RESUMO
Anti-apoptotic proteins that block death receptor-mediated apoptosis favour tumour evasion of the immune system, leading to enhanced tumour progression. However, it is unclear whether blocking the mitochondrial pathway of apoptosis will protect tumours from immune cell attack. Here, we report that the anti-apoptotic protein Bcl-xL , known for its ability to block the mitochondrial pathway of apoptosis, exerted tumour-progressive activity in a murine lymphoma model. Bcl-xL overexpressing tumours exhibited a more aggressive development than control tumours. Surprisingly, Bcl-xL protection of tumours from NK cell-mediated attack did not involve protection from NK cell-mediated cytotoxicity. Instead, Bcl-xL -blocked apoptosis resulting from hypoxia and/or nutrient loss associated with the inhibition of angiogenesis caused by NK cell-secreted IFN-γ. These results support the notion that NK cells may inhibit tumour growth also by mechanisms other than direct cytotoxicity. Hence, the present results unravel a pathway by which tumours with a block in the mitochondrial pathway of apoptosis can evade the immune system.
Assuntos
Interferon gama/fisiologia , Células Matadoras Naturais/imunologia , Linfoma/imunologia , Neovascularização Patológica/prevenção & controle , Evasão Tumoral , Proteína bcl-X/fisiologia , Animais , Linhagem Celular Tumoral , Cicloexanos/farmacologia , Citotoxicidade Imunológica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , O-(Cloroacetilcarbamoil)fumagilol , Sesquiterpenos/farmacologiaAssuntos
Inibidores da Angiogênese/farmacologia , Neoplasias/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Estilbenos/farmacologia , Cicatrização/efeitos dos fármacos , Alantoide/irrigação sanguínea , Animais , Divisão Celular/efeitos dos fármacos , Embrião de Galinha , Córion/irrigação sanguínea , Córnea/irrigação sanguínea , Fatores de Crescimento Endotelial/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fibrossarcoma/patologia , Linfocinas/farmacologia , Camundongos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias/irrigação sanguínea , Neovascularização Patológica , Resveratrol , Rosales/química , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio Vascular , Vinho/análiseRESUMO
Most endocrine hormones are produced in tissues and organs with permeable microvessels that may provide an excess of hormones to be transported by the blood circulation to the distal target organ. Here, we investigate whether leptin, an endocrine hormone, induces the formation of vascular fenestrations and permeability, and we characterize its angiogenic property in the presence of other angiogenic factors. We provide evidence that leptin-induced new blood vessels are fenestrated. Under physiological conditions, capillary fenestrations are found in the leptin-producing adipose tissue in lean mice. In contrast, no vascular fenestrations were detected in the adipose tissue of leptin-deficient ob/ob mice. Thus, leptin plays a critical role in the maintenance and regulation of vascular fenestrations in the adipose tissue. Leptin induces a rapid vascular permeability response when administrated intradermally. Further, leptin synergistically stimulates angiogenesis with fibroblast growth factor (FGF)-2 and vascular endothelial growth factor (VEGF), the two most potent and commonly expressed angiogenic factors. These findings demonstrate that leptin has another new function-the increase of vascular permeability.
Assuntos
Permeabilidade Capilar/fisiologia , Fatores de Crescimento Endotelial/farmacologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Leptina/fisiologia , Linfocinas/farmacologia , Neovascularização Fisiológica/fisiologia , Tecido Adiposo , Animais , Capilares/citologia , Permeabilidade Capilar/efeitos dos fármacos , Bovinos , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Córnea/irrigação sanguínea , Córnea/efeitos dos fármacos , Córnea/ultraestrutura , Neovascularização da Córnea , Sinergismo Farmacológico , Fatores de Crescimento Endotelial/administração & dosagem , Endotélio Vascular/citologia , Feminino , Fator 2 de Crescimento de Fibroblastos/administração & dosagem , Humanos , Leptina/administração & dosagem , Linfocinas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular , Fatores de Crescimento do Endotélio VascularRESUMO
Novel analogues of the cell-penetrating peptides penetratin and transportan were synthesized. The distribution of the biotin-labeled peptides in Bowes melanoma cell line has been investigated by indirect fluorescence with fluorescein-streptavidin detection. The time course of uptake of (125)I-labeled transportan analogues has been characterized in the same cell line. Molecular modeling was used to analyze the penetration and the orientation of molecules in a simulated biological membrane. The results, both from molecular modeling and fluorescence studies, imply that penetratin and transportan do not enter the cells by related mechanisms and that they do not belong to the same family of translocating peptides.