RESUMO
The expression of brain-derived neurotrophic factor (BDNF) is observed not only in the brain, but also in peripheral tissues including white adipose tissues (WATs). Here, we showed that the mRNA expression of Bdnf in inguinal WAT (iWAT) and epididymal WAT (eWAT) increased within 2 weeks of feeding mice with a high-fat diet (HFD). In mice on a 2-week HFD, the induction of Bdnf expression in WATs was significantly correlated with increases in body weight, suggesting that Bdnf expression may increase at an early stage of obesity. The mRNA expression of hypoxia-inducible factor 1α and platelet-derived growth factor, which are involved in neovascularization and the subsequent expansion of adipose tissues, increased in the iWAT of mice on the 2-week HFD. We also found that the expression of macrophage marker F4/80 in iWAT increased under the HFD. Interestingly, HFD-induced Bdnf expression in iWAT was not observed when macrophages were removed by the administration of clodronate liposomes. Accordingly, mice receiving clodronate liposomes also exhibited a significant reduction in the HFD-induced increase in body weight. In conclusion, increased body weight in HFD-induced obese model mice was accompanied by the induction of Bdnf expression in iWAT and was probably mediated by macrophages. Our findings imply a novel function for BDNF in iWAT at an early stage of obesity.
Assuntos
Fator Neurotrófico Derivado do Encéfalo , Dieta Hiperlipídica , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ácido Clodrônico , Lipossomos/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Peso Corporal , Macrófagos/metabolismo , RNA Mensageiro/metabolismo , Camundongos Endogâmicos C57BLRESUMO
PURPOSE OF THE STUDY: Confluence-dependent resistance (CDR) is a phenomenon in which the efficacy of anti-cancer agents decreases when cell density increases. CDR in lung cancer has never been reported. The purpose of this study is to investigate if CDR can occur in NSCLC cells and to find a role for transforming growth factor (TGF)-ß as a mechanism of CDR. MATERIALS AND METHODS: Non-small cell lung cancer (NSCLC) cell lines A549 and H2228 were exposed to cisplatin in a variety of cell density conditions. RNA interference targeting TGF-ß receptor I was performed to silence the TGF-ß pathway. RESULTS: CDR to cisplatin was induced in NSCLC cells, whereas CDR to crizotinib, an inhibitor of activin receptor-like kinase, was not observed. During confluent conditions, the TGF-ß1 concentration in the culture medium was the highest. Exogenous TGF-ß1 inhibited cell proliferation and reduced sensitivity to cisplatin. Inhibition of the TGF-ß pathway increased in terms of sensitivity to cisplatin at confluency. CONCLUSIONS: CDR to cisplatin can occur in NSCLC cells, and the TGF-ß pathway is associated with the regulation of CDR.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/fisiopatologia , Fator de Crescimento Transformador beta/fisiologia , Células A549 , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Redes e Vias Metabólicas/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
PURPOSE: No lung cancer xenograft model using non-obese diabetic (NOD)-scid Il2rg (-/-) mice has been reported. The purpose of this study is to select a suitable mouse strain as a xenogenic host for testing tumorigenicity of lung cancer. MATERIALS AND METHODS: We directly compared the susceptibility of four immunodeficient mouse strains, c-nu, C.B-17 scid, NOD-scid, and NOD/LtSz-scid Il2rg (-/-) (NSG) mice, for tumor formation from xenotransplanted lung cancer cell lines. Various numbers (10(1)-10(5) cells/head) of two lung cancer cell lines, A549 and EBC1, were subcutaneously inoculated and tumor sizes were measured every week up to 12 weeks. RESULTS: When 10(4) EBC1 cells were inoculated, no tumor formation was observed in BALB/c-nu or C.B-17 scid mice. Tumors developed in two of the five NOD-scid mice (40%) and in all the five NSG mice (100%). When 10(3) EBC1 cells were injected, no tumors developed in any strain other than NSG mice, while tumorigenesis was achieved in all the five NSG mice (100%, P=0.0079) within 9 weeks. NSG mice similarly showed higher susceptibility to xenotransplantation of A549 cells. Tumor formation was observed only in NSG mice after inoculation of 10(3) or fewer A549 cells (40% vs 0% in 15 NSG mice compared with others, respectively, P=0.0169). We confirmed that the engrafted tumors originated from inoculated human lung cancer cells by immunohistochemical staining with human cytokeratin and vimentin. CONCLUSION: NSG mice may be the most suitable strain for testing tumorigenicity of lung cancer, especially if only a few cells are available.
