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1.
Cancer Med ; 13(9): e7238, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38716625

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a high recurrence rate and a poor prognosis. Thus, the development of effective treatment and prognostic biomarkers is required. High expression of diacylglycerol kinase alpha (DGKα) is a prognostic factor for the recurrence of hepatocellular carcinoma. However, the relationship between DGKα expression and prognosis in ICC has not been reported. METHODS: Immunohistochemistry (IHC) with anti-DGKα antibody was performed on surgical specimens of ICC (n = 69). First, DGKα expression in cancer cells was qualitatively classified into four groups (-, 1+, 2+, 3+) and divided into two groups (DGKα- and DGKα+1 + to 3+). The relationship between clinical features and DGKα expression was analyzed. Second, Ki-67 expression was evaluated as a cell proliferation marker. The number of Ki-67-positive cells was counted, and the relationship with DGKα expression was examined. RESULTS: DGKα IHC divided the patients into a DGKα+ group (1+: n = 15; 2+: n = 5; 3+: n = 5) and a DGKα- group (-: n = 44). In the DGKα+ group, patients were older and had advanced disease. Both overall survival and recurrence-free survival (RFS) were significantly worse in the DGKα+ patients. DGKα+ was identified as an independent prognostic factor for RFS by multivariate analysis. Furthermore, the number of Ki-67-positive cells increased in association with the staining levels of DGKα. CONCLUSION: Pathological DGKα expression in ICC was a cancer proliferation marker associated with recurrence. This suggests that DGKα may be a potential therapeutic target for ICC.


Assuntos
Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Proliferação de Células , Colangiocarcinoma , Diacilglicerol Quinase , Antígeno Ki-67 , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidade , Diacilglicerol Quinase/metabolismo , Diacilglicerol Quinase/genética , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/mortalidade , Idoso , Antígeno Ki-67/metabolismo , Adulto , Imuno-Histoquímica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/metabolismo
2.
Signal Transduct Target Ther ; 9(1): 107, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38697972

RESUMO

Cholangiocarcinoma (CCA) is a highly malignant biliary tract cancer with currently suboptimal diagnostic and prognostic approaches. We present a novel system to monitor CCA using exosomal circular RNA (circRNA) via serum and biliary liquid biopsies. A pilot cohort consisting of patients with CCA-induced biliary obstruction (CCA-BO, n = 5) and benign biliary obstruction (BBO, n = 5) was used to identify CCA-derived exosomal circRNAs through microarray analysis. This was followed by a discovery cohort (n = 20) to further reveal a CCA-specific circRNA complex (hsa-circ-0000367, hsa-circ-0021647, and hsa-circ-0000288) in both bile and serum exosomes. In vitro and in vivo studies revealed the three circRNAs as promoters of CCA invasiveness. Diagnostic and prognostic models were established and verified by two independent cohorts (training cohort, n = 184; validation cohort, n = 105). An interpreter-free diagnostic model disclosed the diagnostic power of biliary exosomal circRNA signature (Bile-DS, AUROC = 0.947, RR = 6.05) and serum exosomal circRNA signature (Serum-DS, AUROC = 0.861, RR = 4.04) compared with conventional CA19-9 (AUROC = 0.759, RR = 2.08). A prognostic model of CCA undergoing curative-intent surgery was established by calculating early recurrence score, verified with bile samples (Bile-ERS, C-index=0.783) and serum samples (Serum-ERS, C-index = 0.782). These models, combined with other prognostic factors revealed by COX-PH model, enabled the establishment of nomograms for recurrence monitoring of CCA. Our study demonstrates that the exosomal triple-circRNA panel identified in both bile and serum samples serves as a novel diagnostic and prognostic tool for the clinical management of CCA.


Assuntos
Colangiocarcinoma , Exossomos , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/sangue , Colangiocarcinoma/genética , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/sangue , Colangiocarcinoma/patologia , Exossomos/genética , Masculino , Feminino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/sangue , Pessoa de Meia-Idade , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/patologia , Prognóstico , Colestase/genética , Colestase/diagnóstico , Colestase/sangue
5.
Nat Commun ; 15(1): 3805, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38714664

RESUMO

Genomic alterations that activate Fibroblast Growth Factor Receptor 2 (FGFR2) are common in intrahepatic cholangiocarcinoma (ICC) and confer sensitivity to FGFR inhibition. However, the depth and duration of response is often limited. Here, we conduct integrative transcriptomics, metabolomics, and phosphoproteomics analysis of patient-derived models to define pathways downstream of oncogenic FGFR2 signaling that fuel ICC growth and to uncover compensatory mechanisms associated with pathway inhibition. We find that FGFR2-mediated activation of Nuclear factor-κB (NF-κB) maintains a highly glycolytic phenotype. Conversely, FGFR inhibition blocks glucose uptake and glycolysis while inciting adaptive changes, including switching fuel source utilization favoring fatty acid oxidation and increasing mitochondrial fusion and autophagy. Accordingly, FGFR inhibitor efficacy is potentiated by combined mitochondrial targeting, an effect enhanced in xenograft models by intermittent fasting. Thus, we show that oncogenic FGFR2 signaling drives NF-κB-dependent glycolysis in ICC and that metabolic reprogramming in response to FGFR inhibition confers new targetable vulnerabilities.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Glucose , Glicólise , NF-kappa B , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Transdução de Sinais , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Humanos , NF-kappa B/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Animais , Glicólise/efeitos dos fármacos , Glucose/metabolismo , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/tratamento farmacológico , Camundongos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Pirimidinas/farmacologia , Autofagia/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
6.
J Gastrointest Surg ; 28(5): 738-745, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38704208

RESUMO

BACKGROUND: Liver transplantation (LT) has been shown to be superior to resection in highly selected patients with perihilar cholangiocarcinoma (CCA), yet has traditionally been contraindicated for intrahepatic CCA (iCCA). Herein, we aimed to examine contemporary trends and outcomes for surgical resection and LT for iCCA. METHODS: The National Cancer Database was queried for patients presenting with stage I-III iCCA between 2010 and 2018 who underwent resection or LT. Overall survival (OS) was compared with Kaplan-Meier and multivariable Cox proportional hazards methods stratified by management. Secondary analysis of patients undergoing transplant for CCA was performed with the United Network for Organ Sharing database. RESULTS: Of 2565 patients, 2412 (94.0%) underwent resection and 153 (5.96%) LT of whom 84 (54.9%) received neoadjuvant therapy. Utilization of LT remained between 3.9% and 7.8% annually. Unadjusted 5-year OS was higher for LT than resection (59.8% vs 39.9%, P = .0067), yet adjusted analysis revealed no significant difference in mortality (hazard ratio, 0.91; 95% CI, 0.66-1.27; P = .58). On secondary analysis including 437 patients with all subtypes of CCA, unadjusted 5-year OS was higher for non-CCA indications (79% vs 52%-54%, P < .001). CONCLUSION: Utilization of LT for iCCA remains low and many cases are likely incidental. Although partial hepatectomy remains the standard of care for patients with resectable disease, our findings suggest that highly selected patients with unresectable iCCA may achieve favorable outcomes after LT. Granular, prospective data are needed to identify patients most likely to benefit from transplant and allocate scarce liver grafts.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Hepatectomia , Transplante de Fígado , Humanos , Transplante de Fígado/estatística & dados numéricos , Masculino , Feminino , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/patologia , Pessoa de Meia-Idade , Idoso , Colangiocarcinoma/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/patologia , Resultado do Tratamento , Terapia Neoadjuvante/estatística & dados numéricos , Taxa de Sobrevida , Bases de Dados Factuais , Modelos de Riscos Proporcionais , Estimativa de Kaplan-Meier , Estudos Retrospectivos , Estadiamento de Neoplasias
7.
J Transl Med ; 22(1): 422, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38702814

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm and characterized by desmoplastic matrix. The heterogeneity and crosstalk of tumor microenvironment remain incompletely understood. METHODS: To address this gap, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify and construct a cancer associated fibroblasts (CAFs) infiltration biomarker. We also depicted the intercellular communication network and important receptor-ligand complexes using the single-cell transcriptomics analysis of tumor and Adjacent normal tissue. RESULTS: Through the intersection of TCGA DEGs and WGCNA module genes, 784 differential genes related to CAFs infiltration were obtained. After a series of regression analyses, the CAFs score was generated by integrating the expressions of EVA1A, APBA2, LRRTM4, GOLGA8M, BPIFB2, and their corresponding coefficients. In the TCGA-CHOL, GSE89748, and 107,943 cohorts, the high CAFs score group showed unfavorable survival prognosis (p < 0.001, p = 0.0074, p = 0.028, respectively). Additionally, a series of drugs have been predicted to be more sensitive to the high-risk group (p < 0.05). Subsequent to dimension reduction and clustering, thirteen clusters were identified to construct the single-cell atlas. Cell-cell interaction analysis unveiled significant enhancement of signal transduction in tumor tissues, particularly from fibroblasts to malignant cells via diverse pathways. Moreover, SCENIC analysis indicated that HOXA5, WT1, and LHX2 are fibroblast specific motifs. CONCLUSIONS: This study reveals the key role of fibroblasts - oncocytes interaction in the remodeling of the immunosuppressive microenvironment in intrahepatic cholangiocarcinoma. Subsequently, it may trigger cascade activation of downstream signaling pathways such as PI3K-AKT and Notch in tumor, thus initiating tumorigenesis. Targeted drugs aimed at disrupting fibroblasts-tumor cell interaction, along with associated enrichment pathways, show potential in mitigating the immunosuppressive microenvironment that facilitates tumor progression.


Assuntos
Neoplasias dos Ductos Biliares , Fibroblastos Associados a Câncer , Colangiocarcinoma , Regulação Neoplásica da Expressão Gênica , Análise de Célula Única , Microambiente Tumoral , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Humanos , Microambiente Tumoral/genética , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Prognóstico , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Transcriptoma/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Comunicação Celular
8.
Exp Clin Transplant ; 22(3): 167-179, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38695585

RESUMO

Cholangiocarcinoma is the second most common primary hepatic neoplasm, accounting for 10% to 20% of primary liver tumors and 3% of all gastrointestinal neoplasms. The 3 anatomic types (intrahepatic, perihilar, and distal) have distinct epidemiologies, etiopathogenesis, and clinical outcomes. Surgical resection remains the current standard of treatment, but outcomes remain poor. With the continued expansion of liver transplant programs, use of liver transplant for malignant indications has also increased, with reports of encouraging outcomes. However, given the scarcity of livers fortransplant and accompanying possible complications, liver transplant for treatment of patients with cholangiocarcinomas remains experimental in most of the world. We reviewed the existing literature on treatment modalities for cholangiocarcinoma with emphasis on the pros and cons of surgical resection and indications, protocols, and outcomes of liver transplant as a treatment modality for patients with cholangiocarcinoma.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Transplante de Fígado , Humanos , Colangiocarcinoma/cirurgia , Colangiocarcinoma/patologia , Transplante de Fígado/efeitos adversos , Neoplasias dos Ductos Biliares/cirurgia , Neoplasias dos Ductos Biliares/patologia , Resultado do Tratamento , Fatores de Risco , Hepatectomia/efeitos adversos
9.
J Gene Med ; 26(5): e3689, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38676365

RESUMO

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.


Assuntos
Colangiocarcinoma , Cisplatino , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Proteína 1 de Ligação a Y-Box , beta Catenina , Animais , Feminino , Humanos , Masculino , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , beta Catenina/metabolismo , beta Catenina/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/mortalidade , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Células-Tronco Neoplásicas/metabolismo , Prognóstico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Via de Sinalização Wnt , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína 1 de Ligação a Y-Box/metabolismo , Proteína 1 de Ligação a Y-Box/genética
10.
Aging (Albany NY) ; 16(8): 7311-7330, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38687509

RESUMO

Cholangiocarcinoma, a prevalent hepatic malignancy, exhibits a progressively rising incidence. While Eukaryotic translation initiation factor 3 subunit B (EIF3B) has been implicated in the occurrence and development of various cancers, its specific roles in cholangiocarcinoma remain unexplored. Immunohistochemical (IHC) analysis was employed to detect EIF3B/PCNA expression in cholangiocarcinoma. Cells were manipulated using short hairpin RNA (shRNA)-mediated lentiviruses or overexpression plasmids. Statistical significance was assessed using the Student's t-test and one-way ANOVA, with P < 0.05 considered statistically significant. EIF3B exhibited robust expression in cholangiocarcinoma, demonstrating a significant correlation with the pathological grade of cholangiocarcinoma patients. Furthermore, modulation of EIF3B expression, either depletion or elevation, demonstrated the ability to inhibit or enhance cholangiocarcinoma cell survival and migration in vitro. Mechanistically, we identified Proliferating Cell Nuclear Antigen (PCNA) as a downstream gene of EIF3B, driving cholangiocarcinoma. EIF3B stabilized PCNA by inhibiting PCNA ubiquitination, a process mediated by E3 ligase SYVN1. Similar to EIF3B, PCNA levels were also abundant in cholangiocarcinoma, and knocking down PCNA impeded cholangiocarcinoma development. Intriguingly, silencing PCNA attenuated the promotion induced by EIF3B overexpression. Furthermore, the elevated P21 protein level in shEIF3B RBE cells was partially attenuated after UC2288 (P21 signaling pathway inhibitor) treatment. Our findings underscored the potential of EIF3B as a therapeutic target for cholangiocarcinoma. Unraveling its functions holds promise for the development of more specific and effective targeted therapy strategies.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Fator de Iniciação 3 em Eucariotos , Antígeno Nuclear de Célula em Proliferação , Ubiquitina-Proteína Ligases , Ubiquitinação , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Humanos , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Linhagem Celular Tumoral , Fator de Iniciação 3 em Eucariotos/metabolismo , Fator de Iniciação 3 em Eucariotos/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Regulação Neoplásica da Expressão Gênica , Movimento Celular/genética , Proliferação de Células , Masculino , Feminino , Animais
11.
J Exp Clin Cancer Res ; 43(1): 119, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38641828

RESUMO

BACKGROUND: Refractoriness to surgical resection and chemotherapy makes intrahepatic cholangiocarcinoma (ICC) a fatal cancer of the digestive system with high mortality and poor prognosis. Important function invests circRNAs with tremendous potential in biomarkers and therapeutic targets. Nevertheless, it is still unknown how circRNAs contribute to the evolution of ICC. METHODS: CircRNAs in paired ICC and adjacent tissues were screened by circRNAs sequencing. To explore the impact of circRNAs on ICC development, experiments involving gain and loss of function were conducted. Various experimental techniques, including quantitative real-time PCR (qPCR), western blotting, RNA immunoprecipitation (RIP), luciferase reporter assays, RNA pull-down, chromatin immunoprecipitation (ChIP), ubiquitination assays and so on were employed to identify the molecular regulatory role of circRNAs. RESULTS: Herein, we reported a new circRNA, which originates from exon 9 to exon 15 of the SLCO1B3 gene (named circSLCO1B3), orchestrated ICC progression by promoting tumor proliferation, metastasis and immune evasion. We found that the circSLCO1B3 gene was highly overexpressed in ICC tissues and related to lymphatic metastasis, tumor sizes, and tumor differentiation. Mechanically, circSLCO1B3 not only promoted ICC proliferation and metastasis via miR-502-5p/HOXC8/SMAD3 axis, but also eradicated anti-tumor immunity via suppressing ubiquitin-proteasome-dependent degradation of PD-L1 by E3 ubiquitin ligase SPOP. We further found that methyltransferase like 3 (METTL3) mediated the m6A methylation of circSLCO1B3 and stabilizes its expression. Our findings indicate that circSLCO1B3 is a potential prognostic marker and therapeutic target in ICC patients. CONCLUSIONS: Taken together, m6A-modified circSLCO1B3 was correlated with poor prognosis in ICC and promoted ICC progression not only by enhancing proliferation and metastasis via potentiating HOXC8 expression, but also by inducing immune evasion via antagonizing PD-L1 degradation. These results suggest that circSLCO1B3 is a potential prognostic marker and therapeutic target for ICC.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Metiltransferases , RNA Circular , Humanos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas Nucleares/metabolismo , Prognóstico , Proteínas Repressoras/metabolismo , RNA/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genética
13.
BMC Pediatr ; 24(1): 243, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38580968

RESUMO

Cholangiocarcinoma in patients with Choledochal cysts is rare in childhood; however, it seriously affects the prognosis of the disease. The key to addressing this situation lies in completely removing the extrahepatic cyst. We herein present a case report of a 3-year-old boy with cholangiocarcinoma associated with a choledochal cyst (CDC). Preoperative 3D simulation, based on CT data, played an important role in the treatment of this patient.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Cisto do Colédoco , Masculino , Humanos , Pré-Escolar , Cisto do Colédoco/complicações , Cisto do Colédoco/diagnóstico por imagem , Cisto do Colédoco/cirurgia , Colangiocarcinoma/complicações , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/diagnóstico por imagem , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/complicações , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia
14.
World J Surg Oncol ; 22(1): 110, 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38664770

RESUMO

BACKGROUND: Octamer-binding transcription factor 4-positive circulating tumor cell (OCT4+CTC) exhibits high stemness and invasive potential, which may influence the efficacy of immune checkpoint inhibitors (ICI). This study aimed to assess the prognostic role of OCT4+CTC in advanced cholangiocarcinoma (CCA) patients who received ICI treatment. METHODS: In total, 40 advanced CCA patients who received ICI treatment were included, and CTC and OCT4 counts were detected via a Canpatrol system and an RNA in situ hybridization method before ICI treatment. Patients were subsequently divided into none CTC, OCT4-CTC, and OCT4+CTC groups. Patients were followed up for a median of 10.4 months. RESULTS: The percentages of patients in none CTC, OCT4-CTC, and OCT4+CTC groups were 25.0%, 30.0%, and 45.0%, respectively. The proportion of patients with lymph node metastasis was highest in OCT4+CTC group, followed by none CTC group, and lowest in OCT4-CTC group (P = 0.025). The objective response rate (ORR) was lowest in OCT4+CTC group, moderate in OCT4-CTC group, and highest in none CTC group (P = 0.009), while disease control rate was not different among three groups (P = 0.293). In addition, progression-free survival (PFS) (P < 0.001) and overall survival (OS) (P = 0.001) were shorter in the OCT4+CTC group than in none CTC & OCT4-CTC group. Moreover, OCT4+CTC (versus none CTC) was independently linked with poorer PFS [hazard ratio (HR) = 6.752, P = 0.001] and OS (HR = 6.674, P = 0.003) in advanced CCA patients. CONCLUSION: OCT4+CTC relates to lymph node metastasis and shows a good predictive value for poor treatment response and survival in advanced CCA patients who receive ICI treatment.


Assuntos
Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Colangiocarcinoma , Inibidores de Checkpoint Imunológico , Células Neoplásicas Circulantes , Fator 3 de Transcrição de Octâmero , Humanos , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/sangue , Masculino , Feminino , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/sangue , Células Neoplásicas Circulantes/patologia , Células Neoplásicas Circulantes/metabolismo , Pessoa de Meia-Idade , Fator 3 de Transcrição de Octâmero/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Prognóstico , Taxa de Sobrevida , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Seguimentos , Idoso , Adulto , Metástase Linfática , Estudos Retrospectivos
15.
Am J Surg Pathol ; 48(6): 751-760, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38584480

RESUMO

Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers.


Assuntos
Neoplasias dos Ductos Biliares , Biomarcadores Tumorais , Proteínas de Ligação ao Cálcio , Colangiocarcinoma , Imuno-Histoquímica , Osteopontina , Humanos , Colangiocarcinoma/patologia , Colangiocarcinoma/classificação , Colangiocarcinoma/mortalidade , Colangiocarcinoma/química , Colangiocarcinoma/diagnóstico , Osteopontina/análise , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/classificação , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/química , Neoplasias dos Ductos Biliares/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores Tumorais/análise , Idoso , Estudos Retrospectivos , Proteínas de Ligação ao Cálcio/análise , Adulto , Idoso de 80 Anos ou mais , Proteínas de Neoplasias/análise , Valor Preditivo dos Testes , Ductos Biliares Intra-Hepáticos/patologia , Ductos Biliares Intra-Hepáticos/química
16.
J Nanobiotechnology ; 22(1): 191, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637832

RESUMO

BACKGROUND: Exosomes assume a pivotal role as essential mediators of intercellular communication within tumor microenvironments. Within this context, long noncoding RNAs (LncRNAs) have been observed to be preferentially sorted into exosomes, thus exerting regulatory control over the initiation and progression of cancer through diverse mechanisms. RESULTS: Exosomes were successfully isolated from cholangiocarcinoma (CCA) CTCs organoid and healthy human serum. Notably, the LncRNA titin-antisense RNA1 (TTN-AS1) exhibited a conspicuous up-regulation within CCA CTCs organoid derived exosomes. Furthermore, a significant elevation of TTN-AS1 expression was observed in tumor tissues, as well as in blood and serum exosomes from patients afflicted with CCA. Importantly, this hightened TTN-AS1 expression in serum exosomes of CCA patients manifested a strong correlation with both lymph node metastasis and TNM staging. Remarkably, both CCA CTCs organoid-derived exosomes and CCA cells-derived exosomes featuring pronounced TTN-AS1 expression demonstrated the capability to the proliferation and migratory potential of CCA cells. Validation of these outcomes was conducted in vivo experiments. CONCLUSIONS: In conclusion, our study elucidating that CCA CTCs-derived exosomes possess the capacity to bolster the metastasis tendencies of CCA cells by transporting TTN-AS1. These observations underscore the potential of TTN-AS1 within CTCs-derived exosomes to serve as a promising biomarker for the diagnosis and therapeutic management of CCA.


Assuntos
Colangiocarcinoma , Exossomos , MicroRNAs , Células Neoplásicas Circulantes , RNA Bacteriano , RNA Longo não Codificante , Humanos , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Exossomos/metabolismo , Conectina/genética , Conectina/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Proliferação de Células , Movimento Celular , Colangiocarcinoma/genética , Colangiocarcinoma/metabolismo , Colangiocarcinoma/patologia , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral
17.
Methods Mol Biol ; 2806: 139-151, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38676801

RESUMO

Cholangiocarcinoma (CCA) poses a substantial clinical hurdle as it is often detected at advanced metastatic stages with limited therapeutic options. To enhance our understanding of advanced CCA, it is imperative to establish preclinical models that faithfully recapitulate the disease's characteristics. Patient-derived xenograft (PDX) models have emerged as a valuable approach in cancer research, offering an avenue to reproduce and study the genomic, histologic, and molecular features of the original human tumors. By faithfully preserving the heterogeneity, microenvironmental interactions, and drug responses observed in human tumors, PDX models serve as highly relevant and predictive preclinical tools. Here, we present a comprehensive protocol that outlines the step-by-step process of generating and maintaining PDX models using biopsy samples from patients with advanced metastatic CCA. The protocol encompasses crucial aspects such as tissue processing, xenograft transplantation, and subsequent monitoring of the PDX models. By employing this protocol, we aim to establish a robust collection of PDX models that accurately reflect the genomic landscape, histologic diversity, and therapeutic responses observed in advanced CCA, thereby enabling improved translational research, drug development, and personalized treatment strategies for patients facing this challenging disease.


Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Ensaios Antitumorais Modelo de Xenoenxerto , Colangiocarcinoma/patologia , Colangiocarcinoma/genética , Humanos , Animais , Camundongos , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/genética , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Modelos Animais de Doenças
18.
Anticancer Res ; 44(5): 1939-1946, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38677763

RESUMO

BACKGROUND/AIM: Macropinocytosis is a non-selective form of endocytosis that facilitates the uptake of extracellular substances, such as nutrients and macromolecules, into the cells. In KRAS-driven cancers, including pancreatic ductal adenocarcinoma, macropinocytosis and subsequent lysosomal utilization are known to be enhanced to overcome metabolic stress. In this study, we investigated the role of Casein Kinase 2 (CK2) inhibition in macropinocytosis and subsequent metabolic processes in KRAS mutant cholangiocarcinoma (CCA) cell lines. MATERIALS AND METHODS: The bovine serum albumin (BSA) uptake indicating macropinocytosis was performed by flow cytometry using the HuCCT1 KRAS mutant CCA cell line. To validate macropinosome, the Rab7 and LAMP2 were labeled and analyzed via immunocytochemistry and western blot. The CX-4945 (Silmitasertib), CK2 inhibitor, was used to investigate the role of CK2 in macropinocytosis and subsequent lysosomal metabolism. RESULTS: The TFK-1, a KRAS wild-type CCA cell line, showed only apoptotic morphological changes. However, the HuCCT1 cell line showed macropinocytosis. Although CX-4945 induced morphological changes accompanied by the accumulation of intracellular vacuoles and cell death, the level of macropinocytosis did not change. These intracellular vacuoles were identified as late macropinosomes, representing Rab7+ vesicles before fusion with lysosomes. In addition, CX-4945 suppressed LAMP2 expression following the inhibition of the Akt-mTOR signaling pathway, which interrupts mature macropinosome and lysosomal metabolic utilization. CONCLUSION: Macropinocytosis is used as an energy source in the KRAS mutant CCA cell line HuCCT1. The inhibition of CK2 by CX-4945 leads to cell death in HuCCT1 cells through alteration of the lysosome-dependent metabolism.


Assuntos
Neoplasias dos Ductos Biliares , Caseína Quinase II , Colangiocarcinoma , Lisossomos , Mutação , Naftiridinas , Fenazinas , Pinocitose , Piperazinas , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Lisossomos/metabolismo , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Pinocitose/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Caseína Quinase II/metabolismo , Caseína Quinase II/genética , Caseína Quinase II/antagonistas & inibidores , Piperazinas/farmacologia , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , proteínas de unión al GTP Rab7/metabolismo , Morte Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/genética , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética
20.
Pharm Biol ; 62(1): 314-325, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38571483

RESUMO

CONTEXT: Cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. Although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored. OBJECTIVE: This study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (CCAs). MATERIALS AND METHODS: Cisplatin-resistant CCAs were exposed to varying concentrations of cisplatin (25-400 µg/mL) or BBD (0.25-1.00 mg/mL) for 48 h. IC50 values, inhibition ratios, apoptosis levels, DNA damage, glutathione (GSH) levels, oxidized forms of GSH, total GSH content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits. RESULTS: BBD-reduced the cisplatin IC50 in CCAs from 118.8 to 61.83 µg/mL, leading to increased inhibition rate, apoptosis, and DNA damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and ERCC excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43-115.77% and 22.15-53.39%. The impact of YAP1 knockdown on cisplatin-resistant CCAs resembled BBD. GSH, oxidized GSH species, total GSH content, and glutaminase activity in cisplatin-resistant CCAs with BBD treatment also decreased, while YAP1 overexpression countered BBD's effects. DISCUSSION AND CONCLUSION: This study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research.


Assuntos
Antineoplásicos , Neoplasias dos Ductos Biliares , Carcinoma Pulmonar de Células não Pequenas , Colangiocarcinoma , Neoplasias Pulmonares , Humanos , Cisplatino/farmacologia , Proteínas de Sinalização YAP , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Glutaminase/metabolismo , Glutaminase/farmacologia , Glutaminase/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Fatores de Transcrição/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Resistencia a Medicamentos Antineoplásicos , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral
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