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Hepatocellular carcinoma (HCC) is a lethal form of liver cancer, and the tumor microenvironment, particularly cancer-associated fibroblasts (CAFs), plays a critical role in its progression. This study aimed to elucidate the mechanism by which CAF-derived exosomes regulate the development of HCC. The study employed quantitative real-time polymerase chain reaction for mRNA expression analysis and western blot analysis for protein expression detection. Chromatin immunoprecipitation assay and dual-luciferase reporter assay were performed to investigate the relationship between zinc finger protein 250 (ZNF250) and programmed cell death 1 ligand 1 (PD-L1). Transmission electron microscopy and western blot analysis were used to characterize the isolated exosomes. The transferability of CAF-derived exosomes and normal fibroblasts (NFs)-derived exosomes into HCC cells was analyzed using a green fluorescent labeling dye PKH67. Cell proliferation was assessed via a 5-Ethynyl-2'-deoxyuridine assay, while Transwell assays were conducted to evaluate cell migration and invasion. Flow cytometry was performed to measure cell apoptosis, while enzyme-linked immunosorbent assays were used to assess the levels of tumor necrosis factor-α and perforin. Finally, a xenograft mouse model was constructed to examine the effects of exosomes derived from ZNF250-deficient CAFs on the tumor properties of HCC cells. The study revealed increased expression of ZNF250 in HCC tissues and cells, with ZNF250 transcriptionally activating PD-L1 in HCC cells. ZNF250 expression was associated with HbsAg, clinical stage and tumor size of HCC patients. CAF-derived exosomal ZNF250 can regulate PD-L1 expression in HCC cells. Furthermore, exosomes derived from ZNF250-deficient CAFs inhibited the proliferation, migration, invasion, and immune escape of HCC cells by downregulating PD-L1 expression. Moreover, CAF-derived exosomal ZNF250 promoted tumor formation in vivo. These findings provide insights into the role of CAF-derived exosomes in the suppression of HCC development, highlighting the significance of ZNF250 and PD-L1 regulation in tumor progression.
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Antígeno B7-H1 , Fibroblastos Asociados al Cáncer , Carcinoma Hepatocelular , Movimiento Celular , Proliferación Celular , Exosomas , Neoplasias Hepáticas , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Humanos , Exosomas/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Animales , Ratones , Invasividad Neoplásica , Línea Celular Tumoral , Escape del Tumor , Ratones Desnudos , Masculino , Activación Transcripcional , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación Neoplásica de la Expresión GénicaAsunto(s)
Vacuna BCG , Neoplasias de la Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Humanos , Vacuna BCG/administración & dosificación , Vacuna BCG/uso terapéutico , Administración Intravesical , Estudios de Seguimiento , Invasividad Neoplásica , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Resultado del TratamientoRESUMEN
Background Contrast-enhanced US (CEUS) can be used preoperatively for evaluating muscle invasion in bladder cancer, which is important for determining appropriate treatment. However, diagnostic criteria for assessing this at CEUS have not been standardized. Purpose To develop and validate a CEUS Vesical Imaging Reporting and Data System (VI-RADS) for evaluating muscle invasion in bladder cancer. Materials and Methods This single-center prospective study consecutively enrolled patients with suspected bladder cancer. Participants underwent transabdominal or intracavity CEUS between July 2021 and May 2023. Participants were divided into a training set and a validation set at a 2:1 ratio based on the chronologic order of enrollment. The training set was used to identify major imaging features to include in CEUS VI-RADS, and the likelihood of muscle invasion per category was determined using a pathologic reference standard. The optimal VI-RADS category cutoff for muscle invasion was determined with use of the maximum Youden index. The validation set was assessed by novice and expert readers and used to validate the diagnostic performance and interreader agreement of the developed system. Results Overall, 126 participants (median age, 64 years [IQR, 57-71 years]; 107 male) and 67 participants (median age, 64 years [IQR, 56-69 years]; 49 male) were included in the training and validation set, respectively. In the training set, the optimal CEUS VI-RADS category cutoff for muscle invasion was VI-RADS 4 or higher (Youden index, 0.77). In the validation set, CEUS VI-RADS achieved good performance for both novice and expert readers (area under the receiver operating characteristic curve, 0.80 [95% CI: 0.70, 0.90] vs 0.88 [95% CI: 0.80, 0.97]; P = .09). The interreader agreement regarding the evaluation of CEUS VI-RADS category was 0.77 (95% CI: 0.65, 0.85) for novice readers, 0.87 (95% CI: 0.79, 0.92) for expert readers, and 0.78 (95% CI: 0.70, 0.84) for all readers. Conclusion The developed CEUS VI-RADS showed good performance and interreader agreement for the assessment of muscle invasion in bladder cancer. Chinese Clinical Trial Registry no. ChiCTR2100049435 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Morrell in this issue.
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Medios de Contraste , Invasividad Neoplásica , Ultrasonografía , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Prospectivos , Ultrasonografía/métodos , Invasividad Neoplásica/diagnóstico por imagen , Vejiga Urinaria/diagnóstico por imagen , Vejiga Urinaria/patología , Reproducibilidad de los ResultadosRESUMEN
Background: Diffuse astrocytomas preferentially infiltrate eloquent areas affecting the outcome. A preoperative understanding of isocitrate dehydrogenase (IDH) status may offer opportunities for specific targeted therapies impacting treatment management. The aim of this study was to analyze clinical, topographical, radiological in WHO 2 astrocytomas with different IDH status and the long-term patient's outcome. Methods: A series of confirmed WHO 2 astrocytoma patients (between 2005 and 2015) were retrospectively analyzed. MRI sequences (FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations into the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was used as an overlay for infiltration analysis of each tumor. Long-term follow-up was used to perform a survival analysis. Results: Forty patients with confirmed IDH status (26 IDH-mutant, IDHm/14 IDH-wild type, IDHwt) according to WHO 2021 classification were included with a mean follow-up of 7.8 years. IDHm astrocytomas displayed a lower number of BG-voxels (P < 0.05) and were preferentially located in the anterior insular region. IDHwt group displayed a posterior insular and peritrigonal location. IDHwt group displayed a shorter OS compared with IDHm (P < 0.05), with the infiltration of 7 or more BG-voxels as an independent factor predicting a shorter OS. Conclusions: IDHm and IDHwt astrocytomas differed in preferential location, number of BG-voxels and OS at long follow-up time. The number of BG-voxels affected the OS in IDHwt was possibly reflecting higher tumor invasiveness. We encourage the systematic use of alternative observational tools, such as gradient maps and the Brain-Grid analysis, to better detect differences of tumor invasiveness in diffuse low-grade gliomas subtypes.
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Astrocitoma , Neoplasias Encefálicas , Isocitrato Deshidrogenasa , Imagen por Resonancia Magnética , Humanos , Isocitrato Deshidrogenasa/genética , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Astrocitoma/genética , Femenino , Masculino , Estudios Retrospectivos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Pronóstico , Persona de Mediana Edad , Adulto , Mutación , Anciano , Invasividad Neoplásica , Análisis de Supervivencia , Adulto JovenRESUMEN
Purpose: Matrix metalloproteinase-11 (MMP11), which belongs to the stromelysin subgroup, has been reported to play a role in the progression of colorectal cancer (CRC). However, the significance of MMP11 in the tumor microenvironment, immune/stromal cells, and its mechanism in CRC remain unclear. Methods: The impact of MMP11 knockdown using specific short hairpin RNAs (shRNAs) on the metastasis and invasion of colorectal cancer RKO and SW480 cells was investigated using western blot, quantitative real-time polymerase chain reaction (qRT-PCR), transwell assays, and immunohistochemistry. Results: MMP11 mRNA expression was significantly higher in CRC cells than in normal cells, and its expression was stimulated in CCD-18Co fibroblasts. Additionally, MMP11 expression was found to be higher in individuals aged ≤ 65 years, the T4/T3 group, and Stage III/IV patients. Overall survival (OS) and disease-free survival rates were significantly different between the high and low MMP11 groups. Furthermore, the receiver operating characteristic (ROC) curves for MMP11 at 1-, 3-, and 5-years were 0.450, 0.552, and 0.560, respectively. Moreover, MMP11 promoted the migration and invasion of CRC cells by elevating the expression of Slug protein. Most importantly, MMP11 was positively associated with M0-macrophages and negatively associated with M1-macrophages, NK cells activated, NK cells resting, T cells CD4 memory activated, and T cells follicular helper, indicating the remarkable interactions of MMP11 with tumor immunology. Conclusions: MMP11 plays an important role in colorectal cancer development, and its mechanism in CRC needs to be further explored in the future.
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Movimiento Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 11 de la Matriz , Invasividad Neoplásica , Factores de Transcripción de la Familia Snail , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Metaloproteinasa 11 de la Matriz/genética , Metaloproteinasa 11 de la Matriz/metabolismo , Invasividad Neoplásica/genética , Movimiento Celular/genética , Masculino , Línea Celular Tumoral , Femenino , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Supervivencia sin EnfermedadRESUMEN
Tumours often display invasive behaviours that induce fingering, branching and fragmentation processes. The phenomenon, known as diffusional instability, is driven by differential cell proliferation, migration, and death due to the presence of metabolite and catabolite concentration gradients. An understanding of the intricate dynamics of this spatially heterogeneous process plays a key role in the investigation of tumour growth and invasion. In this study, we developed an in vitro tumour invasion assay to investigate cell invasiveness in tumour spheroids under a chemotactic stimulus. Our method, employing tumour spheroids seeded in a 3D collagen gel within a microfluidic chemotaxis chamber, focuses on the role of diffusive gradients. Using Time-Lapse Microscopy, the dynamic evolution of tumour spheroids was monitored in real-time, providing a comprehensive view of the morphological changes and cell migration patterns under different chemotactic conditions. Specifically, we explored the impact of fetal bovine serum (FBS) gradients on the behaviour of CT26 mouse colon carcinoma cells and compared the effects of varying FBS concentrations to two isotropic control conditions. Furthermore, a finite element in silico model was developed to quantify the diffusive flow of nutrients in the chemotaxis chamber and obtain a detailed understanding of tumour dynamics. Our findings reveal that the presence of a chemotactic gradient significantly influences tumour invasiveness, with higher concentrations of nutrients associated with increased cancer growth and cell migration.
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Movimiento Celular , Quimiotaxis , Esferoides Celulares , Microambiente Tumoral , Esferoides Celulares/patología , Animales , Ratones , Línea Celular Tumoral , Proliferación Celular , Nutrientes/metabolismo , Invasividad Neoplásica , HumanosRESUMEN
BACKGROUND: Postoperative recurrence is a vital reason for poor 5-year overall survival in hepatocellular carcinoma (HCC) patients. The ADV score is considered a parameter that can quantify HCC aggressiveness. This study aimed to identify HCC patients at high-risk of recurrence early using the ADV score. METHODS: The medical data of consecutive HCC patients undergoing hepatectomy from The First Affiliated Hospital of Nanjing Medical University (TFAHNJMU) and Nanjing Drum Tower Hospital (NJDTH) were retrospectively reviewed. Based on the status of microvascular invasion and the Edmondson-Steiner grade, HCC patients were divided into three groups: low-risk group (group 1: no risk factor exists), medium-risk group (group 2: one risk factor exists), and high-risk group (group 3: coexistence of two risk factors). In the training cohort (TFAHNJMU), the R package nnet was used to establish a multi-categorical unordered logistic regression model based on the ADV score to predict three risk groups. The Welch's T-test was used to compare differences in clinical variables in three predicted risk groups. NJDTH served as an external validation center. At last, the confusion matrix was developed using the R package caret to evaluate the diagnostic performance of the model. RESULTS: 350 and 405 patients from TFAHNJMU and NJDTH were included. HCC patients in different risk groups had significantly different liver function and inflammation levels. Density maps demonstrated that the ADV score could best differentiate between the three risk groups. The probability curve was plotted according to the predicted results of the multi-categorical unordered logistic regression model, and the best cut-off values of the ADV score were as follows: low-risk ≤ 3.4 log, 3.4 log < medium-risk ≤ 5.7 log, and high-risk > 5.7 log. The sensitivities of the ADV score predicting the high-risk group (group 3) were 70.2% (99/141) and 78.8% (63/80) in the training and external validation cohort, respectively. CONCLUSION: The ADV score might become a valuable marker for screening patients at high-risk of HCC recurrence with a cut-off value of 5.7 log, which might help surgeons, pathologists, and HCC patients make appropriate clinical decisions.
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Carcinoma Hepatocelular , Hepatectomía , Neoplasias Hepáticas , Recurrencia Local de Neoplasia , Humanos , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/diagnóstico , Estudios Retrospectivos , Femenino , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Persona de Mediana Edad , Factores de Riesgo , Estudios de Seguimiento , Pronóstico , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Detección Precoz del Cáncer/métodos , Invasividad Neoplásica , Tasa de Supervivencia , AncianoRESUMEN
BACKGROUND: The actin-binding protein anillin (ANLN) functions as an oncogene in various cancers but has not been fully studied in oral squamous cell carcinoma (OSCC). This study aimed to investigate the expression of ANLN in OSCC tissues and cell lines, to better understand its role in mediating proliferative, angiogenic, invasive, and metastatic capabilities in this type of cancer. METHODS: ANLN mRNA and protein levels were assessed using qPCR and western immunoblotting. The expression intensity of ANLN was evaluated using immunohistochemical (IHC) staining. Biological functional assays were employed to characterize the behavior of OSCC cells influenced by ANLN. Additionally, comprehensive bioinformatics analysis, including GO analysis and KEGG enrichment analysis, was performed on differentially expressed genes in ANLN-mediated pathways. RESULTS: OSCC tumors and cell lines exhibited higher ANLN expression. Silencing of ANLN significantly suppressed OSCC cell proliferation, as evidenced by a significant reduction in the Ki-67 index both in vitro and in vivo. The migration and invasive ability of OSCC cells were markedly diminished, coinciding with a decrease in epithelial-mesenchymal transition activity. ANLN was also found to promote angiogenic activity in OSCC cells, partly through synergistic effects mediated by vascular endothelial growth factor A (VEGFA). Downregulation of ANLN expression led to decreased VEGFA levels, resulting in reduced angiogenesis characterized by fewer vascular branches. CONCLUSIONS: Our findings highlight the promising role of ANLN as a biomarker for both diagnostic and prognostic in OSCC. Targeting ANLN with inhibitory strategies could impede the oncogenesis processes at the core of OSCC development, presenting significant opportunities for advancing therapeutic interventions.
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Movimiento Celular , Proliferación Celular , Proteínas de Microfilamentos , Neoplasias de la Boca , Invasividad Neoplásica , Neovascularización Patológica , Humanos , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Proliferación Celular/genética , Neovascularización Patológica/genética , Neovascularización Patológica/patología , Neovascularización Patológica/metabolismo , Movimiento Celular/genética , Invasividad Neoplásica/genética , Proteínas de Microfilamentos/metabolismo , Proteínas de Microfilamentos/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Animales , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Silenciador del Gen , Ratones , Transición Epitelial-Mesenquimal/genética , Femenino , Masculino , AngiogénesisRESUMEN
BACKGROUND: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients. METHODS: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA. RESULTS: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS. CONCLUSION: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.
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Neoplasias de la Mama , Linfocitos Infiltrantes de Tumor , Recurrencia Local de Neoplasia , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Persona de Mediana Edad , Estudios Retrospectivos , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/metabolismo , Anciano , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Adulto , Metástasis Linfática/patología , Metástasis Linfática/inmunología , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral/inmunología , Invasividad Neoplásica , PronósticoRESUMEN
PURPOSE: The aim of this study was to explore the potential correlation between the nuclear receptor subfamily 3 group C member 2 (NR3C2) and outcomes of colon cancer, along with the mechanisms underlying this association. METHOD: mRNA (messenger RNA) data and clinical records pertaining to colon cancer were retrieved from The Cancer Genome Atlas (TCGA) database. The analysis of NR3C2 expression discrepancies between normal colon and tumor tissues was conducted using R software. In addition, we also studied the relationship between NR3C2 expression and prognosis, pathological parameters. The relative role of NR3C2 were further predicted through bioinformatics methods and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of NR3C2 in colon cancer. Single-cell data from colon cancer samples in the GEO (Gene Expression Omnibus) database further investigated the mechanism of the lower survival associated with NR3C2 dysregulation. NR3C2 expression in three fresh colon cancer samples and their respective paracancer samples was determined. Furthermore, colon cancer cell models overexpressing NR3C2 and with knockdown NR3C2 were constructed by lentiviral vector transfection. Cell Counting Kit-8 assay, transplantation of tumors in nude mice and transwell assays were used to examine the proliferation, migration and invasion of colon cancer cells. The effect on the Wnt/ß-catenin pathway, activities of cellular autophagy and cell apoptosis were examined by assessing the expression levels of several key proteins, including Bcl-2, Bax, and LC3. RESULTS: We found that NR3C2 was found a significantly lower level in colon cancer tissues than in adjacent tissues, which was associated with distant and lymphatic metastases, clinical stage, and poor clinical outcome, and it was an independent prognostic factor and potential marker of colon cancer. Single-cell transcriptome data identified the subset of circulating T and B cells with high expression of NR3C2, which is involved in TNF signaling pathway. Functional experiments show that downregulation of NR3C2 resultsed in the activation of the Wnt/ß-catenin signaling pathway, and promotesd the proliferation and invasion of colon cancer cells while suppressing cell autophagy and apoptosis. CONCLUSION: NR3C2 may regulate Wnt/ß-catenin to affect the proliferation, invasion apoptosis and autophagy of colon cancer, and this axis is a potential target for the treatment of colon cancer.
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Proliferación Celular , Neoplasias del Colon , Ratones Desnudos , Invasividad Neoplásica , Vía de Señalización Wnt , Humanos , Neoplasias del Colon/patología , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Animales , Ratones , Masculino , Pronóstico , Femenino , Movimiento Celular/genética , Ratones Endogámicos BALB C , Línea Celular Tumoral , Receptores de Hormona Tiroidea/metabolismo , Receptores de Hormona Tiroidea/genética , Regulación Neoplásica de la Expresión Génica , Apoptosis , beta Catenina/metabolismo , beta Catenina/genética , Persona de Mediana Edad , Receptores de MineralocorticoidesRESUMEN
OBJECTIVE: To establish an animal model of oral squamous cell carcinoma invading the mandible through multi-sample experiments that verified the stability, repeatability, tumorigenicity and mandible destruction rate of the model. METHODS: Oral squamous cell carcinoma cell suspension was injected into the outer side of the mandible through the anterior edge of the masseter muscle of naked mice to observe the tumourforming process. Then, the anatomical, histological and imaging examinations were carried out to determine whether the tumour had invaded the mandible. By comparing the tumour growth of multiple groups of various squamous cell carcinoma cells (CAL27, HN6 and HN30 cells), the changes in body weight and characteristics of tumour formation were compared, and the experience was summarised to further verify the stability, repeatability, tumour formation rate and arch damage rate of the model. RESULTS: The subsequent specimens of tumour-bearing nude mice were validated once the model had been established. In vitro, tumour tissue wrapped around the mandible's tumour-bearing side, and the local texture was tough with no resistance to acupuncture. Haematoxylin and eosin staining revealed that squamous cells were infiltrating the mandible in both the horizontal and sagittal planes. Microcomputed tomography results showed that the mandible on the tumour-bearing side displayed obvious erosion damage. Cell lines with various passage rates clearly had diverse tumour-bearing life cycles. CONCLUSION: This study successfully established an animal model of oral squamous cell carcinoma invasion of the mandible. The model has excellent biological stability, repeatability, tumorigenesis rate and mandible destruction rate.
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Carcinoma de Células Escamosas , Modelos Animales de Enfermedad , Mandíbula , Ratones Desnudos , Neoplasias de la Boca , Invasividad Neoplásica , Animales , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/patología , Ratones , Mandíbula/patología , Línea Celular Tumoral , Microtomografía por Rayos X , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/diagnóstico por imagen , Trasplante de Neoplasias , Masculino , Ratones Endogámicos BALB CRESUMEN
A 15-year-old domestic shorthair cat was presented with gastrointestinal signs, polyuria, polydipsia, and weakness. Abdominal bruit ("whooshing" sound from turbulent blood flow) and hypertension (systolic blood pressure: 200 mmHg) were present. A left adrenal gland mass was detected with abdominal ultrasonography; a subsequent CT examination identified a mass and a thrombus in the ipsilateral renal vein. Adrenalectomy and venotomy were completed but nephrectomy was not necessary. Histological diagnosis was an adrenocortical carcinoma. There were no clinical signs at a follow-up examination 30 mo after surgery. Key clinical message: This report describes successful surgical management of feline adrenocortical carcinoma with renal vein invasion without kidney damage. This case suggests that, after correct diagnosis and in well-selected cases, surgery to remove adrenal tumors and thrombi in cats, despite renal vein invasion, can be done with excellent short- and long-term outcomes.
Sauvegarde des reins lors du traitement chirurgical d'un carcinome corticosurrénalien avec invasion des veines rénales chez un chatUn chat domestique à poil court de 15 ans a été présenté avec des signes gastro-intestinaux, une polyurie, une polydipsie et une faiblesse. Des bruits abdominaux (« sifflement ¼ provenant d'un flux sanguin turbulent) et une hypertension (pression artérielle systolique: 200 mmHg) étaient présents. Une masse de la glande surrénale gauche a été détectée à l'échographie abdominale; un examen tomodensitométrique ultérieur a identifié une masse et un thrombus dans la veine rénale ipsilatérale. La surrénalectomie et la veinotomie ont été réalisées mais la néphrectomie n'a pas été nécessaire. Le diagnostic histologique était un carcinome corticosurrénalien. Il n'y avait aucun signe clinique lors d'un examen de suivi 30 mois après l'intervention chirurgicale.Message clinique clé:Ce rapport décrit la prise en charge chirurgicale réussie du carcinome corticosurrénalien félin avec invasion des veines rénales sans lésion rénale. Ce cas suggère qu'après un diagnostic correct et dans des cas bien sélectionnés, une intervention chirurgicale visant à éliminer les tumeurs surrénales et les thrombi chez les chats, malgré l'invasion des veines rénales, peut être réalisée avec d'excellents résultats à court et à long terme.(Traduit par Dr Serge Messier).
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Enfermedades de los Gatos , Venas Renales , Gatos , Animales , Enfermedades de los Gatos/cirugía , Enfermedades de los Gatos/patología , Carcinoma Corticosuprarrenal/veterinaria , Carcinoma Corticosuprarrenal/cirugía , Carcinoma Corticosuprarrenal/patología , Venas Renales/cirugía , Venas Renales/patología , Neoplasias de la Corteza Suprarrenal/veterinaria , Neoplasias de la Corteza Suprarrenal/cirugía , Neoplasias de la Corteza Suprarrenal/patología , Adrenalectomía/veterinaria , Masculino , Riñón/patología , Riñón/cirugía , Invasividad NeoplásicaRESUMEN
Objectives: The pro-oncogenic effects of NCAPD2 have been extensively studied across various tumor types; however, its precise role within the context of lung adenocarcinoma (LUAD) remains elusive. This study aims to elucidate the biological functions of NCAPD2 in LUAD and unravel the underlying mechanistic pathways. Methods: Utilizing bioinformatics methodologies, we explored the differential expression of NCAPD2 between normal and tumor samples, along with its correlations with clinical-pathological characteristics, survival prognosis, and immune infiltration. Results: In the TCGA-LUAD dataset, tumor samples demonstrated significantly elevated levels of NCAPD2 expression compared to normal samples (p < 0.001). Clinically, higher NCAPD2 expression was notably associated with advanced T, N, and M stages, pathologic stage, gender, smoking status, and diminished overall survival (OS). Moreover, differentially expressed genes (DEGs) associated with NCAPD2 were predominantly enriched in pathways related to cell division. Immune infiltration analysis revealed that NCAPD2 expression levels were linked to the infiltration of memory B cells, naïve CD4+ T cells, activated memory CD4+ T cells, and M1 macrophages. In vitro experiments demonstrated that silencing NCAPD2 suppressed LUAD cell proliferation, migration, invasion, epithelial-mesenchymal transition (EMT), and cell cycle progression. Conclusions: In summary, NCAPD2 may represent a promising prognostic biomarker and novel therapeutic target for LUAD.
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Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Ciclo Celular , Movimiento Celular , Proliferación Celular , Neoplasias Pulmonares , Humanos , Proliferación Celular/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/mortalidad , Pronóstico , Movimiento Celular/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidad , Ciclo Celular/genética , Invasividad Neoplásica , Femenino , Masculino , Transición Epitelial-Mesenquimal/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Biología Computacional/métodosRESUMEN
The microbiome can influence cancer development and progression. However, less is known about the role of the skin microbiota in melanoma. Here, we took advantage of a zebrafish melanoma model to probe the effects of Staphylococcus aureus on melanoma invasion. We found that S. aureus produces factors that enhance melanoma invasion and dissemination in zebrafish larvae. We used a published in vitro 3D cluster formation assay that correlates increased clustering with tumor invasion. S. aureus supernatant increased clustering of melanoma cells and was abrogated by a Rho-Kinase inhibitor, implicating a role for Rho-GTPases. The melanoma clustering response was specific to S. aureus but not to other staphylococcal species, including S. epidermidis. Our findings suggest that S. aureus promotes melanoma clustering and invasion via lipids generated by the lipase Sal2 (officially known as GehB). Taken together, these findings suggest that specific bacterial products mediate melanoma invasive migration in zebrafish.
Asunto(s)
Melanoma , Invasividad Neoplásica , Staphylococcus aureus , Pez Cebra , Animales , Pez Cebra/microbiología , Melanoma/patología , Melanoma/microbiología , Línea Celular Tumoral , Lípidos/química , Movimiento Celular/efectos de los fármacos , Larva/microbiología , Humanos , Proteínas de Pez Cebra/metabolismo , Agregación Celular/efectos de los fármacosRESUMEN
Based on the joint analysis of multi-omic data and the biological experiments, we demonstrate that FOXF1 inhibits invasion and metastasis of lung adenocarcinoma cells and enhances anti-tumor immunity via regulating MFAP4/FAK signal axis in this study. The levels of FOXF1 and MFAP4 are significantly down-regulated in LUAD, and the increased levels of two genes can improve the clinical prognosis of LUAD patients. Fluorescein reporter gene determination, chromatin immunoprecipitation and gene co-expression analysis indicate that MFAP4 level is positively regulated by transcription factor FOXF1. The function enrichment analysis shows that the levels of FOXF1 and MFAP4 are closely associated with an enrichment of tumor metastasis signatures. FOXF1 can inhibit the migration and invasion of LAUD cells by transcriptionally activating MFAP4 expression. And the overexpression of FOXF1/MFAP4 can reduce focal adhesion kinase (FAK) phosphorylation, while their knockdown result in the opposite effects. The increased levels of FOXF1/MFAP4 enhance the antitumor immunity by increasing the infiltration of dendritic cells and CD4+ T cells, and the interactions between LUAD cells and immune cells, and activating multiple anti-tumor immunity-related pathways. In conclusion, our study reveals the potential function of FOXF1/MFAP4/FAK signal axis in inhibiting metastasis of LUAD cells and modulating anti-tumor immunity of LUAD patients.
Asunto(s)
Adenocarcinoma del Pulmón , Factores de Transcripción Forkhead , Neoplasias Pulmonares , Invasividad Neoplásica , Transducción de Señal , Factores de Transcripción Forkhead/metabolismo , Factores de Transcripción Forkhead/genética , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundario , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia , Quinasa 1 de Adhesión Focal/metabolismo , Quinasa 1 de Adhesión Focal/genética , Movimiento Celular , Ratones , Animales , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismoRESUMEN
C-C Chemokine Receptor 7 (CCR7) mediates T-cell acute lymphoblastic leukemia (T-ALL) invasion of the central nervous system (CNS) mediated by chemotactic migration to C-C chemokine ligand 19 (CCL19). To determine if a CCL19 antagonist, CCL198-83, could inhibit CCR7-induced chemotaxis and signaling via CCL19 but not CCL21, we used transwell migration and Ca2+ mobilization signaling assays. We found that in response to CCL19, human T-ALL cells employ ß2 integrins to invade human brain microvascular endothelial cell monolayers. In vivo, using an inducible mouse model of T-ALL, we found that we were able to increase the survival of the mice treated with CCL198-83 when compared to non-treated controls. Overall, our results describe a targetable cell surface receptor, CCR7, which can be inhibited to prevent ß2-integrin-mediated T-ALL invasion of the CNS and potentially provides a platform for the pharmacological inhibition of T-ALL cell entry into the CNS.
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Antígenos CD18 , Quimiocina CCL19 , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores CCR7 , Receptores CCR7/metabolismo , Receptores CCR7/genética , Animales , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Quimiocina CCL19/metabolismo , Antígenos CD18/metabolismo , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Línea Celular Tumoral , Quimiotaxis/efectos de los fármacos , Quimiocina CCL21/metabolismo , Movimiento Celular/efectos de los fármacos , Invasividad NeoplásicaRESUMEN
OBJECTIVE: This study investigated the significance of serum hypoxia-inducible factor (HIF)-1α/HIF-2 α and Chitinase 3-Like protein 1 (YKL-40) levels in the assessment of vascular invasion and prognostic outcomes in patients with Follicular Thyroid Cancer (FTC). METHODS: This prospective study comprised 83 patients diagnosed with FTC, who were subsequently categorized into a recurrence group (17 cases) and a non-recurrence group (66 cases). The pathological features of tumor vascular invasion were classified. Serum HIF-1α/HIF-2α and YKL-40 were quantified using a dual antibody sandwich enzyme-linked immunosorbent assay, while serum Thyroglobulin (Tg) levels were measured using an electrochemiluminescence immunoassay method. The Spearman test was employed to assess the correlation between serum factors, and the predictive value of diagnostic factors was determined using receiver operating characteristic curve analysis. A Cox proportional hazards regression model was utilized to analyze independent factors influencing prognosis. RESULTS: Serum HIF-1α, HIF-2α, YKL-40, and Tg were elevated in patients exhibiting higher vascular invasion. A significant positive correlation was observed between Tg and HIF-1α, as well as between HIF-1α and YKL-40. The cut-off values for HIF-1α and YKL-40 in predicting recurrence were 48.25 pg/mL and 60.15 ng/mL, respectively. Patients exceeding these cut-off values experienced a lower recurrence-free survival rate. Furthermore, serum levels surpassing the cut-off value, in conjunction with vascular invasion (v2+), were identified as independent risk factors for recurrence in patients with FTC. CONCLUSION: Serum HIF-1α/HIF-2α and YKL-40 levels correlate with vascular invasion in FTC, and the combination of HIF-1α and YKL-40 predicts recurrence in patients with FTC.
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Adenocarcinoma Folicular , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Biomarcadores de Tumor , Proteína 1 Similar a Quitinasa-3 , Subunidad alfa del Factor 1 Inducible por Hipoxia , Invasividad Neoplásica , Valor Predictivo de las Pruebas , Humanos , Proteína 1 Similar a Quitinasa-3/sangre , Femenino , Masculino , Subunidad alfa del Factor 1 Inducible por Hipoxia/sangre , Persona de Mediana Edad , Pronóstico , Adulto , Adenocarcinoma Folicular/sangre , Adenocarcinoma Folicular/patología , Adenocarcinoma Folicular/mortalidad , Estudios Prospectivos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/sangre , Biomarcadores de Tumor/sangre , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Anciano , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/patología , Ensayo de Inmunoadsorción Enzimática , Valores de Referencia , Adulto Joven , Estadísticas no Paramétricas , Curva ROCRESUMEN
Invasive growth is a critical process in tumor progression, requiring the activation of various molecular processes in tumor cells at the invasive front. Intercellular communication between heterogeneous tumor cells enhances cellular activation and adaptation to specific microenvironments. One mechanism of intercellular communication is the delivery of miRNAs through tumor cell-derived extracellular vesicles (EVs). In this context we have observed that conditioned media from a highly invasive cell subpopulation (BLM-HI) enhances the invasive capacity of the parental cell line (BLM). Therefore, we hypothesized that this complex change of cellular behavior is influenced by EV-transported miRNAs. The treatment of BLM cells with EVs derived from BLM-HI cells resulted in a significantly enhanced invasive capacity, as observed in Matrigel-embedded spheroids and in 2D Boyden chamber assays, with a dose-dependent effect. Conversely, the invasive capacity of BLM cells was reduced when secretion of EVs was inhibited by a sphingomyelinase inhibitor. To investigate the molecular mechanisms behind this effect, we performed next-generation sequencing and identified an enrichment of miR-1246 in these EVs. In functional analyses we demonstrated that both the EV mediated delivery of miR-1246 as well as overexpression contributes to the enhanced invasiveness of BLM cells. We identified a binding site of miR-1246 in the 3'UTR of cyclin G2 (CCNG2) and demonstrated direct binding by a luciferase reporter assay.Increased expression of CCNG2 has been associated with cancer metastasis and poor patient outcomes in other malignancies. Our study demonstrates that intercellular communication contributes to the transfer of properties, such as increased invasive capacity, between heterogeneous melanoma cells via EV-transported miRNAs.
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Vesículas Extracelulares , Melanoma , MicroARNs , Invasividad Neoplásica , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Melanoma/genética , Melanoma/patología , Melanoma/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Movimiento Celular/genéticaRESUMEN
BACKGROUND: Ewing's sarcoma (ES) is the second most common malignant primary bone tumor in children and adolescents. Peroxiredoxin 2 (PRDX2) is an antioxidant enzyme. AIMS: Here, we investigated the role and mechanism of PRDX2 in the development of ES. METHODS AND RESULTS: PRDX2 expression was knocked down in A673 and RDES cells by specific siRNA interference (si-PRDX2). Knockdown of PRDX2 strongly inhibited the proliferation, growth, migration, invasion, and MMP9 activity and induces apoptosis of A673 and RDES cells. si-PRDX2 significantly inhibited the phosphorylation of Akt and the expression of cyclin D1. The transcription factor that might regulate PRDX2 transcription was predicted with the JASPAR and UCSC databases, and analyzed using dual-luciferase and Chromatin co-immunoprecipitation experiments. SNAI1 could activate the transcription of PRDX2 by binding to predicted promoter binding site. CONCLUSION: PRDX2 may be a potential therapeutic target for ES.
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Neoplasias Óseas , Movimiento Celular , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Metaloproteinasa 9 de la Matriz , Peroxirredoxinas , Sarcoma de Ewing , Humanos , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Proliferación Celular/genética , Movimiento Celular/genética , Sarcoma de Ewing/patología , Sarcoma de Ewing/genética , Sarcoma de Ewing/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Línea Celular Tumoral , Invasividad Neoplásica , Técnicas de Silenciamiento del Gen , Apoptosis , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , ARN Interferente Pequeño/genéticaRESUMEN
NADPH oxidases (NOXs) are a family of membrane proteins responsible for intracellular reactive oxygen species (ROS) generation by facilitating electron transfer across biological membranes. Despite the established activation of NOXs by protein kinase C (PKC), the precise mechanism through which PKC triggers NOX activation during breast cancer invasion remains unclear. The present study aimed to investigate the role of NOX1 and NOX5 in the invasion of MCF7 human breast cancer cells. The expression and activity of NOXs and matrix metalloprotease (MMP)9 were assessed by reverse transcriptionquantitative PCR and western blotting, and the activity of MMP9 was monitored using zymography. Cellular invasion was assessed using the Matrigel invasion assay, whereas ROS levels were quantified using a FACSCalibur flow cytometer. The findings suggested that NOX1 and NOX5 serve crucial roles in 12Otetradecanoylphorbol13acetate (TPA)induced MMP9 expression and invasion of MCF7 cells. Furthermore, a connection was established between PKC and the NOX1 and 5/ROS signaling pathways in mediating TPAinduced MMP9 expression and cellular invasion. Notably, NOX inhibitors (diphenyleneiodonium chloride and apocynin) significantly attenuated TPAinduced MMP9 expression and invasion in MCF7 cells. NOX1 and NOX5specific small interfering RNAs attenuated TPAinduced MMP9 expression and cellular invasion. In addition, knockdown of NOX1 and NOX5 suppressed TPAinduced ROS levels. Furthermore, a PKC inhibitor (GF109203X) suppressed TPAinduced intracellular ROS levels, MMP9 expression and NOX activity in MCF7 cells. Therefore, NOX1 and NOX5 may serve crucial roles in TPAinduced MMP9 expression and invasion of MCF7 breast cancer cells. Furthermore, the present study indicated that TPAinduced MMP9 expression and cellular invasion were mediated through PKC, thus linking the NOX1 and 5/ROS signaling pathways. These findings offer novel insights into the potential mechanisms underlying their antiinvasive effects in breast cancer.