RESUMEN
Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.
Asunto(s)
Inhibidores de la Angiogénesis/metabolismo , Inhibidores de la Angiogénesis/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas/metabolismo , Proteínas/farmacología , Sulfonamidas , Animales , Pruebas de Carcinogenicidad , Movimiento Celular , Embrión de Pollo , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Endotelio Vascular , Inhibidores Enzimáticos/farmacología , Factor 2 de Crecimiento de Fibroblastos/farmacología , Técnicas de Transferencia de Gen , Isoquinolinas/farmacología , Ratones , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Fisiológica/efectos de los fármacos , Proteína Relacionada con la Hormona Paratiroidea , Mapeo Peptídico , Proteínas/genética , Proteínas de Unión al GTP rac/metabolismoRESUMEN
PURPOSE: Metastatic bone disease is one of the major causes of morbidity and mortality in prostate cancer patients. Bisphosphonates are currently used to inhibit bone resorption and reduce tumor-induced skeletal complications. More effective bisphosphonates would enhance their clinical value. EXPERIMENTAL DESIGN: We tested several bisphosphonates in a green fluorescent protein (GFP)-expressing human prostate cancer nude mouse model. The in vivo effects of four bisphosphonates, including pamidronate, etidronic acid, and olpadronate, on bone tumor burden in mice intratibially inoculated with PC-3-GFP human prostate cancer cells were visualized by whole-body fluorescence imaging and X-ray. RESULTS: The PC-3-GFP cells produced extensive bone lesions when injected into the tibia of immunocompromised mice. The skeletal progression of the PC-3-GFP cell growth was monitored by GFP fluorescence and the bone destruction was evaluated by X-ray. We showed that 3,3-dimethylaminopropane-1-hydroxy-1,1-diphosphonic acid (olpadronate) was the most effective bisphosphonate treatment in reducing tumor burden as assessed by GFP imaging and radiography. The GFP tumor area and X-ray score significantly correlated. Reduced tumor growth in the bone was accompanied by reduced serum calcium, parathyroid hormone-related protein, and osteoprotegerin. CONCLUSIONS: The serum calcium, parathyroid hormone-related protein, and osteoprotegerin levels were significantly correlated with GFP area and X-ray scores. Treatment with olpadronate reduced tumor growth in the bone measured by GFP and X-ray imaging procedures. Imaging of GFP expression enables monitoring of tumor growth in the bone and the GFP results complement the X-ray assessment of bone disease. The data in this report suggest that olpadronate has potential as an effective inhibitor of the skeletal progression of clinical prostate cancer.
Asunto(s)
Neoplasias Óseas/prevención & control , Difosfonatos/uso terapéutico , Proteínas Fluorescentes Verdes/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Conservadores de la Densidad Ósea/uso terapéutico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Calcio/sangre , Línea Celular Tumoral , Progresión de la Enfermedad , Glicoproteínas/sangre , Proteínas Fluorescentes Verdes/genética , Humanos , Masculino , Ratones , Ratones Desnudos , Osteoprotegerina , Pamidronato , Proteína Relacionada con la Hormona Paratiroidea/sangre , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores Citoplasmáticos y Nucleares/sangre , Receptores del Factor de Necrosis Tumoral/sangre , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To describe a case of metastatic rhabdomyosarcoma originating from the sphenoid sinus in a patient previously treated with conventional irradiation for a prolactinoma, presenting as hypercalcemia in the setting of a normal level of serum parathyroid hormone-related protein (PTHrP). METHODS: We report the case of a patient who underwent remote pituitary irradiation for a prolactinoma and then presented decades later with hypercalcemia of unknown cause. His clinical course, the initial biochemical and radiologic investigations, and the results of examination of pathology specimens are reviewed. RESULTS: The patient was found to have a mass in the sphenoid sinus. The pathologic features were consistent with alveolar rhabdomyosarcoma. Although he had a normal serum PTHrP level, staining of his tumor with an antibody against PTHrP revealed local production of PTHrP at the tumor margins. His bone marrow biopsy specimen showed 100% involvement with rhabdomyosarcoma. CONCLUSION: PTHrP staining of pathology specimens might explain hypercalcemia of undetermined cause in patients with a known malignant lesion, in whom elevated serum PTHrP levels cannot be demonstrated.