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Metabolic reprogramming, an important hallmark of cancer, helps cancer achieve rapid proliferation. Metabolic changes in tumors regulate multiple metabolic pathways of immune cells, thereby suppressing antitumor immunity. Recent studies have been focused on in-depth investigation into the changes in the metabolism of glucose, amino acids, and lipids. Researchers have also conducted in-depth exploration of the interactive metabolic regulation of tumor cells and immune cells. Targeting various metabolic mechanisms while combining available anti-tumor therapies and enhancing the anti-tumor effects of immunotherapy by satisfying the metabolic demands of immune cells has offered new perspectives for therapies targeting the immune metabolism of tumors and enhancing anti-tumor immune responses. Studies on novel immune checkpoint molecules and cellular immunotherapies are also ongoing. Herein, we reviewed the latest findings on the mechanisms of immune metabolism underlying tumor immunosuppression and their application in immunotherapy. We also suggested some ideas for the future development of the regulation of immune metabolism.
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Neoplasias , Humanos , Neoplasias/terapia , Inmunoterapia , Microambiente TumoralRESUMEN
Oxidative stress (OS), characterized by the excessive accumulation of reactive oxygen species (ROS), is an emerging hallmark of cancer. Tumorigenesis and development driven by ROS require an aberrant redox homeostasis, that activates onco-signaling and avoids ROS-induced programmed death by orchestrating antioxidant systems. These processes are revealed to closely associate with noncoding RNAs (ncRNAs). On the basis of the available evidence, ncRNAs have been widely identified as multifarious modulators with the involvement of several key redox sensing pathways, such as NF-κB and Nrf2 signaling, therefore potentially becoming effective targets for cancer therapy. Furthermore, the vast majority of ncRNAs with property of easy detected in fluid samples (e.g., blood and urine) facilitate clinicians to monitor redox homeostasis, indicating a novel method for cancer diagnosis. Herein, focusing on carcinoma initiation, metastasis and chemoradiotherapy resistance, we aimed to discuss the ncRNAs-ROS network involved in cancer progression, and the potential clinical application as biomarkers and therapeutic targets.
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Regulación Neoplásica de la Expresión Génica , Neoplasias/genética , Neoplasias/metabolismo , ARN no Traducido/genética , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Terapia Combinada , Manejo de la Enfermedad , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Metástasis de la Neoplasia , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Estrés Oxidativo , Pronóstico , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
Cellular metabolism constitutes a fundamental process in biology. During tumor initiation and progression, each cellular component in the cancerous niche undergoes dramatic metabolic reprogramming, adapting to a challenging microenvironment of hypoxia, nutrient deprivation, and other stresses. While the metabolic hallmarks of cancer have been extensively studied, the metabolic states of the immune cells are less well elucidated. Here we review the metabolic disturbance and fitness of the immune system in the tumor microenvironment (TME), focusing on the impact of oncometabolites to the function of immune cells and the clinical significance of targeting metabolism in anti-tumor immunotherapy. Metabolic alterations in the immune system of TME offer novel therapeutic insight into cancer treatment.
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Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Metabolismo Energético , Neoplasias/etiología , Neoplasias/metabolismo , Microambiente Tumoral/inmunología , Adaptación Biológica , Animales , Transformación Celular Neoplásica/genética , Reprogramación Celular , Terapia Combinada , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Inmunomodulación , Inmunoterapia , Neoplasias/diagnóstico , Neoplasias/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: In this study, we aimed at elucidating the postoperative survival and prognostic factors in patients with biliary neuroendocrine neoplasm (NEN). METHODS: Cases of biliary system NEN and adenocarcinoma from 1975 to 2016 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. A propensity score matching (PSM) method was used to adjust baseline differences in clinicopathological characteristics in our analysis. The Kaplan-Meier analysis was carried out for survival analysis. RESULTS: A total of 233 patients with biliary system NEN were enrolled in this study, of which 119 patients' lesions located in gallbladder, while the others' located in bile duct. The postoperative overall survival of bile duct NEN is significantly longer than that of gallbladder NEN (P < 0.001). For gallbladder NENs, surgery method (P = 0.020) and lymph node metastasis (P = 0.018) were identified as independent prognostic factors. In terms of ampulla of vater (AOV) NENs, age (P = 0.017) and lymph node metastasis (P = 0.006) were identified as independent prognostic factors, while grade (P = 0.002) and lymph node metastasis (P = 0.036) were identified as independent prognostic factors for extrahepatic bile duct (EBD) NENs. PSM analysis indicated that patients with biliary duct NENs have a better postoperative prognosis than biliary duct adenocarcinoma. CONCLUSIONS: Patients with NEN have better overall survival than patients with adenocarcinoma. Gallbladder NEN has an adverse prognosis than that of biliary tract NEN. The pathological subtype, differentiation, lymph node metastasis, surgery method, and lymph node resection could affect the postoperative prognosis of the gallbladder and biliary tract NEN.
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Adenocarcinoma , Neoplasias de los Conductos Biliares , Conductos Biliares Extrahepáticos , Neoplasias de la Vesícula Biliar , Neoplasias Gastrointestinales , Tumores Neuroendocrinos , Adenocarcinoma/patología , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Extrahepáticos/patología , Conductos Biliares Intrahepáticos/patología , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/cirugía , Neoplasias Gastrointestinales/patología , Humanos , Metástasis Linfática , Tumores Neuroendocrinos/diagnóstico , Tumores Neuroendocrinos/cirugía , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVES: In this retrospective study, we examined the CA17 tissue expression and analyzed its clinical significance in cholangiocarcinoma (CCA). MATERIALS AND METHODS: Immunohistochemistry was performed to assess CA17 expression on tissue microarrays in a training cohort enrolling 120 CCA patients and a validation cohort comprising 60 CCA patients. Image pro plus was applied to score the staining intensity and expression level of CA17 marker. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of CA17. RESULTS: CA17 cancer biomarker over-expression was significantly observed in CCA compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis. Meanwhile, patients with high expression of CA17 correlated with worse postoperative overall survival (OS) and recurrence-free survival. Besides, multivariate analysis identified that CA17 expression was an independent prognostic factor for cholangiocarcinoma patients, which indicated that the CA17 could be more efficient than serum CA19-9 in predicting the OS of CCA patients. Notably, the nomogram integrating CA17 expression had better prognostic performance as compared with current TNM staging systems. CONCLUSION: CA17 was an independent adverse prognostic factor for CCA patients' survival, which may serve as a promising prognostic biomarker for CCA patients.
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Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Colangiocarcinoma/patología , Recurrencia Local de Neoplasia/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/cirugía , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The MUC16 C-terminal (MUC16c) level is associated with tumor serum CA-125 levels, however, the roles remain unclear in gallbladder carcinoma (GBC). In this study, we found that MUC16c promoted glucose uptake and glycolysis for GBC cell proliferation. Mass spectrometry analysis suggested that MUC16c could combine with aldolase. The ALDOC mRNA and protein are overexpressed in GBC tumors. The IHC results also showed the consistent up-regulation of. ALDOC and MUC16c level in GBC tumor tissues than in peritumor tissues. We determined that MUC16c combining with ALDOC promoted ALDOC protein stability and disrupted the ability of ALDOC sensing glucose deficiency, which activated AMPK pathway and increased GBC cell proliferation. ALDOC knockdown significantly inhibited the glucose uptake and glycolysis induced by MUC16c. Our study established important roles of MUC16c promoting GBC cell glycolysis and proliferation and revealed the underlying mechanism of CA-125-related heavy tumor metabolic burden in GBC.
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Antígeno Ca-125/metabolismo , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Fructosa-Bifosfato Aldolasa/metabolismo , Neoplasias de la Vesícula Biliar/metabolismo , Proteínas de la Membrana/metabolismo , Antígeno Ca-125/genética , Fructosa-Bifosfato Aldolasa/genética , Neoplasias de la Vesícula Biliar/genética , Regulación Neoplásica de la Expresión Génica/genética , Glucólisis/genética , Humanos , Proteínas de la Membrana/genéticaRESUMEN
In recent years, immunotherapy, as an emerging anti-tumor therapy, has shown great potential in the treatment of both solid and hematologic tumors. There is increasing preclinical and clinical evidence linking the composition of gut microbiome with the efficacy as well as adverse effects of immune checkpoint inhibitor anti-tumor therapy. We summarized in this review the modulatory role of the gut microbiome in antitumor therapy with different immune checkpoint inhibitors. We also discussed the limitations of existing research and prospective development of the further clinical strategies.
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Microbioma Gastrointestinal , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias/tratamiento farmacológico , Estudios ProspectivosRESUMEN
Chemokines play a key role in orchestrating the recruitment and positioning of myeloid cells within the tumor microenvironment. However, the tropism regulation and functions of these cells in hepatocellular carcinoma (HCC) are not completely understood. Herein, by scrutinizing the expression of all chemokines in HCC cell lines and tissues, we found that CCL15 was the most abundantly expressed chemokine in human HCC. Further analyses showed that CCL15 expression was regulated by genetic, epigenetic, and microenvironmental factors, and negatively correlated with patient clinical outcome. In addition to promoting tumor invasion in an autocrine manner, CCL15 specifically recruited CCR1+ cells toward HCC invasive margin, approximately 80% of which were CD14+ monocytes. Clinically, a high density of marginal CCR1+ CD14+ monocytes positively correlated with CCL15 expression and was an independent index for dismal survival. Functionally, these tumor-educated monocytes directly accelerated tumor invasion and metastasis through bursting various pro-tumor factors and activating signal transducer and activator of transcription 1/3, extracellular signal-regulated kinase 1/2, and v-akt murine thymoma viral oncogene homolog signaling in HCC cells. Meanwhile, tumor-derived CCR1+ CD14+ monocytes expressed significantly higher levels of programmed cell death-ligand 1, B7-H3, and T-cell immunoglobulin domain and mucin domain-3 that may lead to immune suppression. Transcriptome sequencing confirmed that tumor-infiltrating CCR1+ CD14+ monocytes were reprogrammed to upregulate immune checkpoints, immune tolerogenic metabolic enzymes (indoleamine and arginase), inflammatory/pro-angiogenic cytokines, matrix remodeling proteases, and inflammatory chemokines. Orthotopic animal models confirmed that CCL15-CCR1 axis forested an inflammatory microenvironment enriched with CCR1+ monocytes and led to increased metastatic potential of HCC cells. Conclusion: A complex tumor-promoting inflammatory microenvironment was shaped by CCL15-CCR1 axis in human HCC. Blockade of CCL15-CCR1 axis in HCC could be an effective anticancer therapy.
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Carcinoma Hepatocelular/inmunología , Quimiocinas CC/fisiología , Progresión de la Enfermedad , Neoplasias Hepáticas/inmunología , Proteínas Inflamatorias de Macrófagos/fisiología , Monocitos/fisiología , Escape del Tumor/fisiología , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/patología , Células Tumorales CultivadasRESUMEN
OBJECTIVE: Immunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: We investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry. RESULTS: We found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity. CONCLUSION: CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
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Neoplasias de los Conductos Biliares , Colangiocarcinoma , Antígeno B7-H1 , Linfocitos T CD8-positivos , Humanos , Ligandos , Linfocitos Infiltrantes de Tumor , Pronóstico , Receptor de Muerte Celular Programada 1RESUMEN
BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (ICC) is the second-most lethal primary liver cancer. Little is known about intratumoral heterogeneity (ITH) and its impact on ICC progression. We aimed to investigate the ITH of ICC in the hope of helping to develop new therapeutic strategies. METHODS: We obtained 69 spatially distinct regions from six operable ICCs. Patient-derived primary cancer cells (PDPCs) were established for each region, followed by whole-exome sequencing (WES) and multi-level validation. RESULTS: We observed widespread ITH for both somatic mutations and clonal architecture, shaped by multiple mechanisms, like clonal "illusion", parallel evolution and chromosome instability. A median of 60.3% of mutations were heterogeneous, among which 85% of the driver mutations were located on the branches of tumor phylogenetic trees. Many truncal and clonal driver mutations occurred in tumor suppressor genes, such as TP53, SMARCB1 and PBRM1 that are involved in DNA repair and chromatin-remodeling. Genome doubling occurred in most cases (5/6) after the accumulation of truncal mutations and was shared by all intratumoral sub-regions. In all cases, ongoing chromosomal instability is evident throughout the evolutionary trajectory of ICC. The recurrence of ICC1239 provided evidence to support the polyclonal metastatic seeding in ICC. The change of mutation landscape and internal diversity among subclones during metastasis, such as the loss of chemoresistance mediator, can be used for new treatment strategies. Targeted therapy against truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, was developed in 5/6 patients. CONCLUSIONS: Integrated investigations of spatial ITH and clonal evolution may provide an important molecular foundation for enhanced understanding of tumorigenesis and progression in ICC. LAY SUMMARY: We applied multiregional whole-exome sequencing to investigate the evolution of intrahepatic cholangiocarcinoma (ICC). The results revealed that many factors, such as parallel evolution and chromosome instability, may participate and promote the branch diversity of ICC. Interestingly, in one patient with primary and recurrent metastatic tumors, we found evidence of polyclonal metastatic seeding, indicating that symbiotic communities of multiple clones existed and were maintained during metastasis. More realistically, some truncal alterations, such as IDH1, JAK1, and KRAS mutations and EGFR amplification, could be promising treatment targets in patients with ICC.
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Neoplasias de los Conductos Biliares/genética , Colangiocarcinoma/genética , Inestabilidad Cromosómica/genética , Evolución Clonal/genética , ADN de Neoplasias/genética , Mutación , Anciano , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/patología , Colangiocarcinoma/patología , Progresión de la Enfermedad , Exoma , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Radiomics is an emerging field in oncological research. In this study, we aimed at developing a radiomics score (rad-score) to estimate postoperative recurrence and survival in patients with solitary hepatocellular carcinoma (HCC). METHODS: A total of 319 solitary HCC patients (training cohort: n = 212; validation cohort: n = 107) were enrolled. Radiomics features were extracted from the artery phase of preoperatively acquired computed tomography (CT) in all patients. A rad-score was generated by using the least absolute shrinkage and selection operator (lasso) logistic model. Kaplan-Meier and Cox's hazard regression analyses were used to evaluate the prognostic significance of the rad-score. Final nomograms predicting recurrence and survival of solitary HCC patients were established based on the rad-score and clinicopathological factors. C-index and calibration statistics were used to assess the performance of nomograms. RESULTS: Six potential radiomics features were selected out of 110 texture features to formulate the rad-score. Low rad-score positively correlated with aggressive tumor phenotypes, like larger tumor size and vascular invasion. Meanwhile, low rad-score was significantly associated with increased recurrence and reduced survival. In addition, multivariate analysis identified the rad-score as an independent prognostic factor (recurrence: Hazard ratio (HR): 2.472, 95% confident interval (CI): 1.339-4.564, p = 0.004;survival: HR: 1.558, 95%CI: 1.022-2.375, p = 0.039). Notably, the nomogram integrating rad-score had a better prognostic performance as compared with traditional staging systems. These results were further confirmed in the validation cohort. CONCLUSIONS: The preoperative CT image based rad-score was an independent prognostic factor for the postoperative outcome of solitary HCC patients. This score may be complementary to the current staging system and help to stratify individualized treatments for solitary HCC patients.
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Carcinoma Hepatocelular/diagnóstico por imagen , Hepatectomía/métodos , Neoplasias Hepáticas/diagnóstico por imagen , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/cirugía , Estudios de Cohortes , Diagnóstico por Imagen/métodos , Diagnóstico por Imagen/normas , Diagnóstico por Imagen/estadística & datos numéricos , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Nomogramas , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Periodo Posoperatorio , Pronóstico , Modelos de Riesgos Proporcionales , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Frequently aberrant expression of cytokeratin 7 (CK7) and cytokeratin 19 (CK19) have been observed in several human cancers. In this retrospective study, we aimed at investigating the prognostic significance of CK7 and CK19 in intrahepatic cholangiocarcinoma (ICC). METHODS: Immunohistochemistry was performed to assess CK7 and CK19 expression on tissue microarrays in training cohort enrolling 214 ICC patients and validation cohort comprising 108 ICC patients. Kaplan-Meier analysis, Cox's proportional hazards regression, and nomogram were applied to evaluate the prognostic significance of both CKs. RESULTS: Both CK7 and CK19 expression were significantly up-regulated in ICC compared to their non-tumor counterparts, and positively correlated with aggressive tumor phenotypes, like lymph node metastasis and larger tumor size. Furthermore, high expression of either CK7 or CK19 predicted a significantly dismal postoperative survival. Integrated analysis of CK7 and CK19 expression was identified as a better indicator for survival probability. Notably, the nomogram integrating CK7/CK19 index had a perfect prognostic performance as compared with current staging systems. The results were further confirmed in the validation cohort. CONCLUSIONS: CK7/CK19 index was an independent adverse prognostic factor for ICC patients' survival, and may be helpful to improve postoperative risk stratification and individualized treatment strategies.
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Neoplasias de los Conductos Biliares/patología , Biomarcadores de Tumor/metabolismo , Colangiocarcinoma/patología , Hepatectomía/mortalidad , Queratina-19/metabolismo , Queratina-7/metabolismo , Nomogramas , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/cirugía , Colangiocarcinoma/metabolismo , Colangiocarcinoma/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Nasopharyngeal carcinoma (NPC) arises from the mucosal epithelium of the nasopharynx and is frequently located in the pharyngeal crypts. This is a highly aggressive malignant tumor that frequently leads to distant metastases in many cases and poses a significant public health challenge, particularly in certain geographic regions globally. This review discusses the epidemiology, risk factors, diagnosis, and treatment options for NPC, emphasizing the importance of early detection and comprehensive management strategies in improving patient outcomes. Moreover, the article explores the intricate mechanisms that cause NPC. Comprehending these fundamental principles can assist in creating specific prevention and therapy approaches for NPC. Recent advances in diagnostic methods, including imaging tests and molecular biomarkers, are emphasized to improve early diagnosis and individualized treatment strategies for individuals with NPC. The review also explores the most recent advancements in treating early-stage (stage I and II) NPC patients, highlighting the changing landscape of individualized therapy approaches for this particular set of patients.
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In this editorial we comment on the review by Wang et al published in the recent issue of the World Journal of Gastroenterology in 2023. Small extracellular vesicles (exosomes) play important roles in the tumor microenvironment. In this review, the authors introduce the following points: (1) The composition and function of exosomal microRNAs (miRNAs) of different cell origins in hepatocellular carcinoma (HCC); (2) the crosstalk between exosomal miRNAs from stromal cells and immune cells in the tumor microenvironment and the progression of HCC; and (3) the potential applicability of exosomal miRNAs derived from mesen-chymal stem cells in the treatment of HCC. In addition, the potential applicability of exosomal miRNAs derived from mesenchymal stem cells in the treatment of HCC was introduced. In this review, the authors give us an overview of the exosomal RNA and summarize the function of exosomal RNA in HCC, which provides a deeper understanding of exosomal miRNAs to the readers.
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Carcinoma Hepatocelular , Exosomas , Neoplasias Hepáticas , MicroARNs , Microambiente Tumoral , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Exosomas/metabolismo , Exosomas/genética , MicroARNs/metabolismo , MicroARNs/genética , Microambiente Tumoral/inmunología , Regulación Neoplásica de la Expresión Génica , Células Madre Mesenquimatosas/metabolismo , Progresión de la Enfermedad , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
Ferroptosis is an iron-dependent form of cell death, distinct from apoptosis, necrosis, and autophagy, and is characterized by altered iron homeostasis, reduced defense against oxidative stress, and increased lipid peroxidation. Extensive research has demonstrated that ferroptosis plays a crucial role in the treatment of gynecological malignancies, offering new strategies for cancer prevention and therapy. However, chemotherapy resistance poses an urgent challenge, significantly hindering therapeutic efficacy. Increasing evidence suggests that inducing ferroptosis can reverse tumor resistance to chemotherapy. This article reviews the mechanisms of ferroptosis and discusses its potential in reversing chemotherapy resistance in gynecological cancers. We summarized three critical pathways in regulating ferroptosis: the regulation of glutathione peroxidase 4 (GPX4), iron metabolism, and lipid peroxidation pathways, considering their prospects and challenges as strategies to reverse chemotherapy resistance. These studies provide a fresh perspective for future cancer treatment modalities.
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Abnormal mTORC1 activation by the lysosomal Ragulator complex has been implicated in cancer and glycolytic metabolism associated with drug resistance. Fasting upregulates RNF152 and mediates the metabolic status of cells. We report that RNF152 regulates mTORC1 signaling by targeting a Ragulator subunit, p18, and attenuates gemcitabine resistance in gallbladder cancer (GBC). We detected levels of RNF152 and p18 in tissues and undertook mechanistic studies using activators, inhibitors, and lentivirus transfections. RNF152 levels were significantly lower in GBC than in adjacent non-cancer tissues. Fasting impairs glycolysis, induces gemcitabine sensitivity, and upregulates RNF152 expression. RNF152 overexpression increases the sensitivity of GBC cells to gemcitabine, whereas silencing RNF152 has the opposite effect. Fasting-induced RNF152 ubiquitinates p18, resulting in proteasomal degradation. RNF152 deficiency increases the lysosomal localization of p18 and increases mTORC1 activity, to promote glycolysis and decrease gemcitabine sensitivity. RNF152 suppresses mTORC1 activity to inhibit glycolysis and enhance gemcitabine sensitivity in GBC.
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Due to soared obesity population worldwide, hepatosteatosis is becoming a major risk factor for hepatocellular carcinoma (HCC). Undertaken molecular events during the progression of steatosis to liver cancer are thus under intensive investigation. In this study, we demonstrated that high-fat diet potentiated mouse liver AKT2. Hepatic AKT2 hyperactivation through gain-of-function mutation of Akt2 (Akt2E17K) caused spontaneous hepatosteatosis, injury, inflammation, fibrosis, and eventually HCC in mice. AKT2 activation also exacerbated lipopolysaccharide and D-galactosamine hydrochloride-induced injury/inflammation and N-Nitrosodiethylamine (DEN)-induced HCC. A positive correlation between AKT2 activity and SCD1 expression was observed in human HCC samples. Activated AKT2 enhanced the production of monounsaturated fatty acid which was dependent on SREBP1 upregulation of SCD1. Blockage of active SREBP1 and ablation of SCD1 reduced steatosis, inflammation, and tumor burden in DEN-treated Akt2E17K mice. Therefore, AKT2 activation is crucial for the development of steatosis-associated HCC which can be treated with blockage of AKT2-SREBP1-SCD1 signaling cascade.
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Metabolismo de los Lípidos , Neoplasias Hepáticas , Proteínas Proto-Oncogénicas c-akt , Estearoil-CoA Desaturasa , Proteína 1 de Unión a los Elementos Reguladores de Esteroles , Animales , Humanos , Masculino , Ratones , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/genética , Dieta Alta en Grasa/efectos adversos , Hígado Graso/metabolismo , Hígado Graso/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismo , Estearoil-CoA Desaturasa/metabolismo , Estearoil-CoA Desaturasa/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genéticaRESUMEN
Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.
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Neoplasias , Microambiente Tumoral , Humanos , Células Asesinas Naturales , Inmunoterapia , Neoplasias/metabolismoRESUMEN
Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common and lethal malignant diseases. Immunotherapy has been widely studied and has exhibited potential in ESCC treatment. However, there are only a portion of ESCC patients have benefited from immunotherapy. We herein identified immunotherapeutic response-related signatures (IRRS) and evaluated their performance in ESCC prognosis and immunotherapeutic responsiveness. Methods: We constructed an IRRS using the gene expression data of 274 ESCC patients based on y -30significantly differentially expressed genes, which were compared responders and non-responders from various patient cohorts treated with immunotherapy. Survival analysis was performed in both the GSE53625 and TCGA-ESCC cohorts. We also explored the differences in the tumor microenvironment between the high-IRRS and low-IRRS score groups using single-cell data as a reference. Three immunotherapy cohorts were used to verify the value of the IRRS in predicting immunotherapy response. Results: Twelve immunotherapy-related genes were selected to construct a signature score and were validated as independent prognostic predictors for patients with ESCC. Patients with high IRRS scores exhibited an immunosuppressive phenotype. Therefore, patients with low IRRS scores may benefit from immunotherapy. Conclusions: IRRS score is a biomarker for immunotherapy response and prognosis of ESCC.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Humanos , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/patología , Biomarcadores de Tumor/genética , Pronóstico , Inmunoterapia , Microambiente TumoralRESUMEN
ABSTRACT: Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.