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1.
Gut ; 71(1): 185-193, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33431577

RESUMO

OBJECTIVE: Intrahepatic cholangiocarcinoma (ICC)-a rare liver malignancy with limited therapeutic options-is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. DESIGN: We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. RESULTS: PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Fator de Crescimento Placentário/metabolismo , Animais , Anticorpos Monoclonais/farmacologia , Neoplasias dos Ductos Biliares/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Hipóxia/metabolismo , Camundongos , Fator de Crescimento Placentário/antagonistas & inibidores
2.
Int J Mol Sci ; 22(24)2021 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-34948304

RESUMO

Cholangiocarcinoma (CCA), an aggressive cancer of bile ducts, is a well-known chronic inflammation-related disease. The major impediment in CCA treatment is limited treatment options for advanced disease; hence, an alternative is urgently required. The role of CD147 on cytokine production has been observed in inflammation-related diseases, but not in CCA. Therefore, this study was focused on CD147-promoting proinflammatory cytokine production and functions. Proinflammatory cytokine profiles were compared between CD147 expressing CCA cells and CD147 knockout cells (CD147 KO). Three cytokines, namely interleukin (IL)-6, IL-8, and granulocyte-monocyte colony-stimulating factor (GM-CSF), were dramatically diminished in CD147 KO clones. The involvement of the CD147-related cytokines in CCA invasion was established. CD147-promoted IL-6, IL-8, and GM-CSF secretions were regulated by NF-κB nuclear translocation, Akt activation, and p38 phosphorylation. CD147-fostering IL-6 production was dependent on soluble CD147, CD147 homophilic interaction, and NF-κB function. The overexpression of specific genes in CCA tissues compared to normal counterparts emphasized the clinical importance of these molecules. Altogether, CD147-potentiated proinflammatory cytokine production leading to CCA cell invasion is shown for the first time in the current study. This suggests that modulation of CD147-related inflammation might be a promising choice for advanced CCA treatment.


Assuntos
Basigina/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Interleucina-6/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais/fisiologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Colangiocarcinoma/patologia , Citocinas/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Fosforilação/fisiologia
3.
Anticancer Res ; 41(10): 4917-4928, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593439

RESUMO

BACKGROUND/AIM: The functions of interleukin 33 (IL-33) in cholangiocarcinoma (CCA) are unclear. This study aimed to evaluate the roles of IL-33 in CCA progression. MATERIALS AND METHODS: The effect of intracellular IL-33 using shIL-33 knocked down KKU-055 (IL-33KD-KKU-055) compared to parental (Pa) KKU-055 and extracellular IL-33 using recombinant human IL-33 (rhIL-33) treatment on the proliferation and invasion of CCA cells grown in 3D cultures was studied. Relevant markers were determined by western blot or ELISA. RESULTS: IL-33KD-KKU-055 cells showed increased proliferation and invasion in 3D cultures compared to Pa-KKU-055 cells, with NF-κB and IL-6 up-regulation. Treatment with 2 ng/ml rhIL-33 promoted Pa-KKU-055 cell proliferation by inducing NF-κB and IL-6 expressions. Upon GSK-3ß inactivation and increased nuclear full-length IL-33 (flIL-33), 20 ng/ml rhIL-33 had no effect on proliferation. Both 2 and 20 ng/ml rhIL-33 induced proliferation and invasion of IL-33-negative KKU-213 cells in 3D cultures, as well as NF-κB and IL-6 up-regulation. CONCLUSION: Intracellular and extracellular IL-33 have distinct roles in the mechanisms of CCA progression.


Assuntos
Neoplasias dos Ductos Biliares/prevenção & controle , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/prevenção & controle , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glicogênio Sintase Quinase 3 beta/metabolismo , Interleucina-33/farmacologia , NF-kappa B/metabolismo , Apoptose , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Proliferação de Células , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Glicogênio Sintase Quinase 3 beta/genética , Humanos , NF-kappa B/genética , Invasividade Neoplásica , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Anticancer Res ; 41(10): 5249-5254, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593478

RESUMO

BACKGROUND: Bile duct adenomas (BDA) may be precursor lesions of small duct-type, including mass-forming type intrahepatic cholangiocarcinoma (ICC). CASE REPORT: A 68-year-old woman was transferred to our facility for the treatment of a liver tumor, possibly metastasized from a pancreatic neuroendocrine tumor. Finally, two liver tumors were resected and histopathologically diagnosed as "BDA" and "ICC with a BDA-like component". In the BDA-like component, the MUC6 positive rate was notably lower and the Ki-67 positive rate was higher than the other BDAs and ICC component, respectively. The doubling time of the tumor volume in BDA was very long but was shortened (1,510 and 719 days). Distinct enlargement of the tumor and appearance of enhancement through diagnostic imaging was useful in diagnosing the transformation from a BDA to an ICC. CONCLUSION: An "adenoma-carcinoma sequence" may exist in the transformation process from a BDA to an ICC.


Assuntos
Adenoma/patologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Neoplasias Hepáticas/secundário , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Adenoma/complicações , Adenoma/cirurgia , Idoso , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/complicações , Colangiocarcinoma/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/cirurgia , Tumores Neuroendócrinos/complicações , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/cirurgia , Prognóstico
5.
BMC Gastroenterol ; 21(1): 375, 2021 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645392

RESUMO

BACKGROUND: The prognostic nutritional index, a marker of nutritional status and systemic inflammation, is a known biomarker for various cancers. However, few studies have evaluated the predictive value of the prognostic nutritional index in patients with biliary tract cancer. Therefore, we investigated the prognostic significance of the prognostic nutritional index, and developed a risk-stratification system to identify prognostic factors in patients with biliary tract cancer. METHODS: Between July 2010 and March 2021, 117 patients with biliary tract cancer were recruited to this single-center, retrospective study. The relationship between clinicopathological variables, including the prognostic nutritional index, and overall survival was analyzed using univariate and multivariate analyses. A P < 0.05 was considered statistically significant. RESULTS: The median age was 75 (range 38-92) years. Thirty patients had intrahepatic cholangiocarcinoma; 29, gallbladder carcinoma; 27, distal cholangiocarcinoma; 17, ampullary carcinoma; and 13, perihilar cholangiocarcinoma. Curative (R0) resection was achieved in 99 patients. In univariate analysis, the prognostic nutritional index (< 42), lymph node metastasis, carbohydrate antigen 19-9 level (> 20 U/mL), preoperative cholangitis, tumor differentiation, operation time (≥ 360 min), and R1-2 resection were significant risk factors for overall survival. The prognostic nutritional index (P = 0.027), lymph node metastasis (P = 0.040), and tumor differentiation (P = 0.006) were independent prognostic factors in multivariate analysis. A combined score of the prognostic nutritional index and pathological findings outperformed each marker alone, in terms of discriminatory power. CONCLUSIONS: The prognostic nutritional index, lymph node metastasis, and tumor differentiation were independent prognostic factors after surgical resection in patients with biliary tract cancer. A combined prediction model using the prognostic nutritional index and pathological findings accurately predicted prognosis, and can be used as a novel prognostic factor in patients with biliary tract cancer.


Assuntos
Neoplasias dos Ductos Biliares , Neoplasias do Sistema Biliar , Colangiocarcinoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias do Sistema Biliar/patologia , Colangiocarcinoma/patologia , Colangiocarcinoma/cirurgia , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Avaliação Nutricional , Prognóstico , Estudos Retrospectivos
6.
Molecules ; 26(19)2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34641520

RESUMO

Immunotherapy harnessing immune functions is a promising strategy for cancer treatment. Tumor sensitization is one approach to enhance tumor cell susceptibility to immune cell cytotoxicity that can be used in combination with immunotherapy to achieve therapeutic efficiency. Cordycepin, a bioactive compound that can be extracted from some Cordyceps spp. has been reported to effectively inhibit tumor growth, however, the mechanism of its tumor sensitization activity that enhances immune cell cytotoxicity is unknown. In the present study, we investigated the potency of cordycepin to sensitize a lethal cancer, cholangiocarcinoma (CCA), to natural killer (NK) cells. Treatment with cordycepin prior to and during co-culturing with NK-92 cells significantly increased cell death of KKU-213A as compared to solitary cordycepin or NK treatment. Moreover, sensitization activity was also observed in the combination of NK-92 cells and Cordyceps militaris extract that contained cordycepin as a major component. The cordycepin treatment remarkably caused an increase in TRAIL receptor (DR4 and DR5) expression in KKU-213A, suggesting the possible involvement of TRAIL signaling in KKU-213A sensitization to NK-92 cells. In conclusion, this is the first report on the sensitization activity of cordycepin on CCA cells to NK cytotoxicity, which supports that cordycepin can be further developed as an alternate immunomodulating agent.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Cordyceps/química , Desoxiadenosinas/farmacologia , Células Matadoras Naturais/imunologia , Antineoplásicos Fitogênicos/farmacologia , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Extratos Vegetais/farmacologia , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , Receptor fas/genética
7.
Eur J Cancer ; 157: 31-39, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34474218

RESUMO

PURPOSE: To evaluate the role of adjuvant radiotherapy (RT) after curative resection in patients with extrahepatic bile duct (EHBD) cancer. METHODS: Between January 2000 and December 2015, 1475 patients with EHBD cancer who underwent curative resection were accrued from 14 institutions in Korea. Among these, 959 patients did not receive any adjuvant therapy (RT(-) group), while 516 underwent postoperative RT with or without chemotherapy (RT(+) group). RESULTS: The median age was 67 years. Nodal involvement was present in 482 patients (32.7%), and resection margin was involved in 293 patients (19.9%). RT(+) group had more patients with proximal tumours, advanced tumours, nodal involvement, perineural invasion, and involved resection margin than RT(-) group (all p < 0.001). With a median follow-up of 36 months, there were 211 locoregional recurrences, 307 distant metastases and 322 combined locoregional and distant failures. On multivariate analysis incorporating age, tumour location, differentiation, pT classification, pN classification, perineural invasion and resection margin, adjuvant RT was associated with improved overall survival (hazard ratio, 0.74; 95% confidence interval, 0.63-0.86; p < 0.001). When RT(+) group was separated into RT alone, concurrent chemoradiotherapy (CCRT) and CCRT followed by chemotherapy, the greatest benefit was observed in patients treated with CCRT followed by chemotherapy (hazard ratio, 0.52; 95% confidence interval, 0.41-0.68). CONCLUSIONS: Adjuvant RT combined with chemotherapy improved survival outcomes of resected EHBD cancer patients. Considering the greatest benefit observed in patients receiving CCRT followed by chemotherapy, a randomised controlled trial comparing chemotherapy alone and CCRT followed by chemotherapy is urgently needed.


Assuntos
Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Extra-Hepáticos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Quimiorradioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos
8.
Expert Opin Investig Drugs ; 30(10): 1047-1056, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34579607

RESUMO

INTRODUCTION: The development of novel biomarkers for cancer has exploded over the last decade with advances in novel technologies. Cholangiocarcinoma (CCA), a cancer of the bile ducts, has a dearth of strong disease and pathophysiology biomarkers, making early detection and prognostication a difficult task. AREAS COVERED: In this comprehensive review, we discuss the spectrum of biomarkers for CCA diagnosis and prognostication. We elaborate on novel biomarker discovery through a comprehensive multi-omics approach. We also cover, how certain biomarkers may also serve as unique and potent targets for therapeutic development. EXPERT OPINION: Despite the relatively poor diagnostic and prognostic performance of existing biomarkers for CCA, there is a vast range of novel biomarkers with exquisite diagnostic and prognostic performance for CCA in the pipeline. Moreover, these biomarkers may serve as potential targets for precision medicine. Existing strategies to target unique biomolecular classes are discussed, within the context of an overall 'omics' focused profiling strategy. Omics profiling will simultaneously allow for enhanced biomarker development and identification of unique subtypes of cholangiocarcinoma and how they are influenced by an individual's unique context. In this manner, patient management strategy and clinical trial design can be optimized to the individual.


Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/diagnóstico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Desenvolvimento de Medicamentos , Drogas em Investigação/farmacologia , Humanos , Medicina de Precisão , Prognóstico
9.
Biomed Res Int ; 2021: 8893652, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34337058

RESUMO

This study primarily focused on the effect of the long noncoding RNA (lncRNA) PVT1/miR186/KLF5 axis on the occurrence and progression of cholangiocarcinoma (CCA). miR186 was found both in the lncRNA PVT1 targeting miRNAs and KLF5 targeting miRNAs using bioinformatic analysis. The expression of lncRNA PVT1 and KLF5 in the TFK-1, QBC939, and HuCCT1 cell lines and normal biliary epithelial HIBEpiC cells was detected by RT-qPCR. The significance of lncRNA PVT1 and KLF5 on cell proliferation was analyzed using the MTT assay and clone formation assay in lncRNA PVT1 and KLF5 silencing HuCCT1 cell lines and lncRNA PVT1and KLF5 overexpressing TFK-1 and QBC939 cell lines, respectively. The potential role of lncRNA PVT1 and KLF5 in cell migration was detected using the transwell invasion assay in CCA cell lines and tumor formation assay. Additionally, lncRNA PVT1 and KLF5 were proved to be highly expressed in CCA tissues and cell lines. Silencing and overexpressing of lncRNA PVT1 or KLF5 markedly inhibited or increased the cell proliferation and cell invasion in CCA cell lines, respectively. Silencing and overexpressing of lncRNA PVT1 significantly inhibited and increased the expression of KLF5 in CCA cell lines, respectively. Silencing of lncRNA PVT1 increased the expression of miR186, and silencing of miR186 increased the expression of KLF5 in CCA cell lines. Cotransfection of lncRNA PVT1 and miR186 increased the expression of KLF5 compared with controls. Overall, these results demonstrated that the lncRNA PVT1/miR186/KLF5 axis might exert a key role in the occurrence and progression of CCA, and this axis might provide a new target for treating CCA.


Assuntos
Neoplasias dos Ductos Biliares/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Progressão da Doença , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Animais , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos Nus , MicroRNAs/genética , RNA Longo não Codificante/genética , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
10.
J Surg Oncol ; 124(8): 1561-1568, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34351633

RESUMO

BACKGROUND AND OBJECTIVES: We evaluated the changes in natural killer cell activity (NKA) during the entire treatment period of patients with resectable biliopancreatic cancers and investigated the predictors of the failure of recovery of NKA after surgery. METHODS: A total of 202 patients who underwent curative resection for biliopancreatic cancer were enrolled in the study. NKA levels were measured six times during the treatment period. We investigated whether there was any difference in postoperative NKA recovery according to the period-by-time NKA value. RESULTS: NKA decreased after surgery (mean, 40 pg/ml) compared to the NKA value at admission (200.2 pg/ml), then began to increase from 3 weeks after surgery (139.7 pg/ml) and rose to normal NKA levels at 5 weeks (217.1 pg/ml). The pattern of NKA changes was distinct according to the NKA values at admission. In multivariate analysis, NKA values of less than 250 pg/ml at admission (odds ratio = 5.898, p = 0.044) were a predictor of NKA recovery failure 5 weeks after surgery. CONCLUSIONS: NKA rapidly decreased after curative surgery for biliopancreatic cancer and recovered to normal levels about 5 weeks later. Clinicians should be aware and cautious that patients with low NKA at admission may fail to recover NKA postoperatively.


Assuntos
Neoplasias dos Ductos Biliares/patologia , Neoplasias do Sistema Biliar/patologia , Procedimentos Cirúrgicos do Sistema Biliar/métodos , Células Matadoras Naturais/imunologia , Pancreatectomia/métodos , Neoplasias Pancreáticas/patologia , Recuperação de Função Fisiológica , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias do Sistema Biliar/imunologia , Neoplasias do Sistema Biliar/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos
11.
Cells ; 10(7)2021 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-34359861

RESUMO

Cholangiocarcinoma is a lethal disease with scarce response to current systemic therapy. The rare occurrence and large heterogeneity of this cancer, together with poor knowledge of its molecular mechanisms, are elements contributing to the difficulties in finding an appropriate cure. Cholangiocytes (and their cellular precursors) are considered the liver component giving rise to cholangiocarcinoma. These cells respond to several hormones, neuropeptides and molecular stimuli employing the cAMP/PKA system for the translation of messages in the intracellular space. For instance, in physiological conditions, stimulation of the secretin receptor determines an increase of intracellular levels of cAMP, thus activating a series of molecular events, finally determining in bicarbonate-enriched choleresis. However, activation of the same receptor during cholangiocytes' injury promotes cellular growth again, using cAMP as the second messenger. Since several scientific pieces of evidence link cAMP signaling system to cholangiocytes' proliferation, the possible changes of this pathway during cancer growth also seem relevant. In this review, we summarize the current findings regarding the cAMP pathway and its role in biliary normal and neoplastic cell proliferation. Perspectives for targeting the cAMP machinery in cholangiocarcinoma therapy are also discussed.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Sistema Biliar/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , AMP Cíclico/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais , Animais , Proliferação de Células , Humanos
12.
Expert Opin Investig Drugs ; 30(9): 975-983, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34420429

RESUMO

Introduction: Cholangiocarcinomas (CCA) are rare tumors that are associated with a variety of molecular alterations. Many of these alterations are now actionable using drugs currently in development, and CCA may be a perfect example of application of a precision oncology approach. However, development of drugs in CCA faces the challenge of targeting rare alterations in a rare disease.Areas covered: In this review, we present the current data on targeted therapies in development for CCA, focusing on IDH1, FGFR2, BRAF, and HER2 alterations. We also discuss rationale for targeting other alterations, currently without specific development in CCA. We searched PubMed and google scholar in February 2021 for relevant articles and presentation in recent congress regarding the literature on molecular alterations, drugs in cholangiocarcinomas and biliary tract cancers.Expert opinion: Despite a strong rationale and promising early results, applying a precision oncology approach in CCA for everyday patients is still exposed to significant challenges: obtaining the molecular portrait of these tumors due to difficulties with biopsy access, complexities of drug development in subgroups of these relatively rare tumors, and sub-optimal access to drugs outside clinical trials.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Terapia de Alvo Molecular , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos , Humanos , Imunoterapia/métodos , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Medicina de Precisão
13.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445380

RESUMO

Cholangiocarcinoma (CC) is an aggressive malignancy with an inferior prognosis due to limited systemic treatment options. As preclinical models such as CC cell lines are extremely rare, this manuscript reports a protocol of cholangiocarcinoma patient-derived organoid culture as well as a protocol for the transition of 3D organoid lines to 2D cell lines. Tissue samples of non-cancer bile duct and cholangiocarcinoma were obtained during surgical resection. Organoid lines were generated following a standardized protocol. 2D cell lines were generated from established organoid lines following a novel protocol. Subcutaneous and orthotopic patient-derived xenografts were generated from CC organoid lines, histologically examined, and treated using standard CC protocols. Therapeutic responses of organoids and 2D cell lines were examined using standard CC agents. Next-generation exome and RNA sequencing was performed on primary tumors and CC organoid lines. Patient-derived organoids closely recapitulated the original features of the primary tumors on multiple levels. Treatment experiments demonstrated that patient-derived organoids of cholangiocarcinoma and organoid-derived xenografts can be used for the evaluation of novel treatments and may therefore be used in personalized oncology approaches. In summary, this study establishes cholangiocarcinoma organoids and organoid-derived cell lines, thus expanding translational research resources of cholangiocarcinoma.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Organoides/citologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Neoplasias dos Ductos Biliares/genética , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Técnicas de Cultura de Órgãos/métodos , Organoides/efeitos dos fármacos , Organoides/patologia , Organoides/transplante , Medicina de Precisão , Análise de Sequência de RNA , Células Tumorais Cultivadas , Sequenciamento Completo do Exoma , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Sci Rep ; 11(1): 14866, 2021 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-34290264

RESUMO

Application of 5-fluorouracil (5-FU) in cholangiocarcinoma (CCA) is limited by adverse side effects and chemoresistance. Therefore, the combination therapy of 5-FU with other substances, especially natural products may provide a new strategy for CCA treatment. The aim of this study was to evaluate the combination effects of 5-FU and two ethanolic extracts of Thai noni juice (TNJ) products on CCA cell lines and nude mice xenografts. The results of antiproliferative assay showed the combination treatment of 5-FU and each TNJ ethanolic extract exerted more cytotoxicity on CCA cells than either single agent treatment. Synergistic effects of drug combinations can enable the dose reduction of 5-FU. The mechanism underlying a combination treatment was apoptosis induction through an activation of p53 and Bax proteins. In the nude mouse xenograft model, combination treatments of 5-FU with each TNJ ethanolic extract suppressed the growth of CCA cells implanted mice more than single agent treatments with no effects on mouse body weight, kidney, and spleen. Moreover, low doses of TNJ ethanolic extracts reduced the hepatotoxicity of 5-FU in nude mice. Taken together, these data suggested that the ethanolic extracts of TNJ products can enhance the anti-CCA effect and reduce toxicity of 5-FU.


Assuntos
Antineoplásicos Fitogênicos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Etanol , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Morinda/química , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Animais , Linhagem Celular Tumoral , Interações Medicamentosas , Redução da Medicação , Quimioterapia Combinada , Fluoruracila/uso terapêutico , Fluoruracila/toxicidade , Xenoenxertos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Extratos Vegetais/isolamento & purificação
15.
Cell Death Dis ; 12(7): 678, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34226501

RESUMO

Oncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-ß-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.


Assuntos
Neoplasias dos Ductos Biliares/enzimologia , Movimento Celular , Colangiocarcinoma/enzimologia , Ubiquitina Tiolesterase/metabolismo , Animais , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/secundário , Transição Epitelial-Mesenquimal , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , MAP Quinase Quinase Quinases/genética , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Fenótipo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitinação
16.
BMC Cancer ; 21(1): 865, 2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34320944

RESUMO

BACKGROUND: Cholangiocarcinoma (CCA) is an aggressive disease with poor prognosis. A molecular classification based on mutational, methylation and transcriptomic features could allow identifying tailored therapies to improve CCA patient outcome. Proteomic remains partially unexplored; here, we analyzed the proteomic profile of five intrahepatic cholangiocarcinoma (ICC) derived from Italian patients undergone surgery and one normal bile duct cell line. METHODS: Proteome profile was investigated by using 2D electrophoresis followed by Mass Spectrometry (MS). To validate proteomic data, the expression of four overexpressed proteins (CAT, SOD, PRDX6, DBI/ACBP) was evaluated by immunohistochemistry in an independent cohort of formalin fixed, paraffin-embedded (FFPE) ICC tissues. We also compared proteomic data with those obtained by transcriptomic profile evaluated by microarray analysis of the same tissues. RESULTS: We identified 19 differentially expressed protein spots, which were further characterized by MS; 13 of them were up- and 6 were down-regulated in ICC. These proteins are mainly involved in redox processes (CAT, SODM, PRDX2, PRDX6), in metabolism (ACBP, ACY1, UCRI, FTCD, HCMS2), and cell structure and organization (TUB2, ACTB). CAT is overexpressed in 86% of patients, PRDX6 in 73%, SODM in 100%, and DBI/ACBP in 81% compared to normal adjacent tissues. A concordance of 50% between proteomic and transcriptomic data was observed. CONCLUSIONS: This study pointed out that the impairment of the metabolic and antioxidant systems, with a subsequent accumulation of free radicals, might be a key step in CCA development and progression.


Assuntos
Neoplasias dos Ductos Biliares/metabolismo , Biomarcadores Tumorais , Colangiocarcinoma/metabolismo , Metabolismo Energético , Oxirredução , Proteoma , Proteômica , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Eletroforese em Gel Bidimensional , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Espectrometria de Massas/métodos , Proteômica/métodos
17.
Int J Mol Sci ; 22(14)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34299246

RESUMO

Cholangiocarcinoma (CCA), an aggressive malignancy, is typically diagnosed at an advanced stage. It is associated with dismal 5-year postoperative survival rates, generating an urgent need for prognostic and diagnostic biomarkers. MicroRNAs (miRNAs) are a class of non-coding RNAs that are associated with cancer regulation, including modulation of cell cycle progression, apoptosis, metastasis, angiogenesis, autophagy, therapy resistance, and epithelial-mesenchymal transition. Several miRNAs have been found to be dysregulated in CCA and are associated with CCA-related risk factors. Accumulating studies have indicated that the expression of altered miRNAs could act as oncogenic or suppressor miRNAs in the development and progression of CCA and contribute to clinical diagnosis and prognosis prediction as potential biomarkers. Furthermore, miRNAs and their target genes also contribute to targeted therapy development and aid in the determination of drug resistance mechanisms. This review aims to summarize the roles of miRNAs in the pathogenesis of CCA, their potential use as biomarkers of diagnosis and prognosis, and their utilization as novel therapeutic targets in CCA.


Assuntos
Colangiocarcinoma/genética , MicroRNAs/genética , Apoptose/genética , Autofagia/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/fisiologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/patologia , Transição Epitelial-Mesenquimal/genética , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Prognóstico , Transcriptoma/genética
18.
Anticancer Res ; 41(8): 3769-3778, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281836

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma is a lethal disease with increasing incidence worldwide. New therapeutic compounds are urgently needed for this disease. Here, the inhibitory effect of adenosine on cholangiocarcinoma cells was studied. MATERIALS AND METHODS: Western blot analysis was used to study autophagy and flow cytometry to analyze cell death and the cell cycle. RESULTS: Cholangiocarcinoma and immortalized cholangiocytes responded to adenosine differently, and adenosine inhibited cholangiocarcinoma cell growth by inducing autophagy. Adenosine failed to activate adenylyl cyclase in cholangiocarcinoma cell lines, but activated this enzyme in immortalized cholangiocytes. Adenosine treatment activated AMPK and led to phosphorylation of its downstream proteins including ULK and Raptor. In addition, autophagy induced by adenosine appeared to be a survival mechanism. The combination of adenosine with autophagy inhibitors greatly increased cell death, as compared to the use of either agent alone. Interestingly, immortalized cholangiocytes were more resistant to adenosine. CONCLUSION: Adenosine may have potential for application in cholangiocarcinoma treatment.


Assuntos
Adenosina/farmacologia , Autofagia/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Proteínas Quinases Ativadas por AMP/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/fisiologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , AMP Cíclico/metabolismo , Humanos , Hidroxicloroquina/farmacologia , Macrolídeos/farmacologia , Fosforilação/efeitos dos fármacos , Proteína Regulatória Associada a mTOR/metabolismo
19.
Anticancer Res ; 41(7): 3389-3400, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230134

RESUMO

BACKGROUND/AIM: Cholangiocarcinoma (CCA), a biliary cancer, is a health problem worldwide. The major problem in CCA treatment presents limited options. To date, targeting cancer metabolism is a promising anti-cancer strategy. To elucidate the functional importance of lipid metabolism in CCA, de novo lipogenesis was inhibited using 5-(tetradecyloxy)-2-furoic acid (TOFA), an acetyl CoA carboxylase inhibitor. MATERIALS AND METHODS: Anti-proliferative effects of TOFA were determined both in vitro and in vivo. Its inhibitory effect on cell-cycle and apoptosis was investigated by flow cytometry and western blot analysis of relevant markers. RESULTS: TOFA inhibited CCA cell growth, induced cell-cycle progression accompanied by apoptosis in a dose-dependent manner. Induction of p21, and caspase-3, -8, and -9 cleavages, while down-regulation of cyclin B1 and cyclin D1 were observed in TOFA-treated cells. The therapeutic potential was demonstrated in vivo. CONCLUSION: De novo lipogensis is essential for CCA cell growth and is an alternative target for CCA treatment.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colangiocarcinoma/tratamento farmacológico , Furanos/farmacologia , Acetil-CoA Carboxilase/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação para Baixo/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos
20.
Sci Rep ; 11(1): 11743, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083572

RESUMO

Necroptosis, a regulated form of necrosis, has emerged as a novel therapeutic strategy that could enhance cancer immunotherapy. However, its role in tumorigenesis is still debated because recent studies have reported both anti- and pro-tumoral effects. Here, we aimed to systematically evaluate the associations between tumor necroptosis (mixed lineage kinase domain-like protein, MLKL; phosphorylated MLKL, pMLKL; and receptor-interacting protein kinase 1-receptor-interacting protein kinase 3, RIPK1-RIPK3 interaction) and tumor-infiltrating immune cells (CD8+ and FOXp3+ T cells and CD163+ M2 macrophages) and tumor PD-L1 by immunohistochemistry in 88 cholangiocarcinoma (CCA) patients who had undergone surgical resection. Their associations with clinicopathological characteristics, survival data, and prognosis were evaluated. MLKL was found to be an unfavorable prognostic factor (p-value = 0.023, HR = 2.070) and was inversely correlated with a clinically favorable immune cell signature (high CD8+/high FOXp3+/low CD163+). Both pMLKL and RIPK1-RIPK3 interaction were detected in CCA primary tissues. In contrast to MLKL, pMLKL status was significantly positively correlated with a favorable immune signature (high CD8+/high FOXp3+/low CD163+) and PD-L1 expression. Patients with high pMLKL-positive staining were significantly associated with an increased abundance of CD8+ T cell intratumoral infiltration (p-value = 0.006). Patients with high pMLKL and PD-L1 expressions had a longer overall survival (OS). The results from in vitro experiments showed that necroptosis activation in an RMCCA-1 human CCA cell line selectively promoted proinflammatory cytokine and chemokine expression. Jurkat T cells stimulated with necroptotic RMCCA-1-derived conditioned medium promoted PD-L1 expression in RMCCA-1. Our findings demonstrated the differential associations of necroptosis activation (pMLKL) and MLKL with a clinically favorable immune signature and survival rates and highlighted a novel therapeutic possibility for combining a necroptosis-based therapeutic approach with immune checkpoint inhibitors for more efficient treatment of CCA patients.


Assuntos
Antígeno B7-H1/genética , Neoplasias dos Ductos Biliares/etiologia , Neoplasias dos Ductos Biliares/patologia , Biomarcadores Tumorais , Colangiocarcinoma/etiologia , Colangiocarcinoma/patologia , Necroptose/imunologia , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/mortalidade , Citocinas/genética , Citocinas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Modelos Biológicos , Modelos de Riscos Proporcionais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
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