RESUMO
Prostate cancer represents the second cancer-related cause of death in North American and Chilean men. The main treatment for incurable stages of disease is surgical or pharmacological castration. However, with time and despite the addition of anti-androgens, the disease progresses to a clinical state that has been commonly referred to as hormone refractory. In recent years, the concept of hormone refractoriness has been challenged and replaced by castration resistance, acknowledging that further and optimal hormonal manipulation can be attained, beyond achieving testosterone levels at castration range. The purpose of this review is to summarize the recent therapeutic breakthroughs in the management of metastatic castrate resistant prostate cancer (mCRPC), with greater emphasis in the newer hormonal therapy agents such as Abiraterone and Enzalutamide. Future combination and sequential treatment strategies are contextualized in the current era of personalized cancer medicine and genomic characterization of prostate cancer.
Assuntos
Animais , Ratos , Angiotensina II/fisiologia , Fibronectinas/biossíntese , Células Mesangiais/metabolismo , Inibidor 1 de Ativador de Plasminogênio/biossíntese , Poli(ADP-Ribose) Polimerases/fisiologia , Células Cultivadas , Fibronectinas/genética , Regulação Enzimológica da Expressão Gênica , Mesângio Glomerular/citologia , Mesângio Glomerular/metabolismo , Mesângio Glomerular/patologia , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Células Mesangiais/enzimologia , Células Mesangiais/patologia , Inibidor 1 de Ativador de Plasminogênio/genética , Poli(ADP-Ribose) Polimerases/biossíntese , Poli(ADP-Ribose) Polimerases/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologiaRESUMO
Gene transfer of basic fibroblast growth factor (bFGF) has been shown to induce significant endothelial migration and angiogenesis in ischemic disease models. Here, we investigate what factors are secreted from skeletal muscle cells (SkMCs) transfected with bFGF gene and whether they participate in endothelial cell migration. We constructed replication-defective adenovirus vectors containing the human bFGF gene (Ad/bFGF) or a control LacZ gene (Ad/LacZ) and obtained conditioned media, bFGF-CM and LacZ-CM, from SkMCs infected by Ad/bFGF or Ad/LacZ, respectively. Cell migration significantly increased in HUVECs incubated with bFGF-CM compared to cells incubated with LacZ-CM. Interestingly, HUVEC migration in response to bFGF-CM was only partially blocked by the addition of bFGF-neutralizing antibody, suggesting that bFGF-CM contains other factors that stimulate endothelial cell migration. Several proteins, matrix metalloproteinase-1 (MMP-1), plasminogen activator inhibitor-1 (PAI-1), and cathepsin L, increased in bFGF-CM compared to LacZ-CM; based on 1-dimensional gel electrophoresis and mass spectrometry. Their increased mRNA and protein levels were confirmed by RT-PCR and immunoblot analysis. The recombinant human bFGF protein induced MMP-1, PAI-1, and cathepsin L expression in SkMCs. Endothelial cell migration was reduced in groups treated with bFGF-CM containing neutralizing antibodies against MMP-1 or PAI-1. In particular, HUVECs treated with bFGF-CM containing cell-impermeable cathepsin L inhibitor showed the most significant decrease in cell migration. Cathepsin L protein directly promotes endothelial cell migration through the JNK pathway. These results indicate that cathepsin L released from SkMCs transfected with the bFGF gene can promote endothelial cell migration.
Assuntos
Humanos , Anticorpos Neutralizantes/imunologia , Catepsina L/genética , Movimento Celular , Células Cultivadas , Ensaio Cometa , Dependovirus/genética , Células Endoteliais/citologia , Fator 2 de Crescimento de Fibroblastos/genética , Técnicas de Transferência de Genes , Immunoblotting , Proteínas Quinases JNK Ativadas por Mitógeno , Óperon Lac/genética , Espectrometria de Massas , Metaloproteinase 1 da Matriz/biossíntese , Músculo Esquelético/metabolismo , Neovascularização Fisiológica , Inibidor 1 de Ativador de Plasminogênio/biossíntese , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The plasminogen and plasmin system, which is mainly regulated by urokinase-type plasminogen activator (uPA), its receptor (uPAR) and its inhibitor (PAI-1), is generally believed to play a role in cancer invasion and metastasis. This study was conducted to investigate the role of uPA, uPAR and PAI-1 in the invasion and metastasis of gastric adenocarcinoma. The expression of mRNAs for uPA and PAI-1 was determined by Northern blot analysis in nine primary gastric cancer tissues, nine paired metastatic lymph nodes and normal gastric mucosa. The mRNA of uPA was not or faintly detected in normal mucosa, while the expression was increased in both primary gastric cancer tissues and metastatic lymph nodes to a similar degree. The mRNA expression for PAI-1 in the gastric cancer tissues was not different from that in the paired metastatic lymph nodes and normal mucosae. uPAR was determined by immunohistochemical staining, demonstrating that five (56%) and six (67%) out of nine primary gastric cancer tissues and nine paired metastatic lymph nodes were positive, respectively and the intensity was stronger in metastatic lymph nodes. The results support the concept that most gastric cancer cells may have an innately moderate level of uPA and uPAR, and that increase of uPAR expression can be considered to be closely associated with cancer invasion and metastasis.