RESUMEN
Oncogenic mutations are abundant in the tissues of healthy individuals, but rarely form tumours1-3. Yet, the underlying protection mechanisms are largely unknown. To resolve these mechanisms in mouse mammary tissue, we use lineage tracing to map the fate of wild-type and Brca1-/-;Trp53-/- cells, and find that both follow a similar pattern of loss and spread within ducts. Clonal analysis reveals that ducts consist of small repetitive units of self-renewing cells that give rise to short-lived descendants. This offers a first layer of protection as any descendants, including oncogenic mutant cells, are constantly lost, thereby limiting the spread of mutations to a single stem cell-descendant unit. Local tissue remodelling during consecutive oestrous cycles leads to the cooperative and stochastic loss and replacement of self-renewing cells. This process provides a second layer of protection, leading to the elimination of most mutant clones while enabling the minority that by chance survive to expand beyond the stem cell-descendant unit. This leads to fields of mutant cells spanning large parts of the epithelial network, predisposing it for transformation. Eventually, clone expansion becomes restrained by the geometry of the ducts, providing a third layer of protection. Together, these mechanisms act to eliminate most cells that acquire somatic mutations at the expense of driving the accelerated expansion of a minority of cells, which can colonize large areas, leading to field cancerization.
Asunto(s)
Proteína BRCA1 , Linaje de la Célula , Transformación Celular Neoplásica , Glándulas Mamarias Animales , Mutación , Proteína p53 Supresora de Tumor , Animales , Ratones , Femenino , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/patología , Glándulas Mamarias Animales/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Linaje de la Célula/genética , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Transformación Celular Neoplásica/genética , Células Clonales/metabolismo , Células Clonales/citología , Carcinogénesis/genética , Carcinogénesis/patología , Autorrenovación de las Células/genéticaRESUMEN
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients' survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients' poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-ß signaling pathway. TGF-ß signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-ß signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention.
Asunto(s)
Carcinogénesis , Proliferación Celular , Neoplasias Colorrectales , Transducción de Señal , Factor de Crecimiento Transformador beta , Animales , Femenino , Humanos , Masculino , Ratones , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Movimiento Celular , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Regulación Neoplásica de la Expresión Génica , Ratones Endogámicos BALB C , Ratones Desnudos , Metástasis de la Neoplasia , Pronóstico , Pirazoles/farmacología , Quinolinas/farmacología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
The intricate interplay between the host and its microbiota has garnered increasing attention in the past decade. Specifically, the emerging recognition of microorganisms within diverse cancer tissues, previously presumed sterile, has ignited a resurgence of enthusiasm and research endeavors. Four potential migratory routes have been identified as the sources of intratumoral microbial "dark matter," including direct invasion of mucosal barriers, spreading from normal adjacent tissue, hematogenous spread, and lymphatic drainage, which contribute to the highly heterogeneous features of intratumor microbiota. Importantly, multitudes of studies delineated the roles of intratumor microbiota in cancer initiation and progression, elucidating underlying mechanisms such as genetic alterations, epigenetic modifications, immune dysfunctions, activating oncogenic pathways, and inducing metastasis. With the deepening understanding of intratumoral microbial composition, novel microbiota-based strategies for early cancer diagnosis and prognostic stratification continue to emerge. Furthermore, intratumor microbiota exerts significant influence on the efficacy of cancer therapeutics, particularly immunotherapy, making it an enticing target for intervention in cancer treatment. In this review, we present a comprehensive discussion of the current understanding pertaining to the developmental history, heterogeneous profiles, underlying originations, and carcinogenic mechanisms of intratumor microbiota, and uncover its potential predictive and intervention values, as well as several inevitable challenges as a target for personalized cancer management strategies.
Asunto(s)
Carcinogénesis , Microbiota , Neoplasias , Humanos , Neoplasias/microbiología , Neoplasias/terapia , Carcinogénesis/patología , AnimalesRESUMEN
Long non-coding RNAs (lncRNAs) play an important role in the progression of gastric cancer (GC), but its specific regulatory mechanism remains to be further studied. We previously identified that lncRNA B3GALT5-AS1 was upregulated in GC serum. Here, we investigated the functions and molecular mechanisms of B3GALT5-AS1 in GC tumorigenesis. qRT-PCR was used to detect B3GALT5-AS1 expression in GC. EdU, CCK-8, and colony assays were utilized to assess the proliferation ability of B3GAL5-AS1, and transwell, tube formation assay were used to assess the invasion and metastasis ability. Mechanically, FISH and nuclear plasmolysis PCR identified the subcellular localization of B3GALT5-AS1. RIP and CHIP assays were used to analyse the regulation of B3GALT5-AS1 and B3GALT5. We observed that B3GALT5-AS1 was highly expressed in GC, and silencing B3GALT5-AS1 could inhibit the proliferation, invasion, and migratory capacities of GC. Additionally, B3GALT5-AS1 was bound to WDR5 and modulated the expression of B3GALT5 via regulating the ZEB1/ß-catenin pathway. High-expressed B3AGLT5-AS1 promoted GC tumorigenesis and regulated B3GALT5 expression via recruiting WDR5. Our study is expected to provide a new idea for clinical diagnosis and treatment.
Asunto(s)
Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Galactosiltransferasas , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante , Neoplasias Gástricas , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , beta Catenina , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , beta Catenina/metabolismo , beta Catenina/genética , Proliferación Celular/genética , Línea Celular Tumoral , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/metabolismo , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Movimiento Celular/genética , Galactosiltransferasas/genética , Galactosiltransferasas/metabolismo , Animales , Ratones , Ratones Desnudos , Transducción de Señal , Carcinogénesis/genética , Carcinogénesis/patología , MasculinoRESUMEN
Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.
Asunto(s)
Carcinogénesis , Colesterol , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Colesterol/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinogénesis/genética , Línea Celular Tumoral , Ratones , Ratones Desnudos , Proliferación Celular , Metástasis de la Neoplasia , Movimiento Celular , Masculino , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.
Asunto(s)
Isocitrato Deshidrogenasa , Macrófagos , Ratones Noqueados , Mitocondrias , Microambiente Tumoral , Isocitrato Deshidrogenasa/metabolismo , Isocitrato Deshidrogenasa/genética , Animales , Mitocondrias/metabolismo , Macrófagos/metabolismo , Ratones , Carcinogénesis/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Humanos , Línea Celular Tumoral , Activación de Macrófagos , Técnicas de CocultivoRESUMEN
BACKGROUND: Family with sequence similarity 109, member B (FAM109B) is involved in endocytic transport and affects genetic variation in brain methylation. It is one of the important genes related to immune cell-associated diseases. In the tumor immune system, methylation can regulate tumor immunity and influence the maturation and functional response of immune cells. Whether FAM109B is involved in tumor progression and its correlation with the tumor immune microenvironment has not yet been disclosed. METHODS: A comprehensive pan-cancer analysis of FAM109B expression, prognosis, immunity, and TMB was conducted. The expression, clinical features, and prognostic value of FAM109B in low-grade gliomas (LGG) were evaluated using TCGA, CGGA, and Gravendeel databases. The expression of FAM109B was validated by qRT-PCR, immunohistochemistry (IHC), and Western blotting (WB). The relationship between FAM109B and methylation, Copy Number Variation (CNV), prognosis, immune checkpoints (ICs), and common chemotherapy drug sensitivity in LGG was explored through Cox regression, Kaplan-Meier curves, and Spearman correlation analysis. FAM109B levels and their distribution were studied using the TIMER database and single-cell analysis. The potential role of FAM109B in gliomas was further investigated through in vitro and in vivo experiments. RESULTS: FAM109B was significantly elevated in various tumor types and was associated with poor prognosis. Its expression was related to aggressive progression and poor prognosis in low-grade glioma patients, serving as an independent prognostic marker for LGG. Glioma grade was negatively correlated with FAM109B DNA promoter methylation. Immune infiltration and single-cell analysis showed significant expression of FAM109B in tumor-associated macrophages (TAMs). The expression of FAM109B was closely related to gene mutations, immune checkpoints (ICs), and chemotherapy drugs in LGG. In vitro studies showed increased FAM109B expression in LGG, closely related to cell proliferation. In vivo studies showed that mice in the sh-FAM109B group had slower tumor growth, slower weight loss, and longer survival times. CONCLUSIONS: FAM109B, as a novel prognostic biomarker for low-grade gliomas, exhibits specific overexpression in TAMs and may be a potential therapeutic target for LGG patients.
Asunto(s)
Neoplasias Encefálicas , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Glioma , Clasificación del Tumor , Macrófagos Asociados a Tumores , Glioma/genética , Glioma/patología , Glioma/metabolismo , Humanos , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Macrófagos Asociados a Tumores/inmunología , Metilación de ADN/genética , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/inmunología , Pronóstico , Carcinogénesis/genética , Carcinogénesis/patología , Variaciones en el Número de Copia de ADN/genética , Microambiente Tumoral , Línea Celular Tumoral , Femenino , Masculino , Ratones Desnudos , Ratones , Estimación de Kaplan-Meier , Bases de Datos GenéticasRESUMEN
Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways.
Asunto(s)
Carcinogénesis , Metabolismo Energético , Neoplasias , Transducción de Señal , Humanos , Transducción de Señal/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/genética , Metabolismo Energético/efectos de los fármacos , Carcinogénesis/patología , Carcinogénesis/efectos de los fármacos , Carcinogénesis/metabolismo , Carcinogénesis/genética , AnimalesRESUMEN
Lung cancer treatment and detection can be improved by the identification of new biomarkers. Novel approaches in investigating circular RNAs (circRNAs) as biomarkers have yielded promising results. A circRNA molecule circHIPK3 was found to be widely expressed in non-small-cell lung cancer (NSCLC) cells, where it plays a crucial role in lung cancer tumorigenesis. CircHIPK3 promotes lung cancer progression by sponging oncosuppressive miRNAs such as miR-124, miR-381-3p, miR-149, and miR-107, which results in increased cell proliferation, migration, and resistance to therapies. Inhibiting circHIPK3 has been demonstrated to suppress tumour growth and induce apoptosis, which suggests its potential use in the development of new lung cancer treatment strategies targeting circHIPK3-related pathways. As a biomarker, circHIPK3 shows promise for early detection and monitoring of lung cancer. CircHIPK3 increased expression levels in lung cancer cells, and its potential link to metastasis risk highlights its clinical relevance. Given the promising preliminary findings, more clinical trials are needed to validate circHIPK3 efficacy as a biomarker. Moreover, future research should determine if the mechanisms discovered in NSCLC apply to small cell lung cancer (SCLC) to investigate circHIPK3-targeted therapies for SCLC.
Asunto(s)
Biomarcadores de Tumor , Carcinogénesis , Neoplasias Pulmonares , ARN Circular , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , ARN Circular/genética , ARN Circular/metabolismo , Carcinogénesis/genética , Carcinogénesis/patología , Regulación Neoplásica de la Expresión Génica , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , AnimalesRESUMEN
Metastasis is the leading cause of cancerrelated death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stemcell phenotype and anoikis resistance in OS are mostly unknown. Foslike antigen 1 (FOSL1) is important in maintaining a stemlike phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stemlike properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumorsphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stemcell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumorsphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemnessrelated factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1mediated stemlike properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem celllike phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.
Asunto(s)
Anoicis , Carcinogénesis , Regulación Neoplásica de la Expresión Génica , Células Madre Neoplásicas , Osteosarcoma , Proteínas Proto-Oncogénicas c-fos , Factores de Transcripción SOXB1 , Osteosarcoma/patología , Osteosarcoma/genética , Osteosarcoma/metabolismo , Humanos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Factores de Transcripción SOXB1/metabolismo , Factores de Transcripción SOXB1/genética , Anoicis/genética , Animales , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Línea Celular Tumoral , Ratones , Carcinogénesis/genética , Carcinogénesis/patología , Metástasis de la Neoplasia , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Ratones Desnudos , Masculino , Femenino , Ratones Endogámicos BALB CRESUMEN
How prostate cancer cells and their precursors mediate changes in the tumor microenvironment (TME) to drive prostate cancer progression is unclear, in part due to the inability to longitudinally study the disease evolution in human tissues. To overcome this limitation, we perform extensive single-cell RNA-sequencing (scRNA-seq) and molecular pathology of the comparative biology between human prostate cancer and key stages in the disease evolution of a genetically engineered mouse model (GEMM) of prostate cancer. Our studies of human tissues reveal that cancer cell-intrinsic activation of MYC signaling is a common denominator across the well-known molecular and pathological heterogeneity of human prostate cancer. Cell communication network and pathway analyses in GEMMs show that MYC oncogene-expressing neoplastic cells, directly and indirectly, reprogram the TME during carcinogenesis, leading to a convergence of cell state alterations in neighboring epithelial, immune, and fibroblast cell types that parallel key findings in human prostate cancer.
Asunto(s)
Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-myc , Microambiente Tumoral , Masculino , Microambiente Tumoral/genética , Humanos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Animales , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Regulación Neoplásica de la Expresión Génica , Transducción de Señal , Análisis de la Célula Individual , Modelos Animales de Enfermedad , Comunicación Celular , Carcinogénesis/genética , Carcinogénesis/patología , Ratones Transgénicos , RNA-SeqRESUMEN
Keratinocytes are major cellular components of the skin and are strongly involved in its homeostasis. Oncogenic events, starting mainly from excessive sun exposure, lead to the dysregulation of their proliferation and differentiation programs and promote the initiation and progression of non-melanoma skin cancers (NMSCs). Primary melanomas, which originate from melanocytes, initiate and develop in close interaction with keratinocytes, whose role in melanoma initiation, progression, and immune escape is currently being explored. Recent studies highlighted, in particular, unexpected modes of communication between melanocytic cells and keratinocytes, which may be of interest as sources of new biomarkers in melanomagenesis or potential therapeutic targets. This review aims at reporting the various contributions of keratinocytes in skin basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, with a greater focus on the latter in order to highlight some recent breakthrough findings. The readers are referred to recent reviews when contextual information is needed.
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Carcinoma Basocelular , Carcinoma de Células Escamosas , Progresión de la Enfermedad , Queratinocitos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Carcinoma Basocelular/patología , Carcinoma Basocelular/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/metabolismo , Melanoma/metabolismo , Melanoma/patología , Animales , Carcinogénesis/patología , Carcinogénesis/metabolismoRESUMEN
Colorectal cancer remains a major global health concern. Colonoscopy, the gold-standard colorectal cancer diagnostic, relies on the visual detection of lesions and necessitates invasive biopsies for confirmation. Alternative diagnostic methods, based on nanomedicine, can facilitate early detection of malignancies. Here, we examine the uptake of surface-enhanced Raman scattering nanoparticles (SERS NPs) as a marker for intestinal tumor detection and imaging using an established Drosophila melanogaster model for gut disease. Young and old Oregon-R and w1118 flies were orally administered SERS NPs and scanned without and upon gut lumen clearance to assess nanoparticle retention as a function of aging. Neither young nor old flies showed significant NP retention in their body after gut lumen clearance. Moreover, tumorigenic flies of the esg-Gal4/UAS-RasV12 genotype were tested for SERS NP retention 2, 4 and 6 days after RasV12 oncogene induction in their midgut progenitor cells. Tumorigenic flies showed a statistically significant NP retention signal at 2 days, well before midgut epithelium impairment. The signal was then visualized in scans of dissected guts revealing areas of NP uptake in the posterior midgut region of high stem cell activity.
Asunto(s)
Envejecimiento , Drosophila melanogaster , Nanopartículas , Espectrometría Raman , Animales , Espectrometría Raman/métodos , Drosophila melanogaster/metabolismo , Envejecimiento/metabolismo , Nanopartículas/química , Carcinogénesis/patología , Carcinogénesis/metabolismoRESUMEN
The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.
Asunto(s)
Infecciones por Helicobacter , Neoplasias Gástricas , Canales Catiónicos TRPV , Humanos , Canales Catiónicos TRPV/metabolismo , Canales Catiónicos TRPV/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Infecciones por Helicobacter/metabolismo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/patología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Estudios Retrospectivos , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Helicobacter pylori/patogenicidad , Metaplasia/metabolismo , Metaplasia/patología , Gastritis/metabolismo , Gastritis/patología , Gastritis/microbiología , Adulto , Inmunohistoquímica , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Gastritis Atrófica/metabolismo , Gastritis Atrófica/patologíaRESUMEN
Endometrial cancer (EC), one of the most prevalent carcinomas in females, is associated with increasing mortality. We identified the CHD4 R975H mutation as a high-frequency occurrence in EC patients through a comprehensive survey of EC databases. Computational predictions suggest that this mutation profoundly impacts the structural and functional integrity of CHD4. Functional assays revealed that the CHD4 R975H mutation enhances EC cell invasion, proliferation, and colony formation, promoting a cancer stem cell (CSC)-like phenotype. RNA-seq analysis of cells expressing CHD4 R975H mutant revealed a transcriptomic landscape marked by the activation of several cancer-promoting signaling pathways, including TNF-α signaling via NF-κB, KRAS, P53, mTOR, TGF-ß, EGFR, Myc and growth factor signaling. Validation assays confirmed the activation of these pathways, further demonstrating that CHD4 R975H mutation induces stemness in EC cells and M2-like polarization of tumor-associated macrophages (TAMs). Our study elucidated the oncogenic role of CHD4 R975H mutation, highlighting its dual impact on facilitating cancer stemness and transforming TAMs into an immunosuppressive subtype. These findings contribute valuable insights into the molecular mechanisms driving EC progression and open avenues for targeted therapeutic interventions.
Asunto(s)
Neoplasias Endometriales , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2 , Células Madre Neoplásicas , Transducción de Señal , Animales , Femenino , Humanos , Ratones , Carcinogénesis/genética , Carcinogénesis/patología , Línea Celular Tumoral , Proliferación Celular , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Regulación Neoplásica de la Expresión Génica , Macrófagos/metabolismo , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/genética , Mutación , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patologíaRESUMEN
Accumulating evidence has demonstrated that F-box protein 22 (FBXO22) participates in tumour development and progression in various types of human malignancies. However, the functions and detailed molecular mechanisms of FBXO22 in osteosarcoma tumorigenesis and progression remain elusive. In this study, we aimed to determine the effects of FBXO22 on the cell proliferation, migration and invasion of osteosarcoma cells using cell counting kit-8 and Matrigel Transwell approaches. Moreover, we explored the molecular mechanisms by which FBXO22 mediated oncogenesis and progression in osteosarcoma via Western blotting, immunoprecipitation and ubiquitination. We found that FBXO22 depletion inhibited the proliferation, migration and invasion of osteosarcoma cells, whereas FBXO22 overexpression increased the proliferation and motility of osteosarcoma cells. Mechanistically, FBXO22 promoted the ubiquitination and degradation of FoxO1 in osteosarcoma cells. FBXO22 depletion reduced cell proliferation and motility via regulation of FoxO1. Taken together, our findings provide new insight into FBXO22-induced osteosarcoma tumorigenesis. The inhibition of FBXO22 could be a promising strategy for the treatment of osteosarcoma.
Asunto(s)
Movimiento Celular , Proliferación Celular , Proteínas F-Box , Proteína Forkhead Box O1 , Regulación Neoplásica de la Expresión Génica , Osteosarcoma , Ubiquitinación , Osteosarcoma/metabolismo , Osteosarcoma/patología , Osteosarcoma/genética , Humanos , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O1/genética , Proteínas F-Box/metabolismo , Proteínas F-Box/genética , Movimiento Celular/genética , Línea Celular Tumoral , Proteolisis , Progresión de la Enfermedad , Neoplasias Óseas/metabolismo , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Invasividad Neoplásica , Carcinogénesis/genética , Carcinogénesis/metabolismo , Carcinogénesis/patología , Receptores Citoplasmáticos y NuclearesAsunto(s)
Carcinoma de Células Escamosas , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Glipicanos , Neoplasias Pulmonares , beta Catenina , Glipicanos/genética , Glipicanos/metabolismo , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Proliferación Celular/genética , beta Catenina/metabolismo , beta Catenina/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Regulación hacia Arriba , Carcinogénesis/genética , Carcinogénesis/patología , Carcinogénesis/metabolismo , Línea Celular Tumoral , Animales , Masculino , FemeninoRESUMEN
Mucinous cystic neoplasm (MCN) is one of the precursor lesions of pancreatic ductal adenocarcinoma and intrahepatic cholangiocarcinoma. The aim of this study is to examine the presence of short telomeres in promoting the tumorigenesis of MCN by measuring telomere lengths in distinct components of MCN, including the mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma. A total of 45 patients with MCN (30 pancreatic and 15 hepatic cases) were obtained. Quantitative telomere-specific fluorescent in situ hybridization was performed to measure the telomere length of specific cell types within MCNs, including mucinous lining epithelium, non-mucinous lining epithelium, and ovarian-type stroma, as well as normal ductal epithelium and adenocarcinoma. Relative telomere lengths tended to decrease between normal ductal epithelium, ovarian-type stroma, non-mucinous lining epithelium, mucinous lining epithelium, and adenocarcinoma regardless of the involved organs. Among the analyzed cell types, relative telomere lengths were significantly different between normal ductal epithelium (3.31 ± 0.78), ovarian-type stroma (2.90 ± 0.93), non-mucinous lining epithelium (2.84 ± 0.79), mucinous lining epithelium (2.49 ± 0.93), and adenocarcinoma (1.19 ± 0.59), respectively (P < 0.001, mixed-effects model). As expected, no difference in relative telomere lengths was observed between normal ductal epithelium and ovarian-type stroma; however, significant differences were observed in pair-wise comparisons between ovarian-type stroma vs. non-mucinous lining epithelium (P = 0.001), non-mucinous lining epithelium vs. mucinous lining epithelium (P = 0.005), and mucinous lining epithelium vs. adenocarcinoma (P < 0.001). These findings suggest gradual telomere shortening occurs in the tumorigenesis of MCN, which may have important implications for the progression of this disease.
Asunto(s)
Hibridación Fluorescente in Situ , Neoplasias Hepáticas , Neoplasias Pancreáticas , Acortamiento del Telómero , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Femenino , Persona de Mediana Edad , Masculino , Anciano , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Telómero/patología , Telómero/genética , Adulto , Carcinogénesis/genética , Carcinogénesis/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patologíaRESUMEN
Head and neck cancer (HNC) entails a heterogenous neoplastic disease that arises from the mucosal epithelium of the upper respiratory system and the gastrointestinal tract. It is characterized by high morbidity and mortality, being the eighth most common cancer worldwide. It is believed that the mesenchymal/stem stromal cells (MSCs) present in the tumour milieu play a key role in the modulation of tumour initiation, development and patient outcomes; they also influence the resistance to cisplatin-based chemotherapy, the gold standard for advanced HNC. MSCs are multipotent, heterogeneous and mobile cells. Although no MSC-specific markers exist, they can be recognized based on several others, such as CD73, CD90 and CD105, while lacking the presence of CD45, CD34, CD14 or CD11b, CD79α, or CD19 and HLA-DR antigens; they share phenotypic similarity with stromal cells and their capacity to differentiate into other cell types. In the tumour niche, MSC populations are characterized by cell quiescence, self-renewal capacity, low reactive oxygen species production and the acquisition of epithelial-to-mesenchymal transition properties. They may play a key role in the process of acquiring drug resistance and thus in treatment failure. The present narrative review examines the links between MSCs and HNC, as well as the different mechanisms involved in the development of resistance to current chemo-radiotherapies in HNC. It also examines the possibilities of pharmacological targeting of stemness-related chemoresistance in HNSCC. It describes promising new strategies to optimize chemoradiotherapy, with the potential to personalize patient treatment approaches, and highlights future therapeutic perspectives in HNC.
Asunto(s)
Resistencia a Antineoplásicos , Neoplasias de Cabeza y Cuello , Células Madre Mesenquimatosas , Humanos , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/terapia , Neoplasias de Cabeza y Cuello/inmunología , Células Madre Mesenquimatosas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Carcinogénesis/patología , Carcinogénesis/efectos de los fármacos , Animales , Trasplante de Células Madre MesenquimatosasRESUMEN
BACKGROUND: We have previously demonstrated the significant reliance of pancreatic Cancer Stem Cells (PaCSCs) on mitochondrial oxidative phosphorylation (OXPHOS), which enables versatile substrate utilization, including fatty acids (FAs). Notably, dysregulated lipid scavenging and aberrant FA metabolism are implicated in PDAC progression. METHODS & RESULTS: Our bioinformatics analyses revealed elevated expression of lipid metabolism-related genes in PDAC tissue samples compared to normal tissue samples, which correlated with a stemness signature. Additionally, PaCSCs exhibited heightened expression of diverse lipid metabolism genes and increased lipid droplet accumulation compared to differentiated progenies. Treatment with palmitic, oleic, and linolenic FAs notably augmented the self-renewal and chemotherapy resistance of CD133+ PaCSCs. Conversely, inhibitors of FA uptake, storage and metabolism reduced CSC populations both in vitro and in vivo. Mechanistically, inhibition of FA metabolism suppressed OXPHOS activity, inducing energy depletion and subsequent cell death in PaCSCs. Importantly, combining a FAO inhibitor and Gemcitabine treatment enhanced drug efficacy in vitro and in vivo, effectively diminishing the CSC content and functionality. CONCLUSION: Targeting FAO inhibition represents a promising therapeutic strategy against this highly tumorigenic population.