Asunto(s)

Transformación Celular Neoplásica , Neoplasias , Receptores Toll-Like , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/metabolismo , Receptores Toll-Like/metabolismo , Animales , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/inmunología , Regulación Neoplásica de la Expresión Génica

RESUMEN

Head and neck squamous cell carcinomas (HNSCCs), a heterogeneous group of cancers that arise from the mucosal epithelia cells in the head and neck areas, present great challenges in diagnosis, treatment and prognosis due to their complex aetiology and various clinical manifestations. Several factors, including smoking, alcohol consumption, oncogenic genes, growth factors, Epstein­Barr virus and human papillomavirus infections can contribute to HNSCC development. The unpredictable tumour microenvironment adds to the complexity of managing HNSCC. Despite significant advances in therapies, the prediction of outcome after treatment for patients with HNSCC remains poor, and the 5­year overall survival rate is low due to late diagnosis. Early detection greatly increases the chances of successful treatment. The present review aimed to bring together the latest findings related to the molecular mechanisms of HNSCC carcinogenesis and progression. Comprehensive genomic, transcriptomic, metabolomic, microbiome and proteomic analyses allow researchers to identify important biological markers such as genetic alterations, gene expression signatures and protein markers that drive HNSCC tumours. These biomarkers associated with the stages of initiation, progression and metastasis of cancer are useful in the management of patients with cancer in order to improve their life expectancy and quality of life.

Asunto(s)

Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Microambiente Tumoral , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinogénesis/genética , Pronóstico , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Infecciones por Papillomavirus/patología

RESUMEN

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient's sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.

Asunto(s)

Neoplasias Encefálicas , Transformación Celular Neoplásica , Glioma , Isocitrato Deshidrogenasa , Mutación , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Glioma/genética , Glioma/patología , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/metabolismo , Animales

RESUMEN

B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), remain incurable, with MM particularly prone to relapse. Our study introduces a novel mouse model with active RANK signaling and the TCL1 oncogene, displaying both CLL and MM phenotypes. In younger mice, TCL1 and RANK expression expands CLL-like B1-lymphocytes, while MM originates from B2-cells, becoming predominant in later stages and leading to severe disease progression and mortality. The induced MM mimics human disease, exhibiting features like clonal plasma cell expansion, paraproteinemia, anemia, and kidney and bone failure, as well as critical immunosurveillance strategies that promote a tumor-supportive microenvironment. This research elucidates the differential impacts of RANK activation in B1- and B2-cells and underscores the distinct roles of single versus combined oncogenes in B-cell malignancies. We also demonstrate that human MM cells express RANK and that inhibiting RANK signaling can reduce MM progression in a xenotransplantation model. Our study provides a rationale for further investigating the effects of RANK signaling in B-cell transformation and the shaping of a tumor-promoting microenvironment.

Asunto(s)

Linfocitos B , Transformación Celular Neoplásica , Mieloma Múltiple , Proteínas Proto-Oncogénicas , Transducción de Señal , Animales , Humanos , Ratones , Linfocitos B/metabolismo , Linfocitos B/inmunología , Linaje de la Célula , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Modelos Animales de Enfermedad , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Mieloma Múltiple/metabolismo , Mieloma Múltiple/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Microambiente Tumoral

RESUMEN

Arsenic (As) has been classified as a carcinogen for humans. There is abundant evidence indicating that arsenic increases the risk of bladder cancer among human populations. However, the underlying mechanisms have yet to be fully understood and elucidated. NADPH oxidases (NOXs) are the main enzymes for ROS production in the body. NADPH Oxidase 2 (NOX2), which is the most distinctive and ubiquitously expressed subunit of NOXs, can promote the formation and development of tumors. The utilization of NOX2 as a therapeutic target has been proposed to modulate diseases resulting from the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Matrine has been reported to exhibit various pharmacological effects, including anti-inflammatory, antifibrotic, antitumor, and analgesic properties. However, it has not been reported whether matrine can inhibit malignant transformation induced by arsenic in uroepithelial cells through NOX2. We have conducted a series of experiments using both a sub-chronic NaAsO2 exposure rat model and a long-term NaAsO2 exposure cell model. Our findings indicate that arsenic significantly increases cell proliferation, migration, and angiogenesis in vivo and in vitro. Arsenic exposure resulted in an upregulation of reactive oxygen species (ROS), NOX2, and NLRP3 inflammasome expression. Remarkably, both in vivo and in vitro, the administration of matrine demonstrated a significant improvement in the detrimental impact of arsenic on bladder epithelial cells. This was evidenced by the downregulation of proliferation, migration, and angiogenesis, as well as the expression of the NOX2 and NLRP3 inflammasomes. Collectively, these findings indicate that matrine possesses the ability to reduce NOX2 levels and inhibit the transformation of bladder epithelial cells.

Asunto(s)

Alcaloides , Arsénico , Proliferación Celular , Transformación Celular Neoplásica , Matrinas , NADPH Oxidasa 2 , Quinolizinas , Especies Reactivas de Oxígeno , NADPH Oxidasa 2/metabolismo , NADPH Oxidasa 2/genética , Animales , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Humanos , Arsénico/toxicidad , Arsénico/efectos adversos , Alcaloides/farmacología , Especies Reactivas de Oxígeno/metabolismo , Ratas , Quinolizinas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias de la Vejiga Urinaria/inducido químicamente , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/metabolismo , Movimiento Celular/efectos de los fármacos , Línea Celular , Masculino

RESUMEN

Reprogramming of cancer metabolism has become increasingly concerned over the last decade, particularly the reprogramming of glucose metabolism, also known as the "Warburg effect". The reprogramming of glucose metabolism is considered a novel hallmark of human cancers. A growing number of studies have shown that reprogramming of glucose metabolism can regulate many biological processes of cancers, including carcinogenesis, progression, metastasis, and drug resistance. In this review, we summarize the major biological functions, clinical significance, potential targets and signaling pathways of glucose metabolic reprogramming in human cancers. Moreover, the applications of natural products and small molecule inhibitors targeting glucose metabolic reprogramming are analyzed, some clinical agents targeting glucose metabolic reprogramming and trial statuses are summarized, as well as the pros and cons of targeting glucose metabolic reprogramming for cancer therapy are analyzed. Overall, the reprogramming of glucose metabolism plays an important role in the prediction, prevention, diagnosis and treatment of human cancers. Glucose metabolic reprogramming-related targets have great potential to serve as biomarkers for improving individual outcomes and prognosis in cancer patients. The clinical innovations related to targeting the reprogramming of glucose metabolism will be a hotspot for cancer therapy research in the future. We suggest that more high-quality clinical trials with more abundant drug formulations and toxicology experiments would be beneficial for the development and clinical application of drugs targeting reprogramming of glucose metabolism.This review will provide the researchers with the broader perspective and comprehensive understanding about the important significance of glucose metabolic reprogramming in human cancers.

Asunto(s)

Glucosa , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Neoplasias/diagnóstico , Glucosa/metabolismo , Animales , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Transducción de Señal/efectos de los fármacos , Efecto Warburg en Oncología/efectos de los fármacos , Reprogramación Celular/efectos de los fármacos

RESUMEN

BACKGROUND: Betel quid and its major ingredient, areca nut, are recognized by IARC as major risk factors in oral cancer development. Areca nut extract (ANE) exposure has been linked to OPMD progression and malignant transformation to OSCC. However, the detailed mechanism through which ANE acts on other cell types in the oral microenvironment to promote oral carcinogenesis remains elusive. METHODS: Immunoprofiling of macrophages associated with OPMD and OSCC was carried out by immunohistochemical and immunofluorescence staining. Phosphokinase and cytokine arrays and western blotting were performed to determine the underlying mechanisms. Transwell assays were used to evaluate the migration-promoting effect of ANE. Hamster model was finally applied to confirm the in vivo effect of ANE. RESULTS: We reported that M2 macrophages positively correlated with oral cancer progression. ANE induced M2 macrophage differentiation, CREB phosphorylation and VCAM-1 secretion and increased mitochondrial metabolism. Conditioned medium and VCAM-1 from ANE-treated macrophages promoted migration and mesenchymal phenotypes in oral precancer cells. In vivo studies showed that ANE enhanced M2 polarization and related signaling pathways in the oral buccal tissues of hamsters. CONCLUSION: Our study provides novel mechanisms for areca nut-induced oral carcinogenesis, demonstrating that areca nut promotes M2 macrophage differentiation and secretion of oncogenic cytokines that critically activate malignant transformation of oral premalignant cells.

Asunto(s)

Areca , Diferenciación Celular , Transformación Celular Neoplásica , Macrófagos , Neoplasias de la Boca , Animales , Areca/efectos adversos , Areca/química , Transformación Celular Neoplásica/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Humanos , Macrófagos/metabolismo , Cricetinae , Modelos Animales de Enfermedad , Nueces , Masculino , Reprogramación Metabólica

RESUMEN

Drug transporters play a pivotal role in modulating drug disposition and are subject to alterations under inflammatory conditions. This study aimed to elucidate the intricate expression patterns of drug transporters during both acute and chronic inflammation, which are closely linked to malignant transformation. To investigate acute inflammation, we employed an in vitro model by subjecting Caco-2 cells to various inflammatory stimuli (IL-1ß, TNF-α, or LPS) individually or in combination. The successful induction of inflammation was confirmed by robust increases in IL-6 and NO production. Notably, inflamed Caco-2 cells exhibited significantly diminished levels of ABCB1 and ABCG2, while the expression of ABCC2 was upregulated. For chronic inflammation induction in vivo, we employed the well-established AOM/DSS mouse model known for its association with colitis-driven tumorigenesis. Persistent inflammation was effectively monitored throughout the experiment via elevated IL-6 and NO levels. The sequential stages of tumorigenesis were confirmed through Ki-67 immunohistochemistry. Intriguingly, we observed gradual alterations in the expression patterns of the studied drug transporters during stepwise induction, with ABCB1, ABCG2, and ABCC1 showing downregulation and ABCC2 exhibiting upregulation. Immunohistochemistry further revealed dynamic changes in the expression of ABCB1 and ABCC2 during the induction cycles, closely paralleling the gradual increase in Ki-67 expression observed during the development of precancerous lesions. Collectively, our findings underscore the significant impact of inflammation on drug transporter expression, potentially influencing the process of malignant transformation of the colon.

Asunto(s)

Azoximetano , Neoplasias del Colon , Inflamación , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Humanos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Animales , Células CACO-2 , Ratones , Azoximetano/toxicidad , Inflamación/metabolismo , Inflamación/inducido químicamente , Inflamación/patología , Carcinogénesis/metabolismo , Carcinogénesis/inducido químicamente , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/biosíntesis , Interleucina-6/metabolismo , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Masculino

Asunto(s)

Linfoma de Células B Grandes Difuso , Linfocitos T , Humanos , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/metabolismo , Linfocitos T/patología , Linfocitos T/metabolismo , Transformación Celular Neoplásica/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Masculino , Biomarcadores de Tumor/metabolismo , Persona de Mediana Edad , Femenino

RESUMEN

Lung cancer remains the leading cause of cancer-related deaths, with cigarette smoking being the most critical factor, linked to nearly 90% of lung cancer cases. NNK, a highly carcinogenic nitrosamine found in tobacco, is implicated in the lung cancer-causing effects of cigarette smoke. Although NNK is known to mutate or activate certain oncogenes, its potential interaction with p27 in modulating these carcinogenic effects is currently unexplored. Recent studies have identified specific downregulation of p27 in human squamous cell carcinoma, in contrast to adenocarcinoma. Additionally, exposure to NNK significantly suppresses p27 expression in human bronchial epithelial cells. Subsequent studies indicates that the downregulation of p27 is pivotal in NNK-induced cell transformation. Mechanistic investigations have shown that reduced p27 expression leads to increased level of ITCH, which facilitates the degradation of Jun B protein. This degradation in turn, augments miR-494 expression and its direct regulation of JAK1 mRNA stability and protein expression, ultimately activating STAT3 and driving cell transformation. In summary, our findings reveal that: (1) the downregulation of p27 increases Jun B expression by upregulating Jun B E3 ligase ITCH, which then boosts miR-494 transcription; (2) Elevated miR-494 directly binds to 3'-UTR of JAK1 mRNA, enhancing its stability and protein expression; and (3) The JAK1/STAT3 pathway is a downstream effector of p27, mediating the oncogenic effect of NNK in lung cancer. These findings provide significant insight into understanding the participation of mechanisms underlying p27 inhibition of NNK induced lung squamous cell carcinogenic effect.

Asunto(s)

Bronquios , Carcinoma de Células Escamosas , Transformación Celular Neoplásica , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Células Epiteliales , Neoplasias Pulmonares , Nitrosaminas , Humanos , Nitrosaminas/toxicidad , Bronquios/metabolismo , Bronquios/patología , Bronquios/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Carcinoma de Células Escamosas/inducido químicamente , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , MicroARNs/genética , MicroARNs/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Carcinógenos/toxicidad

RESUMEN

Approximately 25% of cancers are preceded by chronic inflammation that occurs at the site of tumor development. However, whether this multifactorial oncogenic process, which commonly occurs in the intestines, can be initiated by a specific immune cell population is unclear. Here, we show that an intestinal T cell subset, derived from interleukin-17 (IL-17)-producing helper T (TH17) cells, induces the spontaneous transformation of the intestinal epithelium. This subset produces inflammatory cytokines, and its tumorigenic potential is not dependent on IL-17 production but on the transcription factors KLF6 and T-BET and interferon-γ. The development of this cell type is inhibited by transforming growth factor-ß1 (TGFß1) produced by intestinal epithelial cells. TGFß signaling acts on the pretumorigenic TH17 cell subset, preventing its progression to the tumorigenic stage by inhibiting KLF6-dependent T-BET expression. This study therefore identifies an intestinal T cell subset initiating cancer.

Asunto(s)

Mucosa Intestinal , Factor 6 Similar a Kruppel , Proteínas de Dominio T Box , Células Th17 , Animales , Células Th17/inmunología , Ratones , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/genética , Factor 6 Similar a Kruppel/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Transducción de Señal/inmunología , Ratones Endogámicos C57BL , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Noqueados , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones Transgénicos , Proteínas Proto-Oncogénicas/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Neoplasias Intestinales/inmunología , Neoplasias Intestinales/patología , Neoplasias Intestinales/metabolismo , Humanos

RESUMEN

Our previous study identified that nuclear factor-erythroid-2 p45-related factor 2 (NRF2) was activated in arsenite-induced tumorigenesis. However, the underlying mechanisms of NRF2 mediating apoptosis in arsenic-induced skin carcinogenesis remain unknown. This study explored the dynamic changes in apoptosis rate and the expression of apoptosis proteins in immortalized human keratinocytes (HaCaT) malignant transformation caused by 1.0 µM NaAsO2 at passages 0, 1, 7, 14, 21, 28, and 35. The result showed that the apoptosis rate decreased. The apoptosis-related proteins cleaved-caspase-3/caspase-3 ratio decreased in the later stages (passages 21, 28, and 35). Moreover, the expression of intrinsic ER stress pathway-related CHOP, ATF4, ATF6, and the intrinsic mitochondrial pathway-related Bax protein decreased in the later stages, while Bcl-2 and Mcl-1 increased, and NRF2 protein levels also increased. The apoptosis rate increased by silencing NRF2 expression in arsenite-transformed HaCaT (T-HaCaT) cells. Meanwhile, the expression of pro-apoptotic proteins (cleaved-caspase-3/caspase-3, CHOP, Bax) and ATF4, ATF6 increased. On the contrary, antiapoptotic protein levels (Bcl-2 and Mcl-1) decreased. The ability of colony formation and migration of T-HaCaT cells decreased. In conclusion, arsenite activated NRF2 in the later stages, decreasing apoptosis characterized by inhibiting endoplasmic reticulum stress-depended and mitochondria-depended apoptosis pathway, and further promoting NaAsO2-induced HaCaT cellular malignant transformation.

Asunto(s)

Apoptosis , Arsenitos , Queratinocitos , Factor 2 Relacionado con NF-E2 , Humanos , Apoptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Arsenitos/toxicidad , Estrés del Retículo Endoplásmico/efectos de los fármacos , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/metabolismo , Línea Celular

RESUMEN

Richter's transformation (RT) is a progression of chronic lymphocytic leukemia (CLL) to aggressive lymphoma. MGA (Max gene associated), a functional MYC suppressor, is mutated at 3% in CLL and 36% in RT. However, genetic models and molecular mechanisms of MGA deletion that drive CLL to RT remain elusive. We established an RT mouse model by knockout of Mga in the Sf3b1/Mdr CLL model using CRISPR-Cas9 to determine the role of Mga in RT. Murine RT cells exhibited mitochondrial aberrations with elevated oxidative phosphorylation (OXPHOS). Through RNA sequencing and functional characterization, we identified Nme1 (nucleoside diphosphate kinase) as an Mga target, which drives RT by modulating OXPHOS. Given that NME1 is also a known MYC target without targetable compounds, we found that concurrent inhibition of MYC and electron transport chain complex II substantially prolongs the survival of RT mice in vivo. Our results suggest that the Mga-Nme1 axis drives murine CLL-to-RT transition via modulating OXPHOS, highlighting a potential therapeutic avenue for RT.

Asunto(s)

Leucemia Linfocítica Crónica de Células B , Mitocondrias , Fosforilación Oxidativa , Animales , Mitocondrias/metabolismo , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Linfocítica Crónica de Células B/metabolismo , Ratones , Eliminación de Gen , Humanos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Modelos Animales de Enfermedad

RESUMEN

Pancreatic cancer is usually detected at a late stage, when tumors have already metastasized; therefore, it has a poor prognosis with a 5-year survival rate of 11% to 12%. A key to targeting this high mortality is to develop methods for detecting the disease at a stage in which it is still local to the pancreas. However, this needs a better understanding of the events that govern pancreatic cancer oncogenesis. In this issue of Cancer Research, Neuß and colleagues report metabolic changes associated with acinar-to-ductal metaplasia (ADM), an initiating event that leads to the formation of precursor lesions for pancreatic ductal adenocarcinoma (PDAC). Their findings reveal a switch to aerobic glycolysis, increased c-MYC signaling, and increased serine metabolism as driving factors for the ADM process. These findings are important as they demonstrate that metabolic changes that drive the proliferation and metastasis of full-blown PDAC begin in the earliest lesions. The data not only provide insights into how PDAC develops but also a potential explanation for previously described findings, such as circulating lesion cells can be detected even when no carcinoma in situ is present. In summary, this article is highly relevant for furthering our understanding of how metabolic reprogramming drives the earliest events leading to PDAC development and could lay the groundwork for developing methods for early detection or intervention. See related article by Neuß et al., p. 2297.

Asunto(s)

Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Animales

RESUMEN

Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.

Asunto(s)

Proteínas de Ciclo Celular , Neoplasias Pulmonares , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-myc , Humanos , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Línea Celular Tumoral , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Ratones , Animales , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Tumores Neuroendocrinos/metabolismo , Tumores Neuroendocrinos/tratamiento farmacológico , Proteolisis/efectos de los fármacos , Proteínas de Unión a Retinoblastoma/genética , Proteínas de Unión a Retinoblastoma/metabolismo , Ubiquitina-Proteína Ligasas

RESUMEN

Objective: Detecting oral lesions at high risk of becoming cancer may enable early interventions to prevent oral cancer. The diagnosis of dysplasia in an oral lesion is used to predict this risk but is subject to interobserver and intraobserver variability. Studying biomarkers or molecular markers that reflect underlying molecular alterations can serve as an additional and objective method of risk assessment. E-cadherin and beta-catenin, molecular markers of epithelial-mesenchymal transition (EMT), potentially contribute to early malignant progression in oral tissue. This narrative review provides an overview of EMT, its relation to oral cancer, and the interaction among E-cadherin, beta-catenin, and the Wnt pathway in malignant progression of oral tissue. Methods: Full-text literature on EMT, E-cadherin, beta-catenin, oral epithelial dysplasia, and oral cancer was retrieved from PubMed and Google Scholar. Results: Sixty original research articles, reviews, and consensus statements were selected for review. Discussion: EMT, a biological mechanism characterized by epithelial and mesenchymal changes, can contribute to cancer development. Molecular markers of EMT including TWIST, vimentin, and N-cadherin may serve as prognostic markers of oral cancer. Dependent on Wnt pathway activity and the loss of membranous E-cadherin, E-cadherin and beta-catenin can play various roles along the spectrum of malignant progression, including tumour inhibition, early tumour progression, and late-stage tumour progression. Cross-sectional immunohistochemical research has found changes in expression patterns of E-cadherin and beta-catenin from normal oral tissue, oral epithelial dysplasia, to oral squamous cell carcinoma. Conclusion: Future research should explore the longitudinal role of EMT markers in predicting malignant progression in oral tissue.

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Objectif: La détection de lésions buccales présentant un risque élevé d'évoluer en cancer peut permettre des interventions précoces pour prévenir le cancer de la bouche. Le diagnostic de dysplasie dans le cas de lésions buccales sert à prédire ce risque, mais il est soumis à une variabilité d'un observateur à l'autre et avec le même observateur. L'étude de marqueurs biologiques ou de marqueurs moléculaires correspondant à des altérations moléculaires sous-jacentes peut constituer une méthode objective supplémentaire d'évaluation des risques. L'E-cadhérine et la bêta-caténine, des marqueurs moléculaires de la transition épithélio-mésenchymateuse (TEM), pourraient contribuer aux premières étapes de l'évolution maligne du tissu buccal. Cette revue narrative donne un aperçu de la TEM, de ses liens avec le cancer de la bouche et de l'interaction entre l'E-cadhérine, la bêta-caténine et la voie de signalisation Wnt dans l'évolution maligne du tissu buccal. Méthodes: On a obtenu le texte intégral d'études portant sur la TEM, l'E-cadhérine, la bêta-caténine, la dysplasie épithéliale buccale et le cancer de la bouche sur PubMed et Google Scholar. Résultats: Soixante articles sur des études originales, des revues et des déclarations de consensus ont été sélectionnés aux fins d'examen. Discussion: La TEM, un mécanisme biologique caractérisé par des changements épithéliaux et mésenchymateux, peut contribuer à l'apparition d'un cancer. Les marqueurs moléculaires de la TEM, notamment TWIST, la vimentine et la N-cadhérine, peuvent servir de marqueurs pronostiques du cancer de la bouche. En fonction de l'activité de la voie de signalisation Wnt et de la perte de l'E-cadhérine membraneuse, l'E-cadhérine et la bêta-caténine peuvent jouer divers rôles dans le spectre de l'évolution maligne, notamment l'inhibition tumorale, la progression tumorale précoce et l'évolution tumorale avancée. Des études transversales d'immunohistochimie ont révélé des changements dans les modèles d'expression de l'E-cadhérine et de la bêta-caténine avec le passage du tissu buccal normal, de la dysplasie épithéliale buccale au carcinome squameux de la bouche. Conclusion: À l'avenir, des études devraient explorer le rôle longitudinal des marqueurs de la TEM dans la prévision de l'évolution maligne dans les tissus buccaux.

Asunto(s)

Biomarcadores de Tumor , Cadherinas , Transformación Celular Neoplásica , Transición Epitelial-Mesenquimal , Neoplasias de la Boca , beta Catenina , Humanos , beta Catenina/metabolismo , beta Catenina/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Cadherinas/metabolismo , Cadherinas/genética , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/diagnóstico , Vía de Señalización Wnt

RESUMEN

SOCS are a family of negative inhibitors of the molecular cascades induced by cytokines, growth factors and hormones. At molecular level, SOCS proteins inhibit the kinase activity of specific sets of receptor-associated Janus Activated Kinases (JAKs), thereby suppressing the propagation of intracellular signals. Of the eight known members, SOCS1 and SOCS3 inhibit activity of JAKs mainly induced by cytokines and can play key roles in regulation of inflammatory and immune responses. SOCS1 and SOCS3 are the most well-characterized SOCS members in skin inflammatory diseases, where their inhibitory activity on cytokine activated JAKs and consequent anti-inflammatory action has been widely investigated in epidermal keratinocytes. Structurally, SOCS1 and SOCS3 share the presence of a N-terminal domain containing a kinase inhibitory region (KIR) motif able to act as a pseudo-substrate for JAK and to inhibit its activity. During the last decades, the design and employment of SOCS1 and SOCS3-derived peptides mimicking KIR domains in experimental models of dermatoses definitively established a strong anti-inflammatory and ameliorative impact of JAK inhibition on skin inflammatory responses. Herein, we discuss the importance of the findings collected in the past on SOCS1 and SOCS3 function in the inflammatory responses associated to skin immune-mediated diseases and malignancies, for the development of the JAK inhibitor drugs. Among them, different JAK inhibitors have been introduced in the clinical practice for treatment of atopic dermatitis and psoriasis, and others are being investigated for skin diseases like alopecia areata and vitiligo.

Asunto(s)

Transformación Celular Neoplásica , Proteína 1 Supresora de la Señalización de Citocinas , Proteína 3 Supresora de la Señalización de Citocinas , Humanos , Proteína 1 Supresora de la Señalización de Citocinas/metabolismo , Animales , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Transformación Celular Neoplásica/inmunología , Transformación Celular Neoplásica/metabolismo , Transducción de Señal , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Dermatitis/inmunología , Dermatitis/metabolismo , Quinasas Janus/metabolismo , Piel/inmunología , Piel/patología , Piel/metabolismo

RESUMEN

Benzo[a]pyrene (BaP) is associated with the development of lung cancer, but the underlying mechanism has not been completely clarified. Here, we used 10 µM BaP to induce malignant transformation of human bronchial epithelial BEAS-2B cells, named BEAS-2B-T. Results indicated that BaP (6.25, 12.5 and 25 µM) treatment significantly promoted the migration and invasion of BEAS-2B-T cells. Meanwhile, BaP exposure inhibited ferroptosis in BEAS-2B-T, ferroptosis-related indexes Fe2+, malondialdehyde (MDA), lipid peroxidation (LPO) and reactive oxygen species (ROS) decreased significantly. The protein level of ferroptosis-related molecule transferrin receptor (TFRC) decreased significantly, while solute carrier family 7 membrane 11 (SLC7A11), ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) increased significantly. The intervention of ferroptosis dramatically effected the migration and invasion of BEAS-2B-T induced by BaP. Furthermore, the expression of YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) was markedly increased after BaP exposure. YTHDF1 knockdown inhibited BEAS-2B-T migration and invasion by promoting ferroptosis. In the meantime, the contents of Fe2+, MDA, LPO and ROS increased significantly, TFRC was markedly increased, and SLC7A11, FTH1, and GPX4 were markedly decreased. Moreover, overexpression of YTHDF1 promoted BEAS-2B-T migration and invasion by inhibiting ferroptosis. Importantly, knockdown of YTHDF1 promoted ferroptosis and reduced BEAS-2B-T migration and invasion during BaP exposure, and overexpression of YTHDF1 increased migration and invasion of BEAS-2B-T by inhibiting ferroptosis during BaP exposure. RNA immunoprecipitation assays indicated that the binding of YTHDF1 to SLC7A11 and FTH1 markedly increased after YTHDF1 overexpression. Therefore, we concluded that BaP promotes the malignant progression of BEAS-2B-T cells through YTHDF1 upregulating SLC7A11 and FTH1 to inhibit ferroptosis. This study reveals new epigenetic and ferroptosis markers for preventing and treating lung cancer induced by environmental carcinogens.

Asunto(s)

Benzo(a)pireno , Movimiento Celular , Ferroptosis , Ferroptosis/efectos de los fármacos , Humanos , Benzo(a)pireno/toxicidad , Movimiento Celular/efectos de los fármacos , Línea Celular , Transformación Celular Neoplásica/inducido químicamente , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Transferrina/metabolismo , Receptores de Transferrina/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/genética , Peroxidación de Lípido/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Ferritinas , Oxidorreductasas , Antígenos CD

RESUMEN

Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.

Asunto(s)

Caspasa 3 , Transformación Celular Neoplásica , Oncogenes , Factor de Transcripción STAT3 , Animales , Femenino , Humanos , Ratones , Caspasa 3/metabolismo , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Ratones Transgénicos , Mitocondrias/metabolismo , Oncogenes/genética , Fosforilación , Transducción de Señal , Familia-src Quinasas/metabolismo , Familia-src Quinasas/genética , Factor de Transcripción STAT3/metabolismo

RESUMEN

Cutaneous melanoma is an aggressive form of skin cancer derived from skin melanocytes and is associated with significant morbidity and mortality. A significant fraction of melanomas are associated with precursor lesions, benign clonal proliferations of melanocytes called nevi. Nevi can be either congenital or acquired later in life. Identical oncogenic driver mutations are found in benign nevi and melanoma. While much progress has been made in our understanding of nevus formation and the molecular steps required for transformation of nevi into melanoma, the clinical diagnosis of benign versus malignant lesions remains challenging.

Asunto(s)

Melanoma , Nevo , Neoplasias Cutáneas , Humanos , Melanoma/genética , Melanoma/patología , Melanoma/terapia , Melanoma/diagnóstico , Melanoma/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/metabolismo , Nevo/diagnóstico , Nevo/patología , Nevo/genética , Mutación , Melanocitos/metabolismo , Melanocitos/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/metabolismo , Melanoma Cutáneo Maligno