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1.
Cancer Sci ; 111(3): 817-825, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925976

RESUMO

Recent studies have reported that tumor-infiltrating mast cells (TIM) play an important role in tumor regression, but the effect of TIM in gallbladder cancer (GBC) remains unclear. The present study aims to investigate the prognostic value of TIM in GBC patients and its responsiveness to gemcitabine-based adjuvant chemotherapy (ACT). A total of 298 GBC patients from Zhongshan Hospital were recruited for this study. TIM infiltration was measured by immunohistochemical staining. Accumulation of TIM is significantly associated with prolonged overall survival in GBC patients. The benefit from gemcitabine-based ACT was superior among patients with high infiltration of TIM with GBC. Multivariate analysis identified TIM infiltration as an independent prognostic factor for overall survival. A heatmap showed that TIM-activated gene signatures were positively correlated with CD8+ T cells' gene signatures. Gene set enrichment analysis (GSEA) suggested that TIM was related to multiple T cell-related processes and signaling pathways, including the interferon gamma signaling pathway and the leukocyte migration signaling pathway. It was confirmed that CD8+ T cell infiltration was positively correlated with high TIM infiltration in tissue microarray (TMA), suggesting that TIM infiltration was linked to the immune surveillance in GBC. TIM can be used as an independent prognostic factor and a predictor of therapeutic response of gemcitabine-based ACT in GBC patients, which may mediate immune surveillance by recruiting and activating CD8+ T cells in GBC.


Assuntos
Neoplasias da Vesícula Biliar/patologia , Linfócitos do Interstício Tumoral/patologia , Mastócitos/patologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Quimioterapia Adjuvante/métodos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Humanos , Interferon gama/metabolismo , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Pessoa de Meia-Idade , Prognóstico , Transdução de Sinais/efeitos dos fármacos
2.
Bull Cancer ; 107(1): 48-53, 2020 Jan.
Artigo em Francês | MEDLINE | ID: mdl-31980143

RESUMO

The adjuvant treatment of biliary tract cancers has long been poorly defined. In recent years, randomized trial data have been used to define treatment references. The French Prodige 12 and Japanese BCAT trials have not demonstrated any benefit of adjuvant chemotherapy. The English BILCAP trial tested adjuvant capecitabine for six months at the usual dose in a randomized, controlled-only trial involving nearly 450 patients. Although the results in intention to treat were borderline significant on the primary endpoint, overall survival (P=0.097), sensitivity analyzes adjusted for prognostic factors and relapse-free survival analyses are clearly positive. The absolute benefit of +5%/+10% overall survival, combined with low and known toxicity profile, leads to recommending treatment for any cancer of the resected bile ducts (with the exception of gallbladder cancer pT1N0).


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Capecitabina/administração & dosagem , Quimioterapia Adjuvante , Colangiocarcinoma/patologia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Humanos , Análise de Intenção de Tratamento , Radioterapia Adjuvante , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
3.
Gulf J Oncolog ; 1(31): 14-20, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31591986

RESUMO

BACKGROUND: The proposed role of Vitamin D Receptor (VDR) in various cancers underscores the importance of vitamin D compounds as a novel therapeutic agent in the prevention of occurrence and progression of cancer. Vitamin D Receptor (VDR) expression in gallbladder cancer (GBC) has not been widely analyzed yet. In the present study, an attempt has been made to study VDR expression and the role of vitamin D supplementation during palliative chemotherapy in advanced GBC. METHODS: Expression of VDR was analyzed in benign cholecystectomy specimens (n=11), and GBC specimens (n=32). Thirty patients with advanced GBC were subjected to palliative chemotherapy. Out of them, 19 patients were supplemented with Vitamin D and 11 patients were not. Effect of vitamin D supplementation on the change in vitamin D scores and improvement in quality of life (QOL) were assessed by EORTC QLQ c30 version 3.0. and the difference in outcome between the two groups were studied. RESULTS: Mean intensity, staining and immunoreactivity scores signifying VDR expression were decreased in the studied population of GBC when compared to benign disease. In palliative setting, vitamin D supplementation significantly improved the quality of life. However, the effect on disease- specific survival, although present, was not statistically significant. CONCLUSION: VDR expression downregulation is associated with increasing malignant process. Vitamin D may act as sensitizers for tumor cell death besides downplaying potential harmful effects of palliative chemotherapy thus reducing the associated morbidity. This study assumes importance as the first clinical study reporting VDR expression in GBC tissue and the possible role of vitamin D supplementation in patients with advanced disease.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Receptores de Calcitriol/metabolismo , Vitamina D/metabolismo , Adulto , Suplementos Nutricionais/análise , Progressão da Doença , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Taxa de Sobrevida
4.
Am J Case Rep ; 20: 1558-1561, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31644525

RESUMO

BACKGROUND Poorly cohesive cell carcinoma of the gallbladder is extremely rare. CASE REPORT Here we present a case of a 46-year-old male with the clinical diagnosis of acute cholecystitis. The ultrasound showed gallbladder wall thickening and multiple stones. Cholecystectomy was performed, and the gross examination revealed linitis plastica-like thickening of the gallbladder wall. The microscopic examination revealed diffuse infiltration by a poorly differentiated tumor with signet rings. Another component with insular growth pattern and salt-and-pepper nuclei was present. Immunohistochemical findings were consistent with poorly cohesive cell carcinoma of the gallbladder. Imaging studies revealed regional lymph nodes involvement, in addition to peritoneal and liver metastases. The patient was given chemotherapy, and there was no evidence of disease progression at 4 months post-operation. CONCLUSIONS This case supported that all cholecystectomy specimens must be examined. In addition, although poorly cohesive cell carcinoma was reported to be aggressive, the present case showed a protracted clinical course; this pointed to the need for early clinicoradiological suspicion. This is the first case of poorly cohesive cell carcinoma of the gallbladder with a neuroendocrine-like morphology that mimics mixed adenoneuroendocrine carcinoma. Immunohistochemistry is invaluable in such a scenario.


Assuntos
Carcinoma de Células em Anel de Sinete/diagnóstico , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias Hepáticas/secundário , Neoplasias Peritoneais/secundário , Carcinoma Neuroendócrino/patologia , Carcinoma de Células em Anel de Sinete/tratamento farmacológico , Colecistectomia , Colecistite Aguda/diagnóstico , Colecistite Aguda/cirurgia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias Peritoneais/diagnóstico por imagem , Neoplasias Peritoneais/tratamento farmacológico , Coloração e Rotulagem
5.
Chin Clin Oncol ; 8(4): 44, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31484490

RESUMO

Gallbladder cancer is an aggressive cancer that continues to be an important health care issue in certain regions of the world such as Southeast Asia and Latin America. Most patients are diagnosed at an advanced, unresectable stage and systemic therapy is their only option. Gallbladder cancer patients have traditionally been included in clinical trials for biliary tract cancer. Thus, systemic chemotherapy options for this cancer are similar to those for cholangiocarcinoma, including gemcitabine and cisplatin in the first line and FOLFOX in the second-line setting. Ongoing phase III clinical trials may change the systemic therapy paradigm for this cancer. Molecular profiling has indicated important genetic differences between gallbladder cancer and cholangio-carcinoma, which affects choice of targeted therapy. Her2/neu amplification, PIK3CA mutations and DNA repair genetic aberrations are relatively frequent and represent actionable targets for this cancer.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Humanos
6.
Chin Clin Oncol ; 8(4): 43, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31431035

RESUMO

Gallbladder cancer is the most common malignant cancer of the biliary tract and is distinct from other forms of biliary tract cancer in several of its risk factors and molecular aberrations. Locally advanced, unresectable and metastatic gallbladder cancer is associated with a poor prognosis and systemic chemotherapy is the main form of treatment available to these patients. This review is focused on the available evidence supporting the use of first-line chemotherapy specifically for gallbladder cancer. Numerous non-randomised studies have been published and certain forms of monotherapy and combination therapy can both lead to response rates (RRs) of approximately 40% and may prove to affect overall survival, most notably a recent phase II study of triplet therapy with gemcitabine, cisplatin and nab-paclitaxel. There are however relatively few randomised phases II and III studies on which to base recommendations, but they do demonstrate significant survival advantages of gemcitabine-containing combination therapies over best supportive care and chemotherapeutic monotherapy. The ABC-02 trial established the combination of gemcitabine and cisplatin as standard therapy in 2010, but more recent phase III studies reported as conference papers may support alternative, gemcitabine-containing doublet chemotherapy regimens such as gemcitabine in combination with oxaliplatin or S1. This manuscript also highlights the available data from studies examining maintenance chemotherapy, biomarkers, neoadjuvant therapy and second line studies in gallbladder cancer; unfortunately, there is insufficient evidence to make recommendations in these regards. The prognosis for unresectable and metastatic gallbladder cancer remains poor, and biomarkers for stratifying patients to particular first line therapies are not defined. This might be improved by gallbladder cancer specific analysis and reporting, and making histological primary specific data available publicly for further analysis.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Terapia Neoadjuvante/métodos , Feminino , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino
7.
Cancer Sci ; 110(8): 2493-2506, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215139

RESUMO

Gallbladder cancer (GBC) is the most common malignancy of the bile duct and has a high mortality rate. Here, we demonstrated that BRD4 inhibitor JQ1 and histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) synergistically inhibited the GBC cells in vitro and in vivo. Our results showed that cotreatment with JQ1 and SAHA significantly inhibited proliferation, cell viability and metastasis, and induced apoptosis and G2/M arrest in GBC cells, with only minor effects in benign cells. In vivo, tumor volumes and weights of GBC xenograft models were significantly decreased after treatment with JQ1 or SAHA; meanwhile, the cotreatment showed the strongest effect. Further study indicated that the above anticancer effects was associated with the downregulation of BRD4 and suppression of PI3K/AKT and MAPK/ERK pathways. These findings highlight JQ1 and SAHA as potential therapeutic agents and their combination as a promising therapeutic strategy for GBC.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Proteínas Nucleares/antagonistas & inibidores , Fatores de Transcrição/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Neoplasias da Vesícula Biliar/patologia , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Nus , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/patologia , Vorinostat/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
8.
Updates Surg ; 71(2): 217-225, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31254234

RESUMO

At MSKCC, over 50% of the patients presenting with gallbladder cancer have been diagnosed incidentally following elective cholecystectomy for presumed benign disease. While traditional management of incidental gallbladder cancer (IGBC) dictates re-resection with the ultimate goal of achieving cure, surgical decision-making must take into account that this malignancy is characterized by poor tumor biology with frequent distant recurrence. Since early and frequent distant recurrence is the most common cause of surgical failure, the surgical oncologist's goal should be to selectively re-resect only those patients most likely to benefit from an operation. The astute surgeon recognizes the high-risk patients who likely have micrometastatic disease at the time of diagnosis and alters the treatment sequence, delivering neoadjuvant chemotherapy. This strategy acts as a selection tool, as those progressing at distant sites during therapy are spared the morbidity and mortality of surgery and furthermore has the potential to treat micrometastatic disease. However, a chemotherapy first approach must be applied selectively since a poor response risks local progression to unresectability and a decrease in functional status that comes from the toxicities of dual agent chemotherapy that can impair surgical candidacy. To balance these risks and benefits, two other criteria for a neoadjuvant approach must be met: i) reliable identification of those patients who are at high risk of distant recurrence and who are, therefore, most likely to benefit from a systemic therapy first approach and ii) availability of effective chemotherapy options. In this review, we will outline the data and judgement we use to select a treatment sequence at our institution.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Terapia Neoadjuvante , Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Ensaios Clínicos Fase III como Assunto , Neoplasias da Vesícula Biliar/diagnóstico , Neoplasias da Vesícula Biliar/patologia , Humanos , Achados Incidentais , Estadiamento de Neoplasias , Neoplasia Residual , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , Medição de Risco
9.
Gan To Kagaku Ryoho ; 46(4): 775-777, 2019 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-31164532

RESUMO

A 47-year-old woman who had unresectable locally advanced gallbladder cancer(GBC)accompanied with liverinvasion, duodenum invasion, transverse colon invasion, and surrounding lymphatic metastasis received 5 courses of chemotherapy with gemcitabine plus cisplatin. Afterthe chemotherapy, imaging showed down-staging of the GBC, indicating tumor shrinkage. The initial laparoscopic examination revealed no peritoneal seeding or distant metastasis. Subsequently, we performed cholecystectomy with a partial hepatectomy at the gallbladder bed. Malignant findings were not observed in the histopathological examination and the pathological diagnosis was CR with pT0N0M0, Stage 0. The patient was discharged on day 11 after the operation. There has been no recurrence at 14 months after surgery. Although the prognosis of advanced GBC with local invasion is generally poor, chemotherapy might be an effective treatment for patients with initially unresectable locally advanced gallbladder carcinoma.


Assuntos
Neoplasias da Vesícula Biliar , Antineoplásicos/uso terapêutico , Colecistectomia , Cisplatino/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Hepatectomia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia
10.
Acta Biochim Biophys Sin (Shanghai) ; 51(6): 607-614, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31074773

RESUMO

Gallbladder carcinoma (GBC) is the most common and aggressive cancer of the biliary tract. Liensinine has been proved to have hypotensive effect. However, the effect of liensinine on GBC is still unknown. The aim of this study is to investigate the effect and mechanism of liensinine in human GBC cells. Cell viability assay and colony formation assay were performed to assess cell growth and proliferation. Flow cytometry analysis was used to investigate cell cycle apoptosis in vitro. Hoechst 33342 staining was also used to evaluate cell apoptosis. Western blot analysis was used to determine the expression of proteins corresponding to the related cell cycle and apoptosis. The effect of liensinine treatment in vivo was experimented with xenografted tumors. We found that liensinine significantly inhibited the growth of GBC cells both in vivo and in vitro. In vitro, cell growth and proliferation were significantly suppressed by liensinine in a dose- and time-dependent manner. In vivo, liensinine inhibited tumor growth. Liensinine could induce GBC cells G2/M phase arrest by up-regulating the levels of Cyclin B1 and CDK1 proteins. Liensinine also affected GBC cell cycle progression and induced apoptosis by down-regulating phosphorylated protein kinase B (AKT), phosphorylated protein kinase B (p-AKT), phosphatidylinositol 3-kinase (PI3K), and Zinc finger X-chromosomal protein (ZFX) proteins. Liensinine induced G2/M arrest and apoptosis in gallbladder cancer, suggesting that liensinine might represent a novel and effective agent against gallbladder cancer.


Assuntos
Apoptose/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Neoplasias da Vesícula Biliar/tratamento farmacológico , Isoquinolinas/farmacologia , Fenóis/farmacologia , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Isoquinolinas/química , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Nelumbo/química , Fenóis/química , Fosfatidilinositol 3-Quinases/metabolismo , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/metabolismo
11.
Cir Cir ; 87(3): 313-320, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31135772

RESUMO

Objective: To describe the results of the extension of surgical treatment and adjuvant chemotherapy (ACT) in incidental gallbladder cancer (CVB), in terms of postoperative morbidity (POM) and 5-year overall survival rate. Method: Case series of patients operated on for incidental GBC in Clínica Mayor, Temuco, Chile (2001-2016). All cases were treated by partial hepatectomy (segments IVb and V), and regional lymphadenectomy. The minimum follow-up time was 12 months. Outcome variables were MPO and 5-year overall survival rate. Other variables of interest were: infiltration depth in vesicular wall, lymph nodes and resected liver; surgical time, need for reoperation, hospital stay, follow-up and mortality. Descriptive statistics were applied as well as bivariate analysis applying Fisher's exact and t-test and non-parametrical tests for continuous variables and Kaplan Meier curves. Results: The series was composed of 50 patients, whose average age was 58.6 ± 9.6 years; 68.0% of which were women. The mean surgical time and hospital stay were 224 ± 93 min (90 to 480) and 6.9 ± 2.9 days (4 to 20), respectively. POM was 28.0%. 5-year overall survival rate was 47%. There were no reoperations or mortality. Conclusions: The results verified in terms of POM and 5-year overall survival rate are similar to previously reported series.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/cirurgia , Idoso , Quimioterapia Adjuvante , Feminino , Neoplasias da Vesícula Biliar/mortalidade , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Taxa de Sobrevida , Resultado do Tratamento
12.
J Int Med Res ; 47(6): 2768-2777, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31106632

RESUMO

Gallbladder carcinoma (GBC) is a rare and highly aggressive tumor. Early diagnosis is challenging, which results in a poor prognosis using systemic therapy. Recent studies have identified a subset of GBC patients with HER2 gene (ERBB2) amplification that could benefit from HER2-targeted therapy. Here, we report one patient with recurrent metachronous GBC with metastasis, who received the combination of trastuzumab and lapatinib. This approach achieved a partial response for both the brain and the lung metastases. This study demonstrated that HER2 inhibition is a promising therapeutic strategy for GBC with HER2 amplification and, combined with lapatinib, it can effectively target brain metastasis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Vesícula Biliar/tratamento farmacológico , Amplificação de Genes , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundário , Feminino , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/patologia , Humanos , Lapatinib/administração & dosagem , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Trastuzumab/administração & dosagem
13.
Biomed Res Int ; 2019: 9205851, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31019975

RESUMO

The effects of standard clinical therapies including surgery and chemotherapy are poor in advanced gallbladder cancer (GBC). There are a few reported cases of human epidermal growth factor receptor 2 (HER2)-positive GBC that responded well to trastuzumab. But trastuzumab has not yet been used to treat HER2-negative GBC. In this study, we investigated the cytotoxic effects of different combined therapies with trastuzumab and gemcitabine and/or 5-fluorouracil on HER2-negative GBC cell lines in vitro and in vivo. Trastuzumab alone showed almost no cytotoxicity to GBC cells with originally low HER2 gene amplification. Sequential therapy with chemotherapy followed by trastuzumab showed superiority over reverse sequential chemotherapy (P<0.05), concurrent combined chemotherapy (P<0.05), chemotherapy alone (P<0.05), and trastuzumab alone (P<0.05) in terms of cytotoxicity. Sequential therapy with chemotherapy followed by trastuzumab nearly completely inhibited cell viability in HER2-negative GBC cells. Similar results were observed with regard to apoptosis. Western blot analysis showed that gemcitabine/5-fluorouracil increased the expressions of total and phosphorylated forms of HER2, thus enhancing the cytotoxicity of trastuzumab. In vivo study verified the results of in vitro study by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay and immunohistochemical analysis. Moreover, not only the lightest tumor bearing but also the best survival state was detected in sequential therapy with chemotherapy followed by trastuzumab group compared with other groups. Our in vivo and in vitro data suggest that sequential therapy with gemcitabine/5-fluorouracil followed by trastuzumab represents a novel and promising therapeutic strategy against HER2-negative GBC. The upregulation of phosphorylated HER2 and phosphorylated-AKT induced by gemcitabine/5-fluorouracil treatment shows that HER2/AKT pathway is triggered.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Vesícula Biliar , Animais , Apoptose/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Feminino , Fluoruracila/farmacologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Mol Cancer ; 18(1): 82, 2019 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-30953511

RESUMO

BACKGROUND: Gallbladder cancer is the most common biliary tract malignancy and not sensitive to chemotherapy. Autophagy is an important factor prolonging the survival of cancer cells under chemotherapeutic stress. We aimed to investigate the role of long non-coding RNAs (lncRNAs) in autophagy and chemoresistance of gallbladder cancer cells. METHODS: We established doxorubicin (Dox)-resistant gallbladder cancer cells and used microarray analysis to compare the expression profiles of lncRNAs in Dox-resistant gallbladder cancer cells and their parental cells. Knockdown or exogenous expression of lncRNA combined with in vitro and in vivo assays were performed to prove the functional significance of lncRNA. The effects of lncRNA on autophagy were assessed by stubRFP-sensGFP-LC3 and western blot. We used RNA pull-down and mass spectrometry analysis to identify the target proteins of lncRNA. RESULTS: The drug-resistant property of gallbladder cancer cells is related to their enhanced autophagic activity. And we found a lncRNA ENST00000425894 termed gallbladder cancer drug resistance-associated lncRNA1 (GBCDRlnc1) that serves as a critical regulator in gallbladder cancer chemoresistance. Furthermore, we discovered that GBCDRlnc1 is upregulated in gallbladder cancer tissues. Knockdown of GBCDRlnc1, via inhibiting autophagy at initial stage, enhanced the sensitivity of Dox-resistant gallbladder cancer cells to Dox in vitro and in vivo. Mechanically, we identified that GBCDRlnc1 interacts with phosphoglycerate kinase 1 and inhibits its ubiquitination in Dox-resistant gallbladder cancer cells, which leads to the down-regulation of autophagy initiator ATG5-ATG12 conjugate. CONCLUSIONS: Our findings established that the chemoresistant driver GBCDRlnc1 might be a candidate therapeutic target for the treatment of advanced gallbladder cancer.


Assuntos
Autofagia/genética , Neoplasias da Vesícula Biliar/genética , Regulação Neoplásica da Expressão Gênica , Fosfoglicerato Quinase/genética , RNA Longo não Codificante/genética , Idoso , Animais , Antibióticos Antineoplásicos/farmacologia , Autofagia/efeitos dos fármacos , Proteína 12 Relacionada à Autofagia/genética , Proteína 12 Relacionada à Autofagia/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/metabolismo , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Fosfoglicerato Quinase/metabolismo , RNA Longo não Codificante/agonistas , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Redox Biol ; 22: 101149, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30822690

RESUMO

Gallbladder cancer (GBC) is a highly malignant bile duct cancer with poor prognosis characterized by its insensitivity to chemotherapy. Emerging evidence indicates that cytoprotective antioxidation is involved in drug resistance of various cancers; however, the underlying molecular mechanisms remain obscure. Here, we demonstrated that atypical protein kinase Cι (aPKCι) mediated reactive oxygen species (ROS) inhibition in a kinase-independent manner, which played a crucial role in tumorigenesis and chemoresistance. Mechanistically, we found that aPKCι facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) accumulation, nuclear translocation and activated its target genes by competing with Nrf2 for binding to Kelch-like ECH-associated protein 1 (Keap1) through a highly conserved DLL motif. In addition, the aPKCι-Keap1 interaction was required for antioxidant effect, cell growth and gemcitabine resistance in GBC. Importantly, we further confirmed that aPKCι was frequently upregulated and correlated with poor prognosis in patients with GBC. Collectively, our findings suggested that aPKCι positively modulated the Keap1-Nrf2 pathway to enhance GBC growth and gemcitabine resistance, implying that the aPKCι-Keap1-Nrf2 axis may be a potential approach to overcome the drug resistance for the treatment of GBC.


Assuntos
Transformação Celular Neoplásica/metabolismo , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Neoplasias da Vesícula Biliar/metabolismo , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteína Quinase C/metabolismo , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/farmacologia , Modelos Animais de Doenças , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/etiologia , Neoplasias da Vesícula Biliar/mortalidade , Técnicas de Silenciamento de Genes , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/química , Camundongos , Modelos Biológicos , Fator 2 Relacionado a NF-E2/química , Prognóstico , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
18.
BMC Cancer ; 19(1): 10, 2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30611225

RESUMO

BACKGROUND: Gallbladder cancer (GBC) is likely to be diagnosed at progressive stages and shows a very poor prognosis. Combination therapy with gemcitabine and cisplatin (GEMCIS) has been widely used as first-line palliative chemotherapy for advanced GBC. This study was designed to investigate the efficacy of GEMCIS and identify prognostic factors in patients with unresectable GBC. METHODS: Patients with GBC who were treated with GEMCIS from January 2008 to June 2017 in a single tertiary hospital were included. All cases of GBC were diagnosed by pathologic findings and extent of the tumour was assessed by imaging tests. Combination chemotherapy consisted of cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 intravenously on days 1 and 8 every 3 weeks. To determine factors affecting prognosis, Kaplan-Meier survival analysis, log-rank test and the Cox proportional hazard regression linear model were used. All variables with P < 0.1 in univariable analysis were included in the multivariable model. RESULTS: A total of 173 patients received a median of 5.3 ± 4.4 cycles of chemotherapy over 3.8 ± 3.9 months. Most of the patients (94.8%) were stage IVB at the time of diagnosis and the most common site of metastasis was the liver (42.8%). Disease control rate was 59.5%: 2 (1.2%) patients with complete response, 26 (15.0%) patients with partial response and 75 (43.4%) patients with stable disease. Overall survival (OS) and progression-free survival were 8.1 (95% confidence interval [CI], 7.1-10.2) and 5.6 (95% CI 4.5-6.8) months, respectively. Multivariable regression model indicated that metastasis to liver (hazard ratio [HR] = 1.63, 95% CI 1.11-2.40; P = 0.013), neutrophil-to-lymphocyte ratio (NLR) ≥3 (HR 1.65, 95% CI 1.09-2.49; P = 0.017), CEA ≥ 5 ng/mL (HR 1.50, 95% CI 1.02-2.19; P = 0.038), and CA19-9 ≥ 500 U/mL (HR 1.59, 95% CI 1.01-2.50; P = 0.043) were significantly associated with OS. CONCLUSIONS: GEMCIS demonstrated a high disease control rate in patients with unresectable GBC. Factors independently related to OS were metastasis to liver, NLR ≥ 3, CEA ≥ 5 ng/mL and CA19-9 ≥ 500 U/mL.


Assuntos
Antígeno CA-19-9/sangue , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Feminino , Neoplasias da Vesícula Biliar/sangue , Neoplasias da Vesícula Biliar/patologia , Humanos , Estimativa de Kaplan-Meier , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/patologia , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
19.
Int J Cancer ; 144(8): 2008-2019, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30304546

RESUMO

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Vesícula Biliar/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Adulto , Afatinib/farmacologia , Afatinib/uso terapêutico , Idoso , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Vesícula Biliar/patologia , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Oncol Rep ; 40(6): 3501-3510, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30272364

RESUMO

Hypoxia plays a crucial role in cancer development and progression. Overexpression of hypoxia-inducible factor-1α (HIF­1α) has been demonstrated in a hypoxic microenvironment in various tumor types. Metformin has been identified as an antitumor drug in various tumor types. However, its role in cellular migration in a hypoxic microenvironment, and the associated regulatory mechanism, have yet to be fully elucidated. The present study aimed to investigate the clinical significance of HIF­1α, and its biological role, in gallbladder cancer (GBC). Furthermore, the role of metformin in cellular migration, and its underlying mechanism in GBC, were also identified. Real­time quantitative polymerase chain reaction analysis and immunohistochemistry experiments revealed that HIF­1α was significantly upregulated in GBC tissues. HIF­1α overexpression was closely associated with lymph node metastasis and tumor­lymph node­metastasis (TNM) stages. HIF­1α was able to promote cell migration in a hypoxic microenvironment by overexpressing vascular endothelial growth factor (VEGF) in GBC­SD cells, an effect which was partly reversed by small­interfering RNA HIF­1α (siHIF­1α) and 2­methoxyestradiol. Further experiments demonstrated that metformin inhibited hypoxia­induced migration via HIF­1α/VEGF in vitro. In addition, metformin suppressed GBC growth and downregulated the expression of HIF­1α and VEGF in a GBC­SD cell xenograft model. Taken together, these results suggest that HIF­1α may contribute to tumor migration via the overexpression of VEGF in GBC, while metformin is able to inhibit tumor migration by targeting the HIF­1α/VEGF pathway.


Assuntos
Neoplasias da Vesícula Biliar/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metformina/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/metabolismo , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metformina/farmacologia , Estadiamento de Neoplasias , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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