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1.
Gan To Kagaku Ryoho ; 44(11): 977-980, 2017 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-29138370

RESUMO

Recently, hypoxia that is one of cancer microenvironments, takes much attention. Because circumstance that we usually perform experiment is 20% O2 condition, it is likely that different signaling pathways may be activated in vivo cancer. We focused Hedgehog(Hh)signaling as one of activated pathways under hypoxia. It has been shown that Hh signaling is activated under hypoxia, followed by inducing malignant phenotypes in pancreatic cancer. Therefore, Hh signaling inhibitor should elicit anti-tumor effect. However, if we consider "whole-person therapy" we should confirm how Hh signaling affects the function of immune cells. In the present study, we describe hypoxia/Hh signaling/functions of cancer cells and immune cells focusing our previous results.


Assuntos
Neoplasias/metabolismo , Neoplasias/patologia , Transdução de Sinais , Animais , Hipóxia Celular , Células Dendríticas/imunologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias/terapia , Microambiente Tumoral
2.
Cancer Immunol Immunother ; 61(3): 409-24, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21932134

RESUMO

Dendritic cells (DCs) generated from monocytes under 20% O2 are now used as therapeutic tools for cancer patients. However, the O2 concentration is between 3 and 0.5% in most tissues. We evaluated these complicated functions of DCs under oxygen tensions mimicking in vivo situations. Immature DCs (imDCs) were generated from monocytes using IL-4 and GM-CSF under normoxia (20% O2; N-imDCs) or hypoxia (1% O2; H-imDCs). Mature DCs (mDCs) were induced with LPS. DCs were further exposed to normoxia (N/N-DCs) or hypoxia (N/H-DCs and H/H-DCs) conditions. Using a 2-D culture system, H-DCs were smaller in size than N-DCs, and H/H-DCs exhibited higher allo-T cell stimulation ability than N/N-DCs and N/H-DCs. On the other hand, motility and phagocytic ability of H/H-DCs were significantly lower than those of N/H-DCs and N/N-DCs. In a 3-D culture system, however, maturation of H/H-imDCs and N/H-imDCs was suppressed compared with N/N-imDCs as a result of their decreased motility and phagocytosis. Interestingly, silencing of HIF-1α by RNA interference decreased CD83 expression without affecting any antigen presentation abilities except for the ability to stimulate the allo-T cell population. Our data could help our understanding of DCs, especially therapeutic DCs, in vivo.


Assuntos
Apresentação de Antígeno/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Monócitos/imunologia , Antígenos CD/imunologia , Antígenos CD/metabolismo , Técnicas de Cultura de Células , Diferenciação Celular/efeitos dos fármacos , Movimento Celular/imunologia , Proliferação de Células , Células Cultivadas , Células Dendríticas/metabolismo , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Immunoblotting , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Interleucina-4/farmacologia , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Modelos Imunológicos , Monócitos/metabolismo , Oxigênio/farmacologia , Fagocitose/imunologia , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Linfócitos T/metabolismo , Antígeno CD83
3.
Anticancer Res ; 31(7): 2505-10, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21873167

RESUMO

AIM: Natural-killer group 2, member D (NKG2D) is an activating receptor on natural killer cells and activated T-cells, designated cytokine-activated killer (CAK) cells here. The MHC class I chain-related A and B (MICA and MICB, respectively) are ligands of NKG2D and are expressed on various human tumor cells, including hepatocellular carcinoma (HCC) cells. Here, we investigate whether gemcitabine, a chemotherapeutic agent, affects MICA/B expression in HCC. MATERIALS AND METHODS: We used ELISA, RT-PCR and adherent target detachment assays to determine expression of MICA/B in HepG2 HCC cells and the level of cellular cytotoxicity generated by treatment with gemcitabine and/or CAK cells. RESULTS: Surface expression of MICA/B was evident after gemcitabine treatment, and MICB-specific mRNA was up-regulated. Pre-treatment with gemcitabine and subsequent exposure to CAK cells induced greater cytotoxicity than either treatment alone. Inclusion of soluble MICB significantly reduced cytotoxicity. CONCLUSION: Gemcitabine induced MICA/B expression in HepG2 cells, resulting in synergistic enhancement of the cytotoxic effects of NKG2D-high CAK cells. The combination of gemcitabine and CAK cells may have clinical therapeutic significance for HCC.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Carcinoma Hepatocelular/patologia , Desoxicitidina/análogos & derivados , Antígenos de Histocompatibilidade Classe I/biossíntese , Neoplasias Hepáticas/patologia , Monócitos Matadores Ativados/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Carcinoma Hepatocelular/sangue , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/imunologia , Células Cultivadas/efeitos dos fármacos , Terapia Combinada , Citotoxicidade Imunológica , Desoxicitidina/farmacologia , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Técnicas In Vitro , Interleucina-2/farmacologia , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/terapia , Muromonab-CD3/farmacologia , Proteínas Recombinantes/farmacologia , Gencitabina
4.
Cancer Sci ; 102(6): 1144-50, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21338440

RESUMO

The hedgehog (Hh) signaling pathway is activated in various types of cancer including pancreatic ductal adenocarcinoma. It has been shown that extremely low oxygen tension (below 1% O2) is found in tumor tissue including pancreatic ductal adenocarcinoma cells (PDAC) and increases the invasiveness of PDAC. To investigate the contribution of the Hh pathway to hypoxia-induced invasiveness, we examined how hypoxia affects Hh pathway activation and the invasiveness of PDAC. In the present study, three human PDAC lines were cultured under normoxic (20% O2) or hypoxic (1% O2) conditions. Hypoxia upregulated the transcription of Sonic hedgehog (Shh), Smoothened (Smo), Gli1 and matrix metalloproteinase9 (MMP9) and increased the invasiveness of PDAC. Significantly, neither the addition of recombinant Shh (rhShh) nor the silencing of Shh affected the transcription of these genes and the invasiveness of PDAC. On the other hand, silencing of Smo decreased the transcription of Gli1 and MMP9 and PDAC invasiveness. Silencing of Gli1 or MMP9 decreased PDAC invasiveness. These results suggest that hypoxia activates the Hh pathway of PDAC by increasing the transcription of Smo in a ligand-independent manner and increases PDAC invasiveness.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Hipóxia Celular , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proteínas Hedgehog/genética , Humanos , Immunoblotting , Ligantes , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Invasividade Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase , Interferência de RNA , RNA Interferente Pequeno , Receptores Acoplados a Proteínas G/biossíntese , Receptor Smoothened , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Transcrição Gênica , Microambiente Tumoral , Proteína GLI1 em Dedos de Zinco
5.
Case Rep Gastroenterol ; 4(3): 429-434, 2010 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-21060713

RESUMO

Repeated pancreatectomy for pancreatic carcinoma is extremely rare. We report two such patients who underwent pancreatectomy for carcinoma developing in the pancreatic remnant after pylorus-preserving pancreatoduodenectomy (PpPD) for invasive pancreatic ductal carcinoma. One patient underwent PpPD for invasive pancreatic ductal carcinoma and received adjuvant chemotherapy. Follow-up computed tomography (CT) demonstrated a low-density mass in the remnant pancreas, which was diagnosed as a carcinoma by endoscopic ultrasound-guided fine-needle aspiration cytology 5 years 10 months after PpPD. She underwent curative resection of the remnant pancreas and is alive and well 13 months after the second operation. The other patient underwent PpPD for invasive pancreatic ductal carcinoma. Follow-up CT showed a low-density mass in the remnant pancreas after 2 years 11 months. He received systemic chemotherapy with S-1 for 3 months. The tumor shrank, and the patient underwent curative resection of the remnant pancreas 3 years 1 month after the initial operation. Repeated pancreatectomy may provide a chance of long survival for patients with carcinoma developing in the remnant pancreas after pancreatectomy if the recurrence occurring at long term is limited to the remnant pancreas.

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