regimes of ovarian cancer.
Assuntos
Movimento Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisofosfolipídeos/farmacologia , Neoplasias Ovarianas/genética , Inibidores Teciduais de Metaloproteinases/genética , Animais , Células Epiteliais/efeitos dos fármacos , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Humanos , Camundongos , Invasividade Neoplásica , Metástase Neoplásica , Neoplasias Ovarianas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores Teciduais de Metaloproteinases/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
The prevalence of immunologically suppressed patients, including those infected with the AIDS virus, with cancer, and those having had transplant surgery to name a few, has provided an avenue for the rapid proliferation among these patients of the virulent yeast Candida albicans. Previous studies have determined that a potent toxin is produced by C. albicans which may cause extensive tissue damage. The extent of the tissue damage has never been determined, neither has the mechanism been explained. The present work shows that intraperitoneal inoculation of C. albicans produces numerous tumour-like lesions and abscesses on the major organs of experimental laboratory rats. The results demonstrate that damage is caused by the initial release of lysosomal enzymes by the affected tissues.