RESUMO
Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin-engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen.
Assuntos
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/biossíntese , Neoplasias da Mama/terapia , Terapia Genética/métodos , Neoplasias Mamárias Experimentais/terapia , Células-Tronco Mesenquimais/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/terapia , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Técnicas de Cocultura , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células Jurkat , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Transplante de Células-Tronco Mesenquimais , Camundongos Endogâmicos BALB C , Camundongos Nus , Metástase Neoplásica , Receptor ErbB-2/genética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fatores de Tempo , Transfecção , Carga Tumoral , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: The role of genetic variants in the pathogenesis of stroke has not been fully elucidated. Several studies have been examined the association of the Integrin alpha2 (ITGA2) gene-C807T (rs1126643) polymorphism with ischemic stroke susceptibility. However, the results of these studies are inconsistent. In order to explore this association more deeply, we performed a meta-analysis. METHODS: We collected case-control studies concerning the relationship between the C807T polymorphism and ischemic stroke, and odd ratios (OR) with corresponding 95% confidence intervals (CI) were used to describe the relationships. Inconsistency index (I(2)) and Cochran's Q statistic were used to check heterogeneity. Publication bias was tested by funnel plots and Egger's test. RESULTS: Fifteen studies with 2242 cases and 2408 controls were included. Our meta-analysis results indicated an association between the C807T polymorphism and the risk of ischemic stroke in the overall population, Asians and the subgroup of hospital-based people. However, statistically association was not observed for Caucasians and non-hospitalized individuals. CONCLUSIONS: The ITGA2 gene C807T polymorphism may be a susceptible predictor of the risk of ischemic stroke. More data are needed to elucidate the relationship further.
