RESUMO
Glioblastoma multiforme (GBM) is characterized by numerous abnormal blood vessels, which rapidly proliferate and invade brain tissue and express different angiogenic factors. In this study we have investigated whether the expression levels of CD31/ PECAM1 are deregulated in human GBM tissue specimens and we have also correlated the expression levels of CD31/PECAM1 with those of HIF-1α. Finally, we have established a correlation between the expression levels of CD31/PECAM1 and HIF-1α, and those of two other biomarkers, namely N-cadherin and ADAM-10, of aggressiveness in the same tumors. Results have shown an increased expression of CD31/PECAM1 correlated to HIF-1α expression, confirming evidence demonstrating that different types of tumor are able to trigger aberrant angiogenesis through HIF-1α. Moreover, we also established a further correlation among CD31/PECAM1 and HIF-1α and N-cadherin and ADAM-10, two other markers of aggressiveness in the same tumors.
Assuntos
Neoplasias Encefálicas/genética , Glioblastoma/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Idoso , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pessoa de Meia-Idade , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismoRESUMO
Previous studies have found that matrix metalloproteinase-2 (MMP-2) and transforming growth factor-beta (TGF-beta) can be considered as biomarkers and indices of disease progression in several human cancers. In this study, we investigated the plasma levels of MMP-2 and TGF-beta and their correlation in 49 primary cutaneous melanoma and 10 metastatic melanoma. Plasma MMP-2 and TGF-beta levels in patients with primary melanoma were significantly higher than those of healthy controls. These protein levels were significantly higher in patients with metastatic melanoma. A positive correlation between plasma levels of MMP-2 and TGF-beta in melanoma patients supports the hypothesis that TGF-beta triggers the release of MMP-2. The immunohistochemistry analysis shows that MMP-2 and TGF-beta were highly expressed in tumor tissues as well as in matched plasma samples. This finding suggests that these proteins are released from tumor cells. Overall, our data indicate that MMP-2 and TGF-beta may represent novel diagnostic markers and therapeutic targets in melanoma and the determination of their concentration could be a useful diagnostic and prognostic indicator. TGF-beta, leading the tissue invasion mediated by MMP-2, is a strong promoter of tumor progression. Therefore, reducing or blocking the activity of TGF-beta may represent a promising target in therapeutic strategies for limiting the growth of melanoma.
Assuntos
Metaloproteinase 2 da Matriz/metabolismo , Melanoma/patologia , Neoplasias Cutâneas/patologia , Fator de Crescimento Transformador beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Metaloproteinase 2 da Matriz/sangue , Melanoma/sangue , Melanoma/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/metabolismo , Fator de Crescimento Transformador beta/sangueRESUMO
In this study we evaluated the effects of the new NO donating compound (S,R)-3-phenyl-4,5-dihydro-5-isoxazole acetic acid-nitric oxide (GIT-27NO) on the A375 human melanoma cell line. Treatment with the drug led to concentration-dependent reduction of mitochondrial respiration and number of viable cells in cultures. Decreased cell viability correlated with release and internalization of NO and was neutralized by the extracellular scavenger hemoglobin. GIT-27NO neither influenced cell division nor induced accidental or autophagic cell death. Early signs of apoptosis were observed upon coculture with the drug, and resulting in marked accumulation of hypodiploid cells, suggesting that the induction of apoptosis is one primary mode of action of the compound in A375 cells. GIT-27NO significantly inhibited the expression of the transcription repressor and apoptotic resistant factor YY1 and, in parallel, augmented the presence of total p53. The capacity of GIT-27NO to induce p53-mediated apoptosis along with inhibition of YY1 repressor in A375 melanoma cells indicates that GIT-27NO possesses an important anti-cancer pharmacological profile. The findings suggest the potential therapeutic use of GIT-27NO in the clinical setting.
Assuntos
Apoptose/efeitos dos fármacos , Melanoma/tratamento farmacológico , Doadores de Óxido Nítrico/farmacologia , Proteína Supressora de Tumor p53/efeitos dos fármacos , Acetatos , Antineoplásicos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Melanoma/patologia , Doadores de Óxido Nítrico/uso terapêutico , Oxazóis , Fator de Transcrição YY1/antagonistas & inibidoresRESUMO
The proapoptotic cytokine TRAIL has been shown to enhance amyloid-beta-dependent neurotoxicity. Here are reported interactions between TRAIL and nitric oxide (NO) in cultured rat astrocytes in vitro. Rat astrocytes expressed all TRAIL receptor mRNAs and proteins. However, TRAIL failed in inducing apoptosis of astrocytes, whereas these cells released substantial amounts of nitrites. A TRAIL-neutralizing antibody was able to prevent LPS-induced iNOS expression in astrocytes. Interestingly, TRAIL induced its own expression in astrocytes. These data suggest that redundancy between TRAIL and NO in astrocytes could be fueling neuronal damage/death processes, potentially uncovering novel molecular targets for the treatment of neurodegenerative disorders.
