RESUMEN
Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single-cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene (FANCD2) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK-8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2-related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH-MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH-MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH-MB cells and sensitized SHH-MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH-MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH-MB cell-derived tumors in vivo. Our study revealed FANCD2 as a potential therapeutic target in SHH-MB and silencing FANCD2 could sensitize SHH-MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.
Asunto(s)
Neoplasias Cerebelosas , Anemia de Fanconi , Ferroptosis , Meduloblastoma , Ratones , Animales , Humanos , Meduloblastoma/genética , Meduloblastoma/radioterapia , Ferroptosis/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Neoplasias Cerebelosas/genética , Neoplasias Cerebelosas/radioterapia , Línea Celular Tumoral , Proteína del Grupo de Complementación D2 de la Anemia de Fanconi/genéticaRESUMEN
BACKGROUND: Aberrant activation of Wnt/ß-catenin signaling by dysregulated post-translational protein modifications, especially ubiquitination is causally linked to cancer development and progression. Although Lys48-linked ubiquitination is known to regulate Wnt/ß-catenin signaling, it remains largely obscure how other types of ubiquitination, such as linear ubiquitination governs its signaling activity. METHODS: The expression and regulatory mechanism of linear ubiquitin chain assembly complex (LUBAC) on Wnt/ß-catenin signaling was examined by immunoprecipitation, western blot and immunohistochemical staining. The ubiquitination status of ß-catenin was detected by ubiquitination assay. The impacts of SHARPIN, a core component of LUBAC on malignant behaviors of gastric cancer cells were determined by various functional assays in vitro and in vivo. RESULTS: Unlike a canonical role in promoting linear ubiquitination, SHARPIN specifically interacts with ß-catenin to maintain its protein stability. Mechanistically, SHARPIN competes with the E3 ubiquitin ligase ß-Trcp1 for ß-catenin binding, thereby decreasing ß-catenin ubiquitination levels to abolish its proteasomal degradation. Importantly, SHARPIN is required for invasiveness and malignant growth of gastric cancer cells in vitro and in vivo, a function that is largely dependent on its binding partner ß-catenin. In line with these findings, elevated expression of SHARPIN in gastric cancer tissues is associated with disease malignancy and correlates with ß-catenin expression levels. CONCLUSIONS: Our findings reveal a novel molecular link connecting linear ubiquitination machinery and Wnt/ß-catenin signaling via SHARPIN-mediated stabilization of ß-catenin. Targeting the linear ubiquitination-independent function of SHARPIN could be exploited to inhibit the hyperactive ß-catenin signaling in a subset of human gastric cancers.
Asunto(s)
Carcinogénesis/genética , Neoplasias Gástricas/genética , Ubiquitinación/genética , Ubiquitinas/genética , beta Catenina/genética , Humanos , Vía de Señalización Wnt/genéticaRESUMEN
Tumor-associated macrophages (TAMs) constitute a large population of glioblastoma and facilitate tumor growth and invasion of tumor cells, but the underlying mechanism remains undefined. In this study, we demonstrate that chemokine (C-C motif) ligand 8 (CCL8) is highly expressed by TAMs and contributes to pseudopodia formation by GBM cells. The presence of CCL8 in the glioma microenvironment promotes progression of tumor cells. Moreover, CCL8 induces invasion and stem-like traits of GBM cells, and CCR1 and CCR5 are the main receptors that mediate CCL8-induced biological behavior. Finally, CCL8 dramatically activates ERK1/2 phosphorylation in GBM cells, and blocking TAM-secreted CCL8 by neutralized antibody significantly decreases invasion of glioma cells. Taken together, our data reveal that CCL8 is a TAM-associated factor to mediate invasion and stemness of GBM, and targeting CCL8 may provide an insight strategy for GBM treatment.
Asunto(s)
Quimiocina CCL8/metabolismo , Glioblastoma/metabolismo , Macrófagos/metabolismo , Animales , Encéfalo/citología , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Invasividad Neoplásica/fisiopatología , Células Madre Neoplásicas/citología , Células Tumorales CultivadasRESUMEN
Glioblastoma multiforme (GBM) is characterized by highly invasive growth, which leads to extensive infiltration and makes complete tumor excision difficult. Since cytoskeleton proteins are related to leading processes and cell motility, and through analysis of public GBM databases, we determined that an actin-interacting protein, zyxin (ZYX), may involved in GBM invasion. Our own glioma cohort as well as the cancer genome atlas (TCGA), Rembrandt, and Gravendeel databases consistently showed that increased ZYX expression was related to tumor progression and poor prognosis of glioma patients. In vitro and in vivo experiments further confirmed the oncogenic roles of ZYX and demonstrated the role of ZYX in GBM invasive growth. Moreover, RNA-seq and mass-spectrum data from GBM cells with or without ZYX revealed that stathmin 1 (STMN1) was a potential target of ZYX. Subsequently, we found that both mRNA and protein levels of STMN1 were positively regulated by ZYX. Functionally, STMN1 not only promoted invasion of GBM cells but also rescued the invasion repression caused by ZYX loss. Taken together, our results indicate that high ZYX expression was associated with worse prognosis and highlighted that the ZYX-STMN1 axis might be a potential therapeutic target for GBM.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Invasividad Neoplásica/patología , Zixina , Animales , Biomarcadores de Tumor , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Movimiento Celular/genética , Técnicas de Silenciamiento del Gen , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Humanos , Ratones , Ratones Endogámicos NOD , Pronóstico , Estatmina/análisis , Estatmina/genética , Estatmina/metabolismo , Zixina/análisis , Zixina/genética , Zixina/metabolismoRESUMEN
As a hallmark for glioblastoma (GBM), high heterogeneity causes a variety of phenotypes and therapeutic responses among GBM patients, and it contributes to treatment failure. Moreover, hypoxia is a predominant feature of GBM and contributes greatly to its phenotype. To analyse the landscape of gene expression and hypoxic characteristics of GBM cells and their clinical significance in GBM patients, we performed transcriptome analysis of the GBM cell line U87-MG and the normal glial cell line HEB under normoxia and hypoxia conditions, with the results of which were analysed using established gene ontology databases as well as The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia. We revealed core signal pathways, including inflammation, angiogenesis and migration, and for the first time mapped the components of the toll-like receptor 6 pathway in GBM cells. Moreover, by investigating the signal pathways involved in homoeostasis, proliferation and adenosine triphosphate metabolism, the critical response of GBM to hypoxia was clarified. Experiments with cell lines, patient serum and tissue identified IL1B, CSF3 and TIMP1 as potential plasma markers and VIM, STC1, TGFB1 and HMOX1 as potential biopsy markers for GBM. In conclusion, our study provided a comprehensive understanding for signal pathways and hypoxic characteristics of GBM and identified new biomarkers for GBM patients.
Asunto(s)
Perfilación de la Expresión Génica , Glioblastoma/genética , Transcriptoma/genética , Hipoxia Tumoral/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/genética , Glioblastoma/patología , Glicoproteínas/genética , Hemo-Oxigenasa 1/genética , Humanos , Interleucina-1beta/genética , Transducción de Señal/genética , Inhibidor Tisular de Metaloproteinasa-1 , Factor de Crecimiento Transformador beta1/genética , Vimentina/genéticaRESUMEN
Capillary morphogenesis protein 2 (CMG2) was originally identified through its participation in capillary morphogenesis, and subsequently identified as the second receptor for anthrax toxin (ANTXR2). Although tumor-associated functions of CMG2 have also been reported, the clinical significance and functional mechanism of CMG2 in glioma remain to be elucidated. We assessed the clinicopathological relevance of CMG2 in a cohort of 48 glioma patients as well as through public glioma databases, and explored the function of CMG2 using glioblastoma (GBM) models in vitro and in vivo. CMG2 overexpression was associated with increased tumor grade and poor patient survival. CMG2 promoted G2/M-phase transition during the cell cycle of GBM cells in vitro and contributed to tumor growth in vivo. We also observed that CMG2 is implicated in the activation of extracellular signal-regulated kinases (ERKs), epithelial-mesenchymal transition (EMT), migration, and invasion in GBM cells. Transcriptomic analysis of GBM cells with or without CMG2 overexpression indicated that a panel of oncogenic signaling pathways was altered with CMG2 upregulation, implying that CMG2 might orchestrate these signaling pathways to regulate the growth of GBM cells. Yes-associated protein 1 (YAP1) activity was enhanced by CMG2 overexpression but suppressed with CMG2 deficiency. Since YAP1 is critically implicated in GBM, the oncogenic roles of CMG2 in GBM cells might thus be mediated, at least partially, by YAP1. Altogether, CMG2 functioned as an oncogene in glioma cells and is a potential prognostic biomarker or therapeutic target for the clinical treatment of glioma. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Receptores de Péptidos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Bases de Datos Genéticas , Puntos de Control de la Fase G2 del Ciclo Celular , Glioma/genética , Glioma/patología , Células HEK293 , Humanos , Masculino , Ratones SCID , Invasividad Neoplásica , Fosfoproteínas/metabolismo , Pronóstico , Receptores de Péptidos/genética , Transducción de Señal , Factores de Transcripción , Carga Tumoral , Células Tumorales Cultivadas , Proteínas Señalizadoras YAPRESUMEN
Epithelial-mesenchymal transition (EMT) plays a critical role in initiating tumor invasion and metastasis of colorectal cancer (CRC), although the underlying mechanisms remain to be clarified. Herein, we demonstrate that the active form of Rac family small GTPase 1 (RAC1-GTP) is overexpressed in CRCs and promotes the EMT-mediated invasion of CRC cells through activation of the signal transducers and activators of transcription 3 (STAT3) pathway. Increased expression of RAC1-GTP in CRC tissues was positively correlated with the TNM stages of CRCs and indicated poor prognosis of CRC patients. Targeting RAC1-GTP activity by its specific inhibitor NSC23766 markedly suppressed the migration and invasion of CRC cells. Mechanistically, RAC1-GTP directly interacted with STAT3 to promote STAT3 phosphorylation, thus promoted EMT of CRC cells. Enforced expression of constitutively activated STAT3 (STAT3-C) abrogated the suppressive effect of RAC1-GTP disruption on the migration and invasion of CRC cells. Importantly, NSC23766 disrupted EMT in CRC cells and significantly diminished growth of CRC xenografts. Taken together, our data indicate that RAC1-GTP is an important player in EMT-mediated tumor invasion and a potential therapeutic target for CRCs.
Asunto(s)
Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal , Factor de Transcripción STAT3/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Aminoquinolinas/farmacología , Animales , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/patología , Femenino , Células HCT116 , Humanos , Masculino , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Fosforilación , Unión Proteica , Pirimidinas/farmacología , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Proteína de Unión al GTP rac1/antagonistas & inhibidoresRESUMEN
The microvascular profile has been included in the WHO glioma grading criteria. Nevertheless, microvessels in gliomas of the same WHO grade, e.g., WHO IV glioblastoma (GBM), exhibit heterogeneous and polymorphic morphology, whose possible clinical significance remains to be determined. In this study, we employed a fractal geometry-derived parameter, microvascular fractal dimension (mvFD), to quantify microvessel complexity and developed a home-made macro in Image J software to automatically determine mvFD from the microvessel-stained immunohistochemical images of GBM. We found that mvFD effectively quantified the morphological complexity of GBM microvasculature. Furthermore, high mvFD favored the survival of GBM patients as an independent prognostic indicator and predicted a better response to chemotherapy of GBM patients. When investigating the underlying relations between mvFD and tumor growth by deploying Ki67/mvFD as an index for microvasculature-normalized tumor proliferation, we discovered an inverse correlation between mvFD and Ki67/mvFD. Furthermore, mvFD inversely correlated with the expressions of a glycolytic marker, LDHA, which indicated poor prognosis of GBM patients. Conclusively, we developed an automatic approach for mvFD measurement, and demonstrated that mvFD could predict the prognosis and response to chemotherapy of GBM patients.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas , Glioma , Interpretación de Imagen Asistida por Computador/métodos , Microvasos/patología , Neovascularización Patológica/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Fractales , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Inmunohistoquímica , Microvasos/diagnóstico por imagen , Clasificación del Tumor/métodos , Neovascularización Patológica/diagnóstico por imagen , PronósticoRESUMEN
Transplantation of mesenchymal stem cells (MSCs) into the degenerated intervertebral disc (IVD) has shown promise for decelerating or arresting IVD degeneration. Cellular mechanical properties play crucial roles in regulating cell-matrix interactions, potentially reflecting specific changes that occur based on cellular phenotype and behavior. However, the effect of co-culturing of MSCs with nucleus pulposus cells (NPCs) on the mechanical properties of NPCs remains unknown. In our study, we demonstrated that co-culture of degenerated NPCs with MSCs resulted in significantly decreased mechanical moduli (elastic modulus, relaxed modulus, and instantaneous modulus) and increased biological activity (proliferation and expression of matrix genes) in degenerated NPCs, but not normal NPCs. SDF-1, CXCR4 ligand, was highly expressed in MSCs when co-cultured with degenerated NPCs. Inhibition of SDF-1 using CXCR4 antagonist AMD3100 or knocking-down CXCR4 in degenerated NPCs abolished the MSCs-induced decrease in the mechanical moduli and increased biological activity of degenerated NPCs, suggesting a crucial role for SDF-1/CXCR4 signaling. AKT and FAK inhibition attenuated the MSCs- or SDF-1-induced decrease in the mechanical moduli of degenerated NPCs. In conclusion, it was demonstrated in vitro that MSCs regulate the mechanical properties of degenerated NPCs through SDF-1/CXCR4/AKT signaling. These findings highlight a possible mechanical mechanism for MSCs-induced modulation with degenerated NPCs, which may be applicable to MSCs-based therapy for disc degeneration.
Asunto(s)
Quimiocina CXCL12/fisiología , Degeneración del Disco Intervertebral/patología , Células Madre Mesenquimatosas/fisiología , Núcleo Pulposo/patología , Proteínas Proto-Oncogénicas c-akt/fisiología , Receptores CXCR4/fisiología , Transducción de Señal/fisiología , Agrecanos/biosíntesis , Agrecanos/genética , Bencilaminas , Células Cultivadas , Quimiocina CXCL12/antagonistas & inhibidores , Técnicas de Cocultivo , Colágeno Tipo II/biosíntesis , Colágeno Tipo II/genética , Ciclamas , Módulo de Elasticidad , Compuestos Heterocíclicos/farmacología , Humanos , Técnicas In Vitro , Células Madre Mesenquimatosas/metabolismo , Microscopía de Fuerza Atómica , Núcleo Pulposo/citología , Núcleo Pulposo/metabolismo , Interferencia de ARN , ARN Interferente Pequeño/genética , Receptores CXCR4/antagonistas & inhibidoresRESUMEN
Nordihydroguaiaretic acid (NDGA) and its synthetic chiral analog dl-nordihydroguaiaretic acid (Nordy) show collective benefits in anti-tumor, and defending against viral and bacterial infections. Here, we synthetized a new derivative-NDGA-P21 based on NDGA structure. Regardless of the structural similarity, NDGA-P21 exhibited stronger capability in suppression of glioblastoma (GBM) cell growth as compared to Nordy. Mechanically, NDGA-P21 is able to arrest cell cycle of GBM cells in G0/G1 phase, and to block cell proliferation sequentially. It is important to note that NDGA-P21 is able to impair the stemness of glioma stem-like cells (GSLCs) via measurement of colony formation and sphere formation. Taken together, the novel NDGA-based compound NDGA-P21 exhibits potential therty -20 apeutic implications through inhibiting proliferation of glioma cells and self-renewal capability of GSLCs.
Asunto(s)
Antineoplásicos/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Glioma/metabolismo , Masoprocol/análogos & derivados , Masoprocol/farmacología , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , HumanosRESUMEN
Glioma is the most prevalent type of tumor in the brain and is comprised of grades I-IV, according to the WHO classification system. Grade IV glioma is also known as glioblastoma multiforme (GBM), the most malignant type of glioma. Glioma is characterized by a complex molecular background, and gene profiling studies have disclosed critical genetic events in human gliomas, which make targeted therapies the most promising therapeutic strategy. However, crosstalk between the targeted signaling pathways may hinder the efficacy of targeted therapies in gliomas. Therefore, it is necessary to identify effective markers to stratify patients for specific therapeutic procedures. Although several mechanisms have been proposed based on the crosstalk between PI3K/AKT/mTORC1 and Hippo/YAP pathways, the clinical significance of the two pathways has not yet been assessed in a combinatorial manner. In this study, we evaluated the two pathways in human glioma specimens and observed the positive correlation between protein levels of p-mTORS2448 and YAP in gliomas. The findings indicated that high expression of p-mTORS2448 and YAP correlated with poor overall survival of glioma patients. As p-mTORS2448 is a specific marker of mTORC1 activation, our results reveal a potential interaction between mTORC1 and YAP, which might functionally participate in the development and progression of gliomas. In support of this hypothesis, a combination of inhibitors targeting mTORC1 and YAP showed a better inhibitory effect on growth of glioma cell lines. Altogether, our work, for the first time, reveals that p-mTORS2448 and YAP can be used as markers of PI3K/AKT/mTORC1 and Hippo/YAP pathway activity to predict prognosis and are target candidates for personalized medicine.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Procesamiento Proteico-Postraduccional , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Adulto , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Estudios de Cohortes , Activación Enzimática/efectos de los fármacos , Femenino , Glioma/diagnóstico , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Fosfoproteínas/antagonistas & inhibidores , Fosforilación/efectos de los fármacos , Pronóstico , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Factores de Transcripción , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is highly malignant with highly invasive and metastatic capabilities and poor prognosis. It is believed that the ESCC cancer stem-like cells (ECSLCs) are critical for tumorigenicity, invasion and metastasis of ESCC. However, the properties of ECSLCs vary with different markers used in isolation, so that new and more effective markers of ECSLCs need to be identified. This study aimed to estimate the potentiality of Cripto-1 (CR-1) as an ECSLC surface marker and investigate the clinical significance of CR-1 expression in ESCC. METHODS: ESCC cells with CR-1 high or CR-1low were obtained by flow cytometry then their self-renewal capability and tumorigenicity were compared by colony and limiting dilution sphere formation analysis in vitro and xenograft in nude mice in vivo, respectively. Knockdown of CR-1 expression in ESCC cells was conducted with short hairpin RNA. Cell migration and invasion were examined by scratch test and matrigel transwell assay, respectively. Metastatic capability of ESCC cells was assayed by a mouse tail vein metastasis model. The levels of CR-1 expression in cancerous and paired adjacent normal tissues were assessed by IHC and qRT-RCR. RESULTS: CR-1high subpopulation of ESCC cells isolated by FACS expressed high level of genes related to stemness and epithelial-mesenchymal transition (EMT), and possessed high capacities of self-renewal, tumorigenesis, invasion and metastasis. Suppression of CR-1 expression significantly reduced the expression of stemness- and EMT-related genes and the capabilities of self-renewal in vitro, tumorigenicity and metastasis in vivo in ESCC cells. In the clinical ESCC specimens, the expression levels of CR-1 in cancerous tissues were positively correlated to TNM stage, invasive depth, and lymph node metastasis. Cox regression analysis indicated that CR-1 was an independent indicator of prognosis. The expression of CR-1 was found overlapping with aldehyde dehydrogenase 1A1 (ALDH1A1), an intracellular marker for ESCLCs, in ESCC cell lines and specimens. CONCLUSIONS: CR-1 is a functional and cell surface ECSLC marker, and an independent prognostic indicator as well as a potential therapeutic target for ESCC.
Asunto(s)
Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Madre Neoplásicas/patología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Movimiento Celular , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Invasividad Neoplásica , Estadificación de Neoplasias , Trasplante de Neoplasias , Células Madre Neoplásicas/metabolismo , Pronóstico , Análisis de SupervivenciaRESUMEN
Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite great improvements in the therapeutic regimen, relapse and leptomeningeal dissemination still pose great challenges to the long-term survival of MB patients. Developing more effective strategies has become extremely urgent. In recent years, a number of malignancies, including MB, have been found to contain a subpopulation of cancer cells known as cancer stem cells (CSCs), or tumor initiating/propagating cells. The CSCs are thought to be largely responsible for tumor initiation, maintenance, dissemination, and relapse; therefore, their pivotal roles have revealed them to be promising targets in MB therapy. Our growing understanding of the major medulloblastoma molecular subgroups and the derivation of some of these groups from specific stem or progenitor cells adds additional layers to the CSC knowledge base. Herein we review the current knowledge of MB stem cells, highlight the molecular mechanisms relating to MB relapse and leptomeningeal dissemination, and incorporate these with the need to develop more effective and accurate therapies for MB patients.
Asunto(s)
Resistencia a Antineoplásicos/efectos de los fármacos , Meduloblastoma/tratamiento farmacológico , Meduloblastoma/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Animales , Separación Celular , Humanos , Neoplasias Meníngeas/secundario , Recurrencia Local de Neoplasia , Células Madre Neoplásicas/metabolismo , Transducción de SeñalRESUMEN
Semaphorin-3F (SEMA3F), an axonal repulsant in nerve development, has been shown to inhibit the progression of human colorectal cancer (CRC); however, the underlying mechanism remains elusive. In this study we found a negative correlation between the levels of SEMA3F and CXCR4 in CRC specimens from 85 patients, confirmed by bioinformatics analysis of gene expression in 229 CRC samples from the Cancer Genome Atlas. SEMA3F(high) /CXCR4(low) patients showed the lowest frequency of lymph node and distant metastasis and the longest survival. Mechanistically, SEMA3F inhibited the invasion and metastasis of CRC cells through PI3K-AKT-dependent down-regulation of the ASCL2-CXCR4 axis. Specifically, ASCL2 enhanced the invasion and metastasis of CRC cells in vitro and expression of ASCL2 correlated with distant metastasis, tumour size and poor overall survival in CRC patients. Treatment of CRC cells with the CXCR4 antagonist AMD3100 attenuated SEMA3F knockdown-induced invasion and metastasis of CRC cells in vitro and in vivo. Our study thus demonstrates that SEMA3F functions as a suppressor of CRC metastasis via down-regulating the ASCL2-CXCR4 axis.
Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Movimiento Celular , Neoplasias Colorrectales/enzimología , Neoplasias Hepáticas/enzimología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores CXCR4/metabolismo , Transducción de Señal , Animales , Antineoplásicos/farmacología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Movimiento Celular/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Biología Computacional , Femenino , Regulación Neoplásica de la Expresión Génica , Genómica , Células HCT116 , Humanos , Estimación de Kaplan-Meier , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Metástasis Linfática , Masculino , Proteínas de la Membrana/genética , Ratones Desnudos , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas del Tejido Nervioso/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Receptores CXCR4/antagonistas & inhibidores , Receptores CXCR4/genética , Estudios Retrospectivos , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Transfección , Carga TumoralRESUMEN
REGγ is a proteasome coactivator which regulates proteolytic activity in eukaryotic cells. Abundant lines of evidence have showed that REGγ is over expressed in a number of human carcinomas. However, its precise role in the pathogenesis of cancer is still unclear. In this study, by examining 200 human breast cancer specimens, we demonstrated that REGγ was highly expressed in breast cancers, and the expression of REGγ was positively correlated with breast cancer patient estrogen receptor alpha (ERα) status. Moreover, the expression of REGγ was found positively associated with poor clinical features and low survival rates in ERα positive breast cancer patients. Further cell culture studies using MCF7 and BT474 breast cancer cell lines showed that cell proliferation, motility, and invasion capacities were decreased significantly by REGγ knockdown. Lastly, we demonstrated that REGγ indirectly regulates the degradation of ERα protein via ubiquitin-proteasome pathway. In conclusion, our findings provide the evidence that REGγ expression was positively correlated with ERα status and poor clinical prognosis in ERα positive breast cancer patients. As well, we disclose a new connection between the two molecules that are both highly expressed in most breast cancer cases.
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Autoantígenos/metabolismo , Neoplasias de la Mama/metabolismo , Receptor alfa de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Adulto , Anciano , Línea Celular Tumoral , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Células MCF-7 , Persona de Mediana Edad , Invasividad Neoplásica , ARN Interferente Pequeño/metabolismoRESUMEN
Microenvironmental regulation of cancer stem cells (CSCs) strongly influences the onset and spread of cancer. The way in which glioma cells interact with their microenvironment and acquire the phenotypes of CSCs remains elusive. We investigated how communication between vascular endothelial cells and glioma cells promoted the properties of glioma stem cells (GSCs). We observed that CD133(+) GSCs were located closely to Shh(+) endothelial cells in specimens of human glioblastoma multiforme (GBM). In both in vitro and in vivo studies, we found that endothelial cells promoted the appearance of CSC-like glioma cells, as demonstrated by increases in tumourigenicity and expression of stemness genes such as Sox2, Olig2, Bmi1 and CD133 in glioma cells that were co-cultured with endothelial cells. Knockdown of Smo in glioma cells led to a significant reduction of their CSC-like phenotype formation in vitro and in vivo. Endothelial cells with Shh knockdown failed to promote Hedgehog (HH) pathway activation and CSC-like phenotype formation in co-cultured glioma cells. By examination of glioma tissue specimens from 65 patients, we found that the survival of glioma patients was closely correlated with the expression of both Shh by endothelial cells and Gli1 by perivascular glioma cells. Taken together, our study demonstrates that endothelial cells in the tumour microenvironment provide Shh to activate the HH signalling pathway in glioma cells, thereby promoting GSC properties and glioma propagation.
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Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/patología , Glioma/patología , Proteínas Hedgehog/metabolismo , Células Madre Neoplásicas/patología , Antígeno AC133 , Aloinjertos , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Línea Celular Tumoral , Células Endoteliales/patología , Femenino , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas Hedgehog/genética , Humanos , Masculino , Ratones , Persona de Mediana Edad , Péptidos/genética , Péptidos/metabolismo , Fenotipo , Transducción de Señal , Nicho de Células Madre , Microambiente TumoralRESUMEN
Invasion and metastasis are the major cause of deaths in patients with esophageal cancer. In this study, we isolated cancer stem-like cells from an esophageal squamous cell carcinoma cell line EC109 based on aldehyde dehydrogenase 1A1 (ALDH1A1), and found that ALDH1A1(high) cells possessed the capacities of self-renewal, differentiation and tumor initiation, indications of stem cell properties. To support their stemness, ALDH1A1(high) cells exhibited increased potential of invasion and metastasis as compared with ALDH1A1(low) cells. ALDH1A1(high) esophageal squamous cell carcinoma cells expressed increased levels of mRNA for vimentin, matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9), but decreased the level of E-cadherin mRNA, suggesting that epithelial-mesenchymal transition and secretary MMPs may be attributed to the high invasive and metastatic capabilities of ALDH1A1(high) cells. Furthermore, we examined esophageal squamous cell carcinoma specimens from 165 patients and found that ALDH1A1(high) cells were associated with esophageal squamous dysplasia and the grades, differentiation and invasion depth, lymph node metastasis and UICC stage of esophageal squamous cell carcinoma, as well as poor prognosis of patients. Our results provide the strong evidence that ALDH1A1(high) cancer stem-like cells contribute to the invasion, metastasis and poor outcome of human esophageal squamous cell carcinoma.
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Aldehído Deshidrogenasa/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Invasividad Neoplásica/patología , Células Madre Neoplásicas/metabolismo , Anciano , Familia de Aldehído Deshidrogenasa 1 , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Neoplasias Esofágicas/patología , Humanos , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Pronóstico , Retinal-DeshidrogenasaRESUMEN
BACKGROUND: Aldehyde dehydrogenase 1 family member A1 (ALDH1A1) has been identified as a putative cancer stem cell (CSC) marker in breast cancer. However, the clinicopathological and prognostic significance of this protein in breast cancer patients remains controversial. METHODS: This meta-analysis was conducted to address the above issues using 15 publications covering 921 ALDH1A1(+) cases and 2353 controls. The overall and subcategory analyses were performed to detect the association between ALDH1A1 expression and clinicopathological/prognostic parameters in breast cancer patients. RESULTS: The overall analysis showed that higher expression of ALDH1A1 is associated with larger tumor size, higher histological grade, greater possibility of lymph node metastasis (LNM), higher level expression of epidermal growth factor receptor 2 (HER2), and lower level expression of estrogen receptor (ER)/progesterone receptor (PR). The prognosis of breast cancer patients with ALDH1A1(+) tumors was poorer than that of the ALDH1A1(-) patients. Although the relationships between ALDH1A1 expression and some clinicopathological parameters (tumor size, LNM, and the expression of HER2) was not definitive to some degree when we performed a subcategory analysis, the predictive values of ALDH1A1 expression for histological grade and survival of breast cancer patients were significant regardless of the different cutoff values of ALDH1A1 expression, the different districts where the patients were located, the different clinical stages of the patients, the difference in antibodies used in the studies, and the surgery status. CONCLUSIONS: Our results indicate that ALDH1A1 is a biomarker to predict tumor progression and poor survival of breast cancer patients. This marker should be taken into consideration in the development of new diagnostic and therapeutic program for breast cancer.
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Aldehído Deshidrogenasa/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Familia de Aldehído Deshidrogenasa 1 , Biomarcadores de Tumor , Neoplasias de la Mama/mortalidad , Femenino , Expresión Génica , Humanos , Clasificación del Tumor , Estadificación de Neoplasias , Oportunidad Relativa , Pronóstico , Sesgo de Publicación , Retinal-Deshidrogenasa , Carga TumoralRESUMEN
The invasion of malignant glioma cells into the surrounding normal brain tissues is crucial for causing the poor outcome of this tumor type. Recent studies suggest that glioma stem-like cells (GSLCs) mediate tumor invasion. However, it is not clear whether microenvironment factors, such as tumor-associated microglia/macrophages (TAM/Ms), also play important roles in promoting GSLC invasion. In this study, we found that in primary human gliomas and orthotopical transplanted syngeneic glioma, the number of TAM/Ms at the invasive front was correlated with the presence of CD133(+) GSLCs, and these TAM/Ms produced high levels of TGF-ß1. CD133(+) GSLCs isolated from murine transplanted gliomas exhibited higher invasive potential after being cocultured with TAM/Ms, and the invasiveness was inhibited by neutralization of TGF-ß1. We also found that human glioma-derived CD133(+) GSLCs became more invasive upon treatment with TGF-ß1. In addition, compared with CD133(-) committed tumor cells, CD133(+) GSLCs expressed higher levels of type II TGF-ß receptor (TGFBR2) mRNA and protein, and downregulation of TGFBR2 with short hairpin RNA inhibited the invasiveness of GSLCs. Mechanism studies revealed that TGF-ß1 released by TAM/Ms promoted the expression of MMP-9 by GSLCs, and TGFBR2 knockdown reduced the invasiveness of these cells in vivo. These results demonstrate that TAM/Ms enhance the invasiveness of CD133(+) GSLCs via the release of TGF-ß1, which increases the production of MMP-9 by GSLCs. Therefore, the TGF-ß1 signaling pathway is a potential therapeutic target for limiting the invasiveness of GSLCs.
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Glioma/inmunología , Macrófagos/inmunología , Microglía/inmunología , Células Madre Neoplásicas/inmunología , Transducción de Señal/inmunología , Factor de Crecimiento Transformador beta1/fisiología , Regulación hacia Arriba/inmunología , Animales , Comunicación Celular/inmunología , Línea Celular Tumoral , Técnicas de Cocultivo , Glioma/metabolismo , Glioma/patología , Humanos , Recuento de Leucocitos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Microglía/patología , Trasplante de Neoplasias/inmunología , Trasplante de Neoplasias/patología , Células Madre Neoplásicas/patología , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Factor de Crecimiento Transformador beta1/biosíntesisRESUMEN
UNLABELLED: Hepatocellular carcinoma (HCC) exhibits cellular heterogeneity and embryonic stem-cell-related genes are preferentially overexpressed in a fraction of cancer cells of poorly differentiated tumors. However, it is not known whether or how these cancer cells contribute to tumor initiation and progression. Here, our data showed that increased expression of pluripotency transcription factor Nanog in cancer cells correlates with a worse clinical outcome in HCC. Using the Nanog promoter as a reporter system, we could successfully isolate a small subpopulation of Nanog-positive cells. We demonstrate that Nanog-positive cells exhibited enhanced ability of self-renewal, clonogenicity, and initiation of tumors, which are consistent with crucial hallmarks in the definition of cancer stem cells (CSCs). Nanog(Pos) CSCs could differentiate into mature cancer cells in in vitro and in vivo conditions. In addition, we found that Nanog(Pos) CSCs exhibited resistance to therapeutic agents (e.g., sorafenib and cisplatin) and have a high capacity for tumor invasion and metastasis. Knock-down expression of Nanog in Nanog(Pos) CSCs could decrease self-renewal accompanied with decreased expression of stem-cell-related genes and increased expression of mature hepatocyte-related genes. Overexpression of Nanog in Nanog(Neg) cells could restore self-renewal. Furthermore, we found that insulin-like growth factor (IGF)2 and IGF receptor (IGF1R) were up-regulated in Nanog(Pos) CSCs. Knock-down expression of Nanog in Nanog(Pos) CSCs inhibited the expression of IGF1R, and overexpression of Nanog in Nanog(Neg) cells increased the expression of IGF1R. A specific inhibitor of IGF1R signaling could significantly inhibit self-renewal and Nanog expression, indicating that IGF1R signaling participated in Nanog-mediated self-renewal. CONCLUSION: These data indicate that Nanog could be a novel biomarker for CSCs in HCC, and that Nanog could play a crucial role in maintaining the self-renewal of CSCs through the IGF1R-signaling pathway.