Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Anticancer Res ; 41(8): 4047-4052, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281873

RESUMO

BACKGROUND/AIM: Tropomyosin-related kinase B (TrkB)/brain-derived neurotrophic factor (BDNF) signaling plays a role in inducing malignant phenotypes in several aggressive types of cancers. To create a conclusive therapy targeting TrkB/BDNF signaling in solid refractory cancers, the biological significance of TrkB/BDNF signaling was analyzed in pancreatic ductal adenocarcinoma (PDAC) cells. MATERIALS AND METHODS: Three PDAC cell lines were used as target cells to investigate proliferation and invasiveness. Small interfering RNA (siRNA) and the TrkB tyrosine kinase inhibitor k252a were used as TrkB/BDNF signaling inhibitors. RESULTS: All PDAC cell lines expressed TrkB and BDNF. When TrkB and BDNF were inhibited by siRNA or k252a, the invasiveness of PANC-1 and SUIT-2 cells significantly decreased. When TrkB was inhibited by siRNA or k252a, proliferation was significantly inhibited in PDAC cells. CONCLUSION: TrkB/BDNF signaling may be a new therapeutic target for PDAC. Therapies targeting TrkB/BDNF signaling may be a conclusive cancer therapy for refractory solid cancer.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptor trkB/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Carbazóis/farmacologia , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Alcaloides Indólicos/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/genética , Neoplasias Pancreáticas/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Interferente Pequeno/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/genética , Transdução de Sinais/efeitos dos fármacos
2.
Cancer Lett ; 484: 9-15, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380129

RESUMO

Chemotherapy and immunotherapy for pancreatic ductal adenocarcinoma (PDAC) have limited success. One reason for this is thought to be the cancer microenvironment surrounding PDAC. Hypoxia is a feature of the cancer microenvironment. Under hypoxia, different various molecules and signaling pathways are activated compared with normoxia. To develop a new effective therapeutic strategy for PDAC, we need to target these hypoxic conditions to overcome PDAC. To inhibit the malignant phenotype, the cellular changes that occur under hypoxia should be elucidated. Various molecules and signaling that are activated by hypoxia may contribute to the induction of malignant phenotypes of PDAC such as proliferation, invasion, tumorigenesis, chemosensitivity, and autophagy. If we can develop therapeutic approaches to target one of these molecules or signaling pathways, we may proceed to the next therapeutic step of successfully treating refractory PDAC.


Assuntos
Carcinoma Ductal Pancreático/genética , Regulação Neoplásica da Expressão Gênica/genética , Hipóxia , Neoplasias Pancreáticas/genética , Microambiente Tumoral/genética , Antineoplásicos/farmacologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Imunoterapia/métodos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Microambiente Tumoral/efeitos dos fármacos
3.
Anticancer Res ; 39(3): 1179-1184, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842147

RESUMO

BACKGROUND/AIM: Small-cell lung cancer (SCLC) remains one of deadliest types of cancers. Cis-diamminedichloroplatinum (CDDP) is a key chemotherapeutic agent for SCLC, however, its therapeutic effect is limited. Recently, hypoxia in the cancer microenvironment has been suggested to influence the effect of cancer therapy. MATERIALS AND METHODS: Using small interfering RNA inhibition of leukocyte common antigen-related interacting protein alpha 4 (liprin-α4), and of hypoxia-inducible factor (HIF)-1α, proliferation, invasion, migration and chemosensitivity were investigated in SBC-5 SCLC cells, under normoxia and hypoxia. RESULTS: Liprin-α4 was found to contribute to proliferation, but not migration and invasion of SBC-5 cells both under normoxia and hypoxia. Inhibition of liprin-α4 increased chemosensitivity of SBC-5 cells under hypoxia. Liprin-α4 signaling occurs through mitogen-activated protein kinase pathways via activation of HIF1α expression. Inhibition of HIF1α reduced proliferation and increased chemosensitivity of SBC-5 cells under hypoxia. CONCLUSION: Liprin-α4 inhibition may enhance the effect of CDDP and liprin-α4 might be a novel therapeutic target in SCLC.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/terapia , RNA Interferente Pequeno/administração & dosagem , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proteínas Tirosina Fosfatases Semelhantes a Receptores/metabolismo , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo
4.
Anticancer Res ; 38(8): 4543-4547, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30061220

RESUMO

BACKGROUND/AIM: Small cell lung cancer (SCLC) is still a deadly type of cancer for which there are few effective therapeutic strategies. Development of a new molecule targeting agent is urgently desired. Previously we showed that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) are new therapeutic targets for pancreatic cancer. In the present study, we analyzed whether RBPJ/MAML3 inhibition could also be a new therapeutic strategy for SCLC. MATERIALS AND METHODS: Using silencing of RBPJ/MAML3, proliferation, invasion, migration and chemosensitivity of SBC-5 cells were investigated. RESULTS: RBPJ/MAML3 inhibition reduced Smoothened and HES1 expression, suggesting that RBPJ/MAML3 signaling was through Hedgehog and NOTCH pathways. In the analysis of cell functions, RBPJ/MAML3 inhibition significantly reduced proliferation and invasiveness via reduction of expression of matrix metalloproteinases. On the other hand, RBPJ/MAML3 inhibition also reduced chemosensitivity to cis-diamminedichlo-roplatinum and gemcitabine. CONCLUSION: These results suggest that RBPJ and MAML3 could be new therapeutic targets for SCLC, however, chemosensitivity may be reduced in combinational use with other chemo-therapeutic agents.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Neoplasias Pulmonares/metabolismo , Proteínas Nucleares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fatores de Transcrição/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Metaloproteinases da Matriz/metabolismo , Invasividade Neoplásica/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Transativadores
5.
Anticancer Res ; 38(4): 1979-1986, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29599313

RESUMO

We previously reported that brain-derived neurotrophic factor (BDNF)/neurotrophic receptor tyrosine kinase 2 (NTRK2/TRKB) signaling contributes to induction of malignant phenotype of gallbladder cancer (GBC). Recently, pan-TRK inhibitors have been evaluated and their dramatic clinical activity is being shown for a variety of cancer types harboring an NTRK rearrangement in phase I trials. ONO-7579 is an oral pan-TRK inhibitor currently under investigation in phase I/II clinical trial for TRK-rearranged solid tumors. In this study, we evaluated the anticancer effect of ONO-7579 using GBC cells with or without KRAS mutant, NOZ, TYGBK-1. Our study showed that ONO-7579 had a suppressive effect on GBC proliferation in TYGBK-1, and on invasive potential and vascular endothelial growth factor expression in TYGBK-1 and NOZ. Our data indicated that ONO-7579 could be a promising treatment option for patients with GBC.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Glicoproteínas de Membrana/antagonistas & inibidores , Compostos Orgânicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor trkB/antagonistas & inibidores , Fator Neurotrófico Derivado do Encéfalo/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias da Vesícula Biliar/enzimologia , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Glicoproteínas de Membrana/biossíntese , Invasividade Neoplásica , Compostos Orgânicos/química , Receptor trkB/biossíntese , Fator A de Crescimento do Endotélio Vascular/biossíntese
6.
Anticancer Res ; 37(12): 6649-6654, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29187440

RESUMO

BACKGROUND/AIM: In pancreatic cancer, where the microenvironment is extremely hypoxic, analyzing signal transduction under hypoxia is thought to be significantly important. By investigating microarray analysis of pancreatic cancer cells cultured under both normoxia and hypoxia, we found that the expression of leukocyte common antigen-related (LAR)-interacting protein (liprin)-α4 was extremely increased under hypoxia compared to under normoxia. MATERIALS AND METHODS: In the present study, the biological significance of liprin-α4 in pancreatic cancer was investigated and whether liprin-α4 has potential as a therapeutic target for pancreatic cancer was estimated. RESULTS: Suppression of liprin-α4 reduced proliferation of pancreatic cancer cells both in vitro and in vivo. Inhibition of liprin-α4 also reduced invasiveness through the suppression of endothelial-mesenchymal transition. Stimulation by liprin-α4 was through phosphoinositide 3-kinase and mitogen-activated protein kinase signaling pathways. CONCLUSION: Liprin-α4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-α4 could be a new effective therapeutic target for pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias Pancreáticas/genética , Proteínas Tirosina Fosfatases Semelhantes a Receptores/genética , Animais , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Humanos , Hipóxia , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Interferência de RNA , Transdução de Sinais , Transplante Heterólogo
7.
Anticancer Res ; 37(9): 4987-4992, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28870922

RESUMO

BACKGROUND/AIM: Previously we have shown that tropomyosin-related kinase B (TRKB) and Hedgehog (Hh) signalling pathways induce malignant phenotypes in many cancer types. However, results from small cell lung cancer (SCLC) clinical trials using TRK and Hh inhibitors have been disappointing. One reason for this may be the existence of crosstalk between TRKB and Hh signalling pathways. In this study, we detected negative crosstalk between the TRKB and Hh-GLI1 signalling pathways. MATERIALS AND METHODS: The human small cell lung carcinoma cell line, SBC-5, was used. Using small interfering RNA to inhibit TRKB and Hh signalling, whether TRKB and Hh signaling contribute to proliferation and invasiveness in SBC-5 cells were investigated. RESULTS: TRKB expression in GLI1 siRNA-transfected SBC-5 cells was higher than that of control cells. GLI1-knockdown alone did not affect invasiveness of SBC-5 cells. However, combined knockdown of TRKB and GLI1 significantly decreased invasiveness. Moreover, combined TRKB and GLI1 knockdown inhibited proliferation and migration to a greater extent than when either was inhibited alone. CONCLUSION: These results suggest that Hh inhibition increases TrkB expression to counter tumor suppression in SBC-5 cells. The combined use of TRKB and Hh inhibitors may, therefore, be useful for the treatment of refractory SCLC.


Assuntos
Movimento Celular , Proliferação de Células , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Pulmonares/patologia , Glicoproteínas de Membrana/antagonistas & inibidores , Receptor trkB/antagonistas & inibidores , Carcinoma de Pequenas Células do Pulmão/patologia , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Apoptose , Proteínas Hedgehog/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , RNA Interferente Pequeno/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas
8.
Oncotarget ; 8(22): 36211-36224, 2017 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-28423707

RESUMO

This study aims to demonstrate the clinical and biological significance of Brain derived neurotrophic factor (BDNF)/Tropomyosin-related kinase B (TrkB) signaling in gallbladder cancer (GBC) through a series of in vitro and in vivo experiments. TrkB expression was detected in 63 (91.3%) out of 69 surgically resected primary GBC specimens by immunohistochemistry. TrkB expression in the invasive front correlated with T factor (p=0.0391) and clinical staging (p=0.0391). Overall survival was lower in patients with high TrkB expression in the invasive front than in those with low TrkB expression (p=0.0363). In vitro experiment, we used five TrkB-expressing GBC cell lines with or without K-ras mutation. TrkB-mediated signaling increased proliferation and the invasiveness by inducing epithelial mesenchymal transition, and activating matrix metalloproteinases-2 (MMP-2) and MMP-9. Inhibition of TrkB-mediated signaling also decreased hypoxia-inducible factor-1α, vascular endothelial growth factor A (VEGF-A), VEGF-C, and VEGF-D expression. In vivo experiment, inhibition of TrkB-mediated signaling suppressed tumorigenicity and tumor growth in GBC. These findings demonstrate that TrkB-mediated signaling contributes to the induction of malignant phenotypes (proliferation, invasiveness, angiogenesis, lymphangiogenesis, and tumorigenesis) in GBC, and could be a promising therapeutic target regardless of K-ras mutation status.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Neoplasias da Vesícula Biliar/genética , Glicoproteínas de Membrana/genética , Receptor trkB/genética , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transição Epitelial-Mesenquimal , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Regulação Neoplásica da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Metaloproteinases da Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estadiamento de Neoplasias , RNA Interferente Pequeno/genética , Receptor trkB/metabolismo , Transdução de Sinais , Análise de Sobrevida , Carga Tumoral , Fator A de Crescimento do Endotélio Vascular/metabolismo
9.
Anticancer Res ; 37(2): 561-565, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28179302

RESUMO

The role of cluster of differentiation (CD) 24 in breast cancer remains unclear; previously, we showed that CD24 suppresses malignant phenotypes by inactivating Hedgehog signaling through signal transducer and activator of transcription (STAT) 1 inhibition. In this study, we examined how CD24 affects chemosensitivity in breast cancer cells. The CD44+CD24+ breast cancer cell line MCF-7 was transfected with CD24 with/without STAT1 siRNA, and chemosensitivity to 5-fluorouracil (5-FU) and cis-diamminedichloroplatinum (CDDP) was measured. CD24 inhibition reduced chemosensitivity to 5-FU, while STAT1 inhibition did not affect chemosensitivity to 5-FU in CD24 siRNA-transfected cells. Conversely, CD24 inhibition did not affect chemosensitivity to CDDP, while STAT1 inhibition reduced chemosensitivity to CDDP in CD24 siRNA-transfected cells. STAT1 inhibition, but not CD24 inhibition, reduced expression of the ATP-binding cassette (ABC) transporter genes, ABCB1 and ABCG2. In conclusion, CD24 inhibition may modulate chemosensitivity according to drug type, but ABC transporter expression appears not to contribute to this mechanism. This study contributes to determining the role of CD24 in breast cancer.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Antígeno CD24/metabolismo , Transportador 1 de Cassete de Ligação de ATP/biossíntese , Subfamília B de Transportador de Cassetes de Ligação de ATP/biossíntese , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/biossíntese , Neoplasias da Mama/genética , Antígeno CD24/genética , Feminino , Fluoruracila/farmacologia , Humanos , Células MCF-7 , Proteínas de Neoplasias/biossíntese , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Fator de Transcrição STAT1/antagonistas & inibidores , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Transfecção
10.
Cell Immunol ; 310: 199-204, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27522179

RESUMO

We investigated whether hypoxia-induced activation of Hh signaling contributes to PDL-1 expression in cancer and whether it affects the anti-tumor function of activated lymphocytes. Hypoxia augmented PDL-1 expression and inhibition of Hh signaling reduced PDL-1 expression under hypoxia. When activated lymphocytes were cocultured with cancers treated with a Hh inhibitor, activated lymphocyte cell numbers increased under hypoxia. In contrast, this increase was abrogated when cancer cells were treated with a PDL-1 neutralizing antibody. These results suggest that Hh signaling is one of regulatory pathways of PDL-1 expression under hypoxia and that inhibiting Hh signaling may induce lymphocyte anti-tumor activity.


Assuntos
Antígeno B7-H1/metabolismo , Proteínas Hedgehog/antagonistas & inibidores , Hipóxia/imunologia , Linfócitos/imunologia , Neoplasias/imunologia , Antígenos de Neoplasias/imunologia , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Técnicas de Cocultura , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hipóxia/terapia , Ativação Linfocitária , Terapia de Alvo Molecular , Neoplasias/terapia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor Smoothened/genética , Receptor Smoothened/metabolismo , Transativadores , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Alcaloides de Veratrum/farmacologia , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
11.
Anticancer Res ; 36(8): 3945-52, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27466498

RESUMO

Hedgehog signaling is activated in pancreatic cancer and could be a therapeutic target. We previously demonstrated that recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and mastermind-like 3 (MAML3) contribute to the hypoxia-induced up-regulation of Smoothened (SMO) transcription. We have also shown that protein-bound polysaccharide-K (PSK) could be effective for refractory pancreatic cancer that down-regulates SMO transcription under hypoxia. In this study, we evaluated whether the anticancer mechanism of PSK involves inhibiting RBPJ and MAML3 expression under hypoxia. PSK reduced SMO, MAML3 and RBPJ expression in pancreatic cancer cells under hypoxia. PSK also blocked RBPJ-induced invasiveness under hypoxia by inhibiting matrix metalloproteinase expression. Lastly, we showed that PSK attenuated RBPJ-induced proliferation both in vitro and in vivo. These results suggest that PSK suppresses Hedgehog signaling through down-regulation of MAML3 and RBPJ transcription under hypoxia, inhibiting the induction of a malignant phenotype in pancreatic cancer. Our results may lead to development of new treatments for refractory pancreatic cancer using PSK as a Hedgehog inhibitor.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Proteínas Fúngicas/administração & dosagem , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/biossíntese , Proteínas Nucleares/biossíntese , Neoplasias Pancreáticas/tratamento farmacológico , Polissacarídeos/administração & dosagem , Fatores de Transcrição/biossíntese , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/genética , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Camundongos , Invasividade Neoplásica/genética , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Transdução de Sinais/efeitos dos fármacos , Transativadores , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Int J Surg Case Rep ; 25: 16-20, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27289170

RESUMO

INTRODUCTION: Duplication of the alimentary tract is a relatively uncommon congenital anomaly and most cases occur in childhood. Malignancy arising from a gastric duplication cyst is extremely rare. We herein report a very rare case of malignant transformation of a gastric duplication cyst. PRESENTATION OF CASE: A 47-year-old asymptomatic Japanese woman was referred to our hospital with a large abdominal mass adhered to the stomach. Since there was a possibility of malignant transformation, complete resection of the cyst and segmental gastrectomy without regional lymphadenectomy were performed. DISCUSSION: To our knowledge, this is the 2nd report of asymptomatic adenocarcinoma arising from a gastric duplication cyst in the English-language literature. Unfortunately, the patient developed peritoneal metastasis and ascites seven months after the surgery and died. CONCLUSION: From our long-term follow-up experience of this gastric duplication cyst, we recommend making accurate diagnosis as soon as possible with biopsy using endoscopic ultrasonography. When the disease is diagnosed as malignant, we recommend gastrectomy with lymphadenectomy. Even if the disease is diagnosed as benign, we recommend close observation with imaging modalities.

13.
Anticancer Res ; 36(2): 653-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26851020

RESUMO

Development of an effective therapeutic strategy for refractory pancreatic cancer must consider whether chemosensitivity can be induced in chemoresistant cells. We established a pancreatic cancer stem cell-rich cell line using TIG-1 feeder cells and leukemia inhibitory factor (LIF)-rich SNL76/7 conditioned medium. We generated a cell line, namely YNPC031312-B, following isolation of cells from the malignant ascites of a patient with gemcitabine-resistant pancreatic cancer. A YNPC031312-B-Hypoxia cell line was established by maintaining YNPC031312-B cells under tumor-like hypoxic conditions (1% O2). Both cell lines exhibited a pancreatic cancer stem cell phenotype: YNPC031312-B cells were CD24(+)CD44(-)CD133(+)epithelial cell adhesion molecule (EpCAM)(+)alkaline phosphatase(+)Octamer-binding transcription factor (OCT)3/4+and YNPC031312-B-Hypoxia cells were CD24(+)CD44(+)CD133(+)EpCAM(+). YNPC031312-B-Hypoxia cells were larger, had superior migratory ability, and higher gemcitabine sensitivity compared to YNPC031312-B cells. The use of LIF or other factors with similar bioactivity under hypoxic conditions may contribute to the phenotypic change to gemcitabine sensitivity. Our results may aid development of new therapeutic strategies targeting refractory pancreatic cancer.


Assuntos
Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Hipóxia , Fator Inibidor de Leucemia/metabolismo , Complexo Mediador/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Antimetabólitos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Western Blotting , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Técnicas Imunoenzimáticas , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Células Tumorais Cultivadas
14.
Anticancer Res ; 36(2): 673-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26851023

RESUMO

Antigen-presenting cells (APCs) play a pivotal role in cancer immunotherapy. APCs in conventionally used flasks are harvested by enzymatic digestion or cell scraping for application to cancer immunotherapy. However, these methods may impair functional molecules expressed on the APC surface and reduce their effects in cancer immunotherapy. Recently, we found that APCs could be harvested by shaking at 4°C in flasks coated with poly[N-p-vinylbenzyl-O-2-acetoamide-2-deoxy-ß-D-glucopyranosyl-(1→4)-2-acetoamide-2-deoxy-ß-D-gluconamide] (PVGlcNAc) or a copolymer consisting of sulfonylurea (SU) linked to poly[N-p-vinyl-benzyl-4-O-ß-D-galactopyranosyl-D-gluconamide] [P(VLA-co-SU)]. In the present study, we compared the functions of cytotoxic T-lymphocytes (CTLs) induced by APCs generated in PVGlcNAc- or P(VLA-co-SU)-coated flasks and conventional flasks. APCs from PVGlcNAc- or P(VLA-co-SU)-coated flasks showed higher expression of cluster of differentiation (CD)80/86, CD11c, and major histocompatibility complex class II alloantigen I-A(d), and higher cytotoxicity than APCs from conventional flasks. These results suggest that the use of PVGlcNAc- or P(VLA-co-SU)-coated flasks is optimal for harvesting APCs. The generated APCs also have a higher antigen-presenting ability compared to those generated in conventional flasks. Our results may contribute to the development of effective cancer immunotherapies.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Separação Celular/métodos , Dissacarídeos/metabolismo , Lactose/análogos & derivados , Teste de Cultura Mista de Linfócitos , Poliestirenos/metabolismo , Linfócitos T Citotóxicos/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Antígeno B7-1/metabolismo , Antígeno B7-2/metabolismo , Biomarcadores/metabolismo , Antígeno CD11c/metabolismo , Células Cultivadas , Técnicas de Cocultura , Citotoxicidade Imunológica , Antígenos de Histocompatibilidade Classe II/metabolismo , Lactose/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Fenótipo , Polivinil/metabolismo , Linfócitos T Citotóxicos/imunologia
15.
Cancer Lett ; 371(2): 143-50, 2016 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-26655998

RESUMO

We previously demonstrated that Hedgehog (Hh) signaling is activated under hypoxia through upregulation of transcription of Smoothened (SMO) gene. However, the mechanism of hypoxia-induced activation of SMO transcription remains unclear. In the analysis of altered expressions of genes related to Hh signaling between under normoxia and hypoxia by DNA microarray analysis, we picked up 2 genes, a transcriptional regulator, recombination signal binding protein for immunoglobulin-kappa-J region (RBPJ) and a transcriptional co-activator, Mastermind-like 3 (MAML3). Expressions of SMO, MAML3 and RBPJ were increased under hypoxia in pancreatic ductal adenocarcinoma cells (PDAC). RBPJ and MAML3 inhibition under hypoxia led to decreased SMO and GLI1 expressions, whereas SMO expression in MAML3-inhibited and RBPJ-inhibited cells under normoxia showed no change. However, overexpression of RBPJ under normoxia led to increased SMO expression. Additionally, cells knocked down for MAML3 and RBPJ inhibition under hypoxia showed decreased invasiveness through matrix metalloproteinase-2 suppression and decreased proliferation. Xenograft mouse models showed that MAML3 and RBPJ knockdown inhibited tumorigenicity and tumor volume. Our results suggest that hypoxia promotes SMO transcription through upregulation of MAML3 and RBPJ to induce proliferation, invasiveness and tumorigenesis in pancreatic cancer.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Proteínas Nucleares/metabolismo , Oxigênio/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Fatores de Transcrição/metabolismo , Transcrição Genética , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patologia , Hipóxia Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Xenoenxertos , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Proteínas Nucleares/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Interferência de RNA , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Receptor Smoothened , Fatores de Tempo , Transativadores , Fatores de Transcrição/genética , Ativação Transcricional , Transfecção , Carga Tumoral , Regulação para Cima
16.
Anticancer Res ; 31(7): 2419-24, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21873153

RESUMO

Cytotoxic γδ T-cells recognize antigens directly without the need for antigen processing and presentation. Recently, it was reported that they can also present antigens and proliferate in vitro. In this study, we examined whether γδ T-cells isolated from patients with advanced cancer can be used for immunotherapy. Twenty-two inoperable patients with multiple cancer metastases were enrolled in the study. There was no significant difference in the ratio of γδ T-cells within the peripheral blood mononuclear cell population isolated from healthy volunteers and cancer patients. γδ T-Cells isolated from cancer patients were expanded 2- to 5-fold using zoledronic acid or 2-methyl-3butenyl-1-pyrophosphate and IL-2. Autologous CD8(+) T-cells co-cultured with expanded CEA peptide-pulsed γδ T-cells from cancer patients with HLA-A24 killed more CEA-positive HLA-A24-matched gastric cancer cells and secreted higher levels of interferon-γ. These results suggest that γδ T-cells from cancer patients may be ideal candidates for adoptive immunotherapy.


Assuntos
Antígeno Carcinoembrionário/imunologia , Imunoterapia Adotiva , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apresentação do Antígeno , Separação Celular , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Difosfonatos/farmacologia , Feminino , Antígenos HLA-A/imunologia , Antígeno HLA-A24 , Humanos , Imidazóis/farmacologia , Interferon gama/metabolismo , Interleucina-2/farmacologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Compostos Organofosforados/farmacologia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Neoplasias Gástricas/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Ácido Zoledrônico
17.
Cancer Lett ; 306(2): 151-60, 2011 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-21429662

RESUMO

Paclitaxel, one of key drugs to treat a wide range of malignancies, exhibits relative low sensitivity for colorectal cancer. The present study was to examine whether and how phosphatidylinositol 3'-kinase (PI3K) signals affect the sensitivity of colorectal cancer to paclitaxel. Four colorectal cancer cell lines were exposed to paclitaxel in the presence of PI3K signal inhibitors, such as LY294002, siRNA for Akt, or rapamycin, with or without MAPK inhibitor, PD98059. Cell viability and apoptosis were determined by MTT assay, cell cycle analysis in flow cytometer and Hoechst nuclear staining. To analyze the PI3K activity, the expression in phosphorylated Akt and downstream effectors of p70S6 kinase (S6K) were evaluated by Western blot analysis. Paclitaxel alone (5-10 nM) did not induce the apoptosis in all four cell lines. Although LY294002 alone did not affect the cell viability, it suppressed the Akt and S6K activities and induced the sub-G1 arrest/apoptosis when paclitaxel was co-administered, as well as the Akt siRNA and rapamycin did. Simultaneous blockade of PI3K and MAPK pathways more suppressed the S6K activity and further increased the apoptosis. In conclusion, PI3K is involved in low susceptibility of colorectal cancer to paclitaxel and dual PI3K/MAPK targeting agents may evolve a new paclitaxel-based chemotherapy for colorectal cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/enzimologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Paclitaxel/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Apoptose/efeitos dos fármacos , Western Blotting , Proliferação de Células/efeitos dos fármacos , Cromonas/farmacologia , Neoplasias Colorretais/patologia , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Citometria de Fluxo , Humanos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas
18.
Anticancer Res ; 30(9): 3747-57, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20944164

RESUMO

BACKGROUND: This study analysed the contribution of malignant-effusion derived exosomes (Eff-Ex) to the number and function of regulatory T-cells (Treg) in malignant effusions. PATIENTS AND METHODS: Eff-Ex were collected from the malignant effusions of 24 cancer patients. Peripheral blood mononuclear cells (PBMCs) were co-cultured with different concentrations of Eff-Ex. FOXP3(+) CD4(+) T-cells were defined as Treg. Expression of molecules on Eff-Ex was determined by flow cytometric analysis. RESULTS: The number of Treg decreased daily in parallel with the FOXP3 expression level. Purified Eff-Ex prevented the decreases in both Treg number and FOXP3 expression levels in a dose-dependent manner. Pre-treatment of Eff-Ex with a neutralizing mAb against TGF-ß1 significantly reduced these effects and the suppressive function of Treg. CONCLUSION: Elimination of Eff-Ex or control of Eff-Ex expressing TGF-ß1 may be new therapeutic strategies in immunotherapy for advanced cancer patients with malignant effusions.


Assuntos
Exossomos/imunologia , Neoplasias/imunologia , Derrame Pleural Maligno/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta1/imunologia , Separação Celular , Técnicas de Cocultura , Ensaio de Imunoadsorção Enzimática , Exossomos/metabolismo , Citometria de Fluxo , Humanos , Immunoblotting , Leucócitos Mononucleares/imunologia , Neoplasias/metabolismo , Derrame Pleural Maligno/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
19.
Cancer Immunol Immunother ; 59(5): 675-86, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-19862523

RESUMO

Recently, it was reported that Hh signaling is activated in tumor stromal cells but not in tumor cells themselves and that stromal cells may play a role in the proliferation of cancer cells. This suggests the possibility that stromal cells have an important role in the proliferation of tumor cells that may be mediated through Hh signaling. In this report, we present for the first time that inflammation-stimulated monocytes produce Shh through activation of the NF-kappaB signaling pathway, and that the Shh produced promotes the proliferation of pancreatic cancer cells in a paracrine manner through Hh signaling.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/biossíntese , Monócitos/metabolismo , NF-kappa B/metabolismo , Neoplasias Pancreáticas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Ensaio de Desvio de Mobilidade Eletroforética , Imunofluorescência , Expressão Gênica , Humanos , Immunoblotting , Imuno-Histoquímica , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Transdução Genética
20.
Eur J Immunol ; 40(1): 197-203, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19902430

RESUMO

CD25+ FOXP3+CD4+ T cells (Treg) have been considered to play an important role in immune tolerance against several tumor antigens. It has also been indicated that high-level expression of FOXP3 (FOXP3high) is sufficient to confer suppressive activity to normal non-Treg. Here, we showed for the first time that vascular endothelial growth factor receptor 2 (VEGFR2) is selectively expressed by FOXP3high but not FOXP3low Treg. Such VEGFR2+ Treg exist in several tissues including PBMC and malignant effusion-derived lymphocytes. In conclusion, VEGFR2 may be a novel target for controlling Treg with highly suppressive function.


Assuntos
Fatores de Transcrição Forkhead/imunologia , Linfócitos T Reguladores/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Fator de Crescimento Transformador beta/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...