RESUMEN
Tumor metastasis is a main contributor to death in cancer patients. In the last years, a new class of molecules that reduces the metastatic propensity has been identified: metastasis suppressors. These proteins regulate multiple steps in the metastatic cascade, including cell invasion, survival in the vascular and lymphatic circulation, and colonization of distant organ sites. As a consequence, they are very important therapeutic targets. This review discusses our current understanding of metastasis suppressors and how this knowledge might be useful to improve the treatment of cancer patients.
Asunto(s)
Genes Supresores de Tumor , Metástasis de la Neoplasia , Proteínas Supresoras de Tumor/metabolismo , Animales , Atrasentán , Endotelina-1/antagonistas & inhibidores , Humanos , Metástasis de la Neoplasia/tratamiento farmacológico , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , Pirrolidinas/uso terapéutico , Proteínas Supresoras de Tumor/genéticaRESUMEN
Glypican-3 (GPC3) is a proteoglycan involved in proliferation and cell survival. Several reports demonstrated that GPC3 is downregulated in some tumors, such as breast cancer. Previously, we determined that GPC3 reexpression in the murine mammary adenocarcinoma LM3 cells induced an impairment of their invasive and metastatic capacities, associated with a decrease of their motility and an increase of their cell death. We demonstrated that GPC3 inhibits canonical Wnt signaling, as well as it activates non canonical pathway. Now, we identified signaling pathways responsible for the pro-apoptotic role of GPC3 in LM3 cells. We found for the first time that GPC3 inhibits the PI3K/Akt anti-apoptotic pathway while it stimulates the p38MAPK stress-activated one. We report a concomitant modulation of CDK inhibitors as well as of pro- and anti-apoptotic molecules. Our results provide new clues regarding the mechanism involved in the modulation induced by GPC3 of mammary tumor cell growth and survival.
Asunto(s)
Adenocarcinoma/metabolismo , Apoptosis/fisiología , Neoplasias de la Mama/metabolismo , Glipicanos/metabolismo , Transducción de Señal/fisiología , Adenocarcinoma/genética , Animales , Western Blotting , Neoplasias de la Mama/genética , Línea Celular Tumoral , Separación Celular , Femenino , Citometría de Flujo , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glipicanos/genética , Inmunohistoquímica , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
We report on 7 patients referred for treatment of hepatic hemangioendothelioma with increased thyrotropin levels. The serum thyroxine level was decreased in 4 and increased in 2. Immunohistochemistry showed positive staining of tumor, but not of normal liver tissue, for thyrotropin. We propose secretion by the tumor of a thyrotropin-like factor.