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Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.
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Enfermedades del Desarrollo Óseo/genética , Enanismo/genética , Mutación Missense/genética , Proteínas de Neoplasias/genética , Proteínas Ribosómicas/genética , Anemia de Diamond-Blackfan/genética , Animales , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Tumour heterogeneity refers to the fact that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation and metastatic potential. This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity), and it is caused by genetic and non-genetic factors. The heterogeneity of cancer cells introduces significant challenges in using molecular prognostic markers as well as for classifying patients that might benefit from specific therapies. Thus, research efforts for characterizing heterogeneity would be useful for a better understanding of the causes and progression of disease. It has been suggested that the study of heterogeneity within Circulating Tumour Cells (CTCs) could also reflect the full spectrum of mutations of the disease more accurately than a single biopsy of a primary or metastatic tumour. In previous years, many high throughput methodologies have raised for the study of heterogeneity at different levels (i.e., RNA, DNA, protein and epigenetic events). The aim of the current review is to stress clinical implications of tumour heterogeneity, as well as current available methodologies for their study, paying specific attention to those able to assess heterogeneity at the single cell level.
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Heterogeneidad Genética , Neoplasias/genética , Neoplasias/patología , Células Neoplásicas Circulantes/patología , Análisis de la Célula Individual/métodos , Humanos , Metástasis de la Neoplasia/genética , Metástasis de la Neoplasia/patología , FenotipoRESUMEN
It has been established that disturbances in intracellular signaling pathways play a considerable part in the oncologic process. Phosphatidylinositol-3-kinase (PI3K) has become of key interest in cancer therapy because of its high mutation frequency and/or gain in function of its catalytic subunits in cancer cells. We investigated the therapeutic value of BYL719, a new specific PI3Kα inhibitor that blocks the ATP site, on osteosarcoma and bone cells. The in vitro effects of BYL719 on proliferation, apoptosis, and cell cycle were assessed in human and murine osteosarcoma cell. Its impact on bone cells was determined using human mesenchymal stem cells (hMSC) and human CD14+ osteoclast precursors. Two different murine preclinical models of osteosarcoma were used to analyze the in vivo biological activities of BYL719. BYL719 decreased cell proliferation by blocking cell cycle in G0/G1 phase with no outstanding effects on apoptosis cell death in HOS and MOS-J tumor cells. BYL719 inhibited cell migration and can thus be considered as a cytostatic drug for osteosarcoma. In murine preclinical models of osteosarcoma, BYL719 significantly decreased tumor progression and tumor ectopic bone formation as shown by a decrease of Ki67+ cells and tumor vascularization. To explore the maximum therapeutic potential of BYL719, the drug was studied in combination with conventional chemotherapeutic drugs, revealing promising efficacy with ifosfamide. BYL719 also exhibited dual activities on osteoblast and osteoclast differentiation. Overall, the present work shows that BYL719 is a promising drug in either a single or multidrug approach to curing bone sarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Inhibidores de las Quinasa Fosfoinosítidos-3 , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Femenino , Humanos , Concentración 50 Inhibidora , Masculino , Ratones Endogámicos C57BL , Ratones Desnudos , Osteoblastos/efectos de los fármacos , Osteoclastos/efectos de los fármacos , Osteosarcoma/patología , Tiazoles/administración & dosificación , Carga Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Ewing's sarcoma (ES) is the second most frequent primitive malignant bone tumor in adolescents with a very poor prognosis for high risk patients, mainly when lung metastases are detected (overall survival <15% at 5 years). Zoledronic acid (ZA) is a potent inhibitor of bone resorption which induces osteoclast apoptosis. Our previous studies showed a strong therapeutic potential of ZA as it inhibits ES cell growth in vitro and ES primary tumor growth in vivo in a mouse model developed in bone site. However, no data are available on lung metastasis. Therefore, the aim of this study was to determine the effect of ZA on ES cell invasion and metastatic properties. METHODS: Invasion assays were performed in vitro in Boyden's chambers covered with Matrigel. Matrix Metalloproteinase (MMP) activity was analyzed by zymography in ES cell culture supernatant. In vivo, a relevant model of spontaneous lung metastases which disseminate from primary ES tumor was induced by the orthotopic injection of 106 human ES cells in the tibia medullar cavity of nude mice. The effect of ZA (50 µg/kg, 3x/week) was studied over a 4-week period. Lung metastases were observed macroscopically at autopsy and analysed by histology. RESULTS: ZA induced a strong inhibition of ES cell invasion, probably due to down regulation of MMP-2 and -9 activities as analyzed by zymography. In vivo, ZA inhibits the dissemination of spontaneous lung metastases from a primary ES tumor but had no effect on the growth of established lung metastases. CONCLUSION: These results suggest that ZA could be used early in the treatment of ES to inhibit bone tumor growth but also to prevent the early metastatic events to the lungs.
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Conservadores de la Densidad Ósea/farmacología , Neoplasias Óseas/patología , Movimiento Celular/efectos de los fármacos , Difosfonatos/farmacología , Imidazoles/farmacología , Neoplasias Pulmonares/secundario , Sarcoma de Ewing/tratamiento farmacológico , Sarcoma de Ewing/patología , Animales , Conservadores de la Densidad Ósea/administración & dosificación , Neoplasias Óseas/tratamiento farmacológico , Línea Celular Tumoral , Difosfonatos/administración & dosificación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Imidazoles/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones , Carga Tumoral/efectos de los fármacos , Células Tumorales Cultivadas , Ácido ZoledrónicoRESUMEN
Precise spatiotemporal regulations of gene expression are essential for determining cells' fates and functions. Enhancers are cis-acting DNA elements that act as periodic transcriptional thrusters and their activities are cell type specific. Clusters of enhancers, called super-enhancers, are more densely occupied by transcriptional activators than enhancers, driving stronger expression of their target genes, which have prominent roles in establishing and maintaining cellular identities. Here we review the current knowledge on the composition and structure of super-enhancers to understand how they robustly stimulate the expression of cellular identity genes. We also review their involvement in the development of various cell types and both noncancerous and cancerous disorders, implying the therapeutic interest of targeting them to fight against various diseases.
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PURPOSE: Although ventilation/perfusion (V/Q) scintigraphy is a widely used imaging test, different options are possible for the acquisition and interpretation of the scan. The aim of this study was to assess current practices regarding the use and interpretation of lung scintigraphy in various clinical indications. PATIENTS AND METHODS: An online survey comprising 25 questions was sent to nuclear medicine departments in Australia, Canada, France, Germany, and United States between 2022 and 2023. A single response per department was consolidated. RESULTS: Four hundred nineteen responses were collected (Australia: 32, Canada: 58, France: 149, Germany: 92, and United States: 88). For acute pulmonary embolism (PE) diagnosis, 82.8% of centers reported using SPECT acquisitions (Australia: 93.3%, Canada: 91.8%, France: 99.2%, Germany: 96.2%, and United States: 32.1%). Among them, SPECT images were combined with a CT scan in 70.5% of centers. A total of 10.6% of centers reported not using ventilation for acute PE diagnosis. SPECT acquisition was used in 97.8% of centers using 99mTc carbon particles, 97.1% 81mKr gas, 58.7% 99mTc-DTPA, and 19.4% 133Xe gas, respectively. For V/Q SPECT interpretation, the EANM criteria were used in 65.0% of departments. A very wide variety of practices were observed in pregnant women and in COVID-19 patients. SPECT acquisition was widely used in the follow-up of PE and for the screening of chronic thromboembolic pulmonary hypertension (>90% of centers), with inconsistency regarding the interpretation of matched perfusion defects in this setting. CONCLUSIONS: This survey shows the strong adoption of SPECT in the various clinical indications of lung scintigraphy, except in the United States, where planar imaging is still mostly used. The survey also shows variability in interpretation criteria both for PE diagnosis and screening for chronic thromboembolic pulmonary hypertension, highlighting the need for further standardizations of practices.
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In Europe, with an incidence of 7.5 cases per million, Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children, adolescents and young adults, after osteosarcoma. Since the 1980s, conventional treatment has been based on the use of neoadjuvant and adjuvant chemotherapeutic agents combined with surgical resection of the tumor when possible. These treatments have increased the patient survival rate to 70% for localized forms, which drops drastically to less than 30% when patients are resistant to chemotherapy or when pulmonary metastases are present at diagnosis. However, the lack of improvement in these survival rates over the last decades points to the urgent need for new therapies. Genetically, ES is characterized by a chromosomal translocation between a member of the FET family and a member of the ETS family. In 85% of cases, the chromosomal translocation found is (11; 22) (q24; q12), between the EWS RNA-binding protein and the FLI1 transcription factor, leading to the EWS-FLI1 fusion protein. This chimeric protein acts as an oncogenic factor playing a crucial role in the development of ES. This review provides a non-exhaustive overview of ES from a clinical and biological point of view, describing its main clinical, cellular and molecular aspects.
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BACKGROUND: Osteoclasts are major actors in the maintenance of bone homeostasis. The full functional maturation of osteoclasts from monocyte lineage cells is essential for the degradation of old/damaged bone matrix. Diuron is one of the most frequently encountered herbicides, particularly in water sources. However, despite a reported delayed ossification in vivo, its impact on bone cells remains largely unknown. OBJECTIVES: The objectives of this study were to first better characterize osteoclastogenesis by identifying genes that drive the differentiation of CD14+ monocyte progenitors into osteoclasts and to evaluate the toxicity of diuron on osteoblastic and osteoclastic differentiation in vitro. METHODS: We performed chromatin immunoprecipitation (ChIP) against H3K27ac followed by ChIP-sequencing (ChIP-Seq) and RNA-sequencing (RNA-Seq) at different stages of differentiation of CD14+ monocytes into active osteoclasts. Differentially activated super-enhancers and their potential target genes were identified. Then to evaluate the toxicity of diuron on osteoblasts and osteoclasts, we performed RNA-Seq and functional tests during in vitro osteoblastic and osteoclastic differentiation by exposing cells to different concentrations of diuron. RESULTS: The combinatorial study of the epigenetic and transcriptional remodeling taking place during differentiation has revealed a very dynamic epigenetic profile that supports the expression of genes vital for osteoclast differentiation and function. In total, we identified 122 genes induced by dynamic super-enhancers at late days. Our data suggest that high concentration of diuron (50µM) affects viability of mesenchymal stem cells (MSCs) in vitro associated with a decrease of bone mineralization. At a lower concentration (1µM), an inhibitory effect was observed in vitro on the number of osteoclasts derived from CD14+ monocytes without affecting cell viability. Among the diuron-affected genes, our analysis suggests a significant enrichment of genes targeted by pro-differentiation super-enhancers, with an odds ratio of 5.12 (ρ=2.59×10-5). DISCUSSION: Exposure to high concentrations of diuron decreased the viability of MSCs and could therefore affect osteoblastic differentiation and bone mineralization. This pesticide also disrupted osteoclasts maturation by impairing the expression of cell-identity determining genes. Indeed, at sublethal concentrations, differences in the expression of these key genes were mild during the course of in vitro osteoclast differentiation. Taken together our results suggest that high exposure levels of diuron could have an effect on bone homeostasis. https://doi.org/10.1289/EHP11690.
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Herbicidas , Osteogénesis , Humanos , Diurona , Secuencias Reguladoras de Ácidos Nucleicos , Diferenciación CelularRESUMEN
BACKGROUND: Response to bicalutamide after castration failure is not durable and treatment options at this stage are limited. Carbidopa, an L-dopa decarboxylase (AR-coactivator) inhibitor, has been shown to retard prostate tumor growth/PSA production in xenografts. Here, we hypothesize that pharmacological targeting of the AR-axis by combination treatment with bicalutamide plus carbidopa significantly enhances antitumoral activity in vitro and in vivo compared to monotherapy with either drug. METHODS: Carbidopa was tested for its ability to enhance the effects of bicalutamide on cell viability, apoptosis and PSA transactivation in LNCaP and C4-2 cells. The castration-resistant prostate cancer (CRPC) LNCaP xenograft tumor model was used in vivo. After CRPC progression, mice were treated with carbidopa (50 mg/kg) and bicalutamide (50 mg/kg) as monotherapy or in combination. Tumor volume and serum PSA were evaluated weekly. RESULTS: Combination treatment of carbidopa plus bicalutamide significantly inhibited cell viability in both cell lines and induced apoptosis. The combination treatment also decreased androgen-induced PSA transactivation by 62.6% in LNCaP cells and by 55.6% in C4-2 cells compared to control, while bicalutamide monotherapy reduced PSA levels by 27.5% and 29.1% in LNCaP and C4-2 cells. In vivo, bicalutamide monotherapy delayed LNCaP CRPC tumor growth rate by 72.2%, while combination treatment reduced tumor growth by 84.4% compared to control. Serum PSA was also reduced 70.6% with bicalutamide monotherapy, while combination therapy reduced PSA levels by 76.7% compared to control. CONCLUSIONS: This study demonstrates preclinical proof-of-principle that pharmacological targeting of prostate tumors by combination treatment of bicalutamide plus carbidopa significantly reduces AR activity, and thereby delays CRPC tumor progression in vivo.
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Adenocarcinoma/patología , Anilidas/farmacología , Antineoplásicos/farmacología , Carbidopa/farmacología , Nitrilos/farmacología , Orquiectomía , Neoplasias de la Próstata/patología , Receptores Androgénicos/efectos de los fármacos , Compuestos de Tosilo/farmacología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Anilidas/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carbidopa/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Progresión de la Enfermedad , Dopaminérgicos/farmacología , Dopaminérgicos/uso terapéutico , Sinergismo Farmacológico , Quimioterapia Combinada , Humanos , Técnicas In Vitro , Masculino , Ratones , Ratones Desnudos , Nitrilos/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Receptores Androgénicos/metabolismo , Compuestos de Tosilo/uso terapéutico , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Osteosarcoma (OS) is the most frequent primary bone tumor, mainly affecting children and young adults. Despite therapeutic advances, the 5-year survival rate is 70% but drastically decreases to 20-30% for poor responders to therapies or for patients with metastasis. No real evolution of the survival rates has been observed for four decades, explained by poor knowledge of the origin, difficulties related to diagnosis and the lack of targeted therapies for this pediatric tumor. This review will describe a non-exhaustive overview of osteosarcoma disease from a clinical and biological point of view, describing the origin, diagnosis and therapies.
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TP53 (TP53), p73 (TP73), and p63 (TP63) are members of the p53 transcription factor family, which has many activities spanning from embryonic development through to tumor suppression. The utilization of two promoters and alternative mRNA splicing has been shown to yield numerous isoforms in p53, p63, and p73. TAp73 is thought to mediate apoptosis as a result of nuclear accumulation following chemotherapy-induced DNA damage, according to a number of studies. Overexpression of the nuclear ΔNp63 and ΔNp73 isoforms, on the other hand, suppresses TAp73's pro-apoptotic activity in human malignancies, potentially leading to metastatic spread or inhibition. Another well-known pathway that has been associated to metastatic spread is the TGF pathway. TGFs are a family of structurally related polypeptide growth factors that regulate a variety of cellular functions including cell proliferation, lineage determination, differentiation, motility, adhesion, and cell death, making them significant players in development, homeostasis, and wound repair. Various studies have already identified several interactions between the p53 protein family and the TGFb pathway in the context of tumor growth and metastatic spread, beginning to shed light on this enigmatic intricacy.
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Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.
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Current therapeutic approaches to osteoporosis display some potential adverse effects and a limited efficacy on non-vertebral fracture reduction. Some sulfonylamidines targeting the scaffold proteins prohibitins-1 and 2 (PHB1/2) have been showed to inhibit the formation of osteoclasts in charge of bone resorption. Herein, we report the development of a second generation of anti-osteoclastic PHB ligands. The most potent compound, IN45, showed 88% inhibition at the low concentration of 5 µM, indicates that it might serve as a basis for the development of new antiosteoporotic drugs.
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Amidinas/química , Amidinas/farmacología , Osteogénesis/efectos de los fármacos , Proteínas Represoras/metabolismo , Células Cultivadas , Descubrimiento de Drogas , Humanos , Ligandos , Osteoclastos/citología , Osteoclastos/efectos de los fármacos , Prohibitinas , Compuestos de Azufre/química , Compuestos de Azufre/farmacologíaRESUMEN
Osteosarcoma (OS) is the most common form of primary bone tumor affecting mainly children and young adults. Despite therapeutic progress, the 5-year survival rate is 70%, but it drops drastically to 30% for poor responders to therapies or for patients with metastases. Identifying new therapeutic targets is thus essential. Heat Shock Proteins (HSPs) are the main effectors of Heat Shock Response (HSR), the expression of which is induced by stressors. HSPs are a large family of proteins involved in the folding and maturation of other proteins in order to maintain proteostasis. HSP overexpression is observed in many cancers, including breast, prostate, colorectal, lung, and ovarian, as well as OS. In this article we reviewed the significant role played by HSPs in molecular mechanisms leading to OS development and progression. HSPs are directly involved in OS cell proliferation, apoptosis inhibition, migration, and drug resistance. We focused on HSP27, HSP60, HSP70 and HSP90 and summarized their potential clinical uses in OS as either biomarkers for diagnosis or therapeutic targets. Finally, based on different types of cancer, we consider the advantage of targeting heat shock factor 1 (HSF1), the major transcriptional regulator of HSPs in OS.
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Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Chaperonas Moleculares/metabolismo , Osteosarcoma/diagnóstico , Osteosarcoma/terapia , Animales , Neoplasias Óseas/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Humanos , Modelos Biológicos , Osteosarcoma/metabolismoRESUMEN
Osteosarcoma (OS) is the most common malignant bone tumor in children and teenagers. In many cases, such as poor response to treatment or the presence of metastases at diagnosis, the survival rate of patients remains very low. Although in the literature, more and more studies are emerging on the role of Ubiquitin-Specific Proteases (USPs) in the development of many cancers, few data exist regarding OS. In this context, RNA-sequencing analysis of OS cells and mesenchymal stem cells differentiated or not differentiated into osteoblasts reveals increased expression of four USPs in OS tumor cells: USP6, USP27x, USP41 and USP43. Tissue microarray analysis of patient biopsies demonstrates the nucleic and/or cytoplasmic expression of these four USPs at the protein level. Interestingly, Kaplan-Meyer analysis shows that the expression of two USPs, USP6 and USP41, is correlated with patient survival. In vivo experiments using a preclinical OS model, finally demonstrate that PR619, a USP inhibitor able to enhance protein ubiquitination in OS cell lines, reduces primary OS tumor growth and the development of lung metastases. In this context, in vitro experiments show that PR619 decreases the viability of OS cells, mainly by inducing a caspase3/7-dependent cell apoptosis. Overall, these results demonstrate the relevance of targeting USPs in OS.
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Neoplasias Óseas/tratamiento farmacológico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Inhibidores de Proteasas/farmacología , Proteasas Ubiquitina-Específicas/antagonistas & inhibidores , Animales , Apoptosis , Neoplasias Óseas/enzimología , Neoplasias Óseas/patología , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/secundario , Ratones , Osteosarcoma/enzimología , Osteosarcoma/patología , Pronóstico , Células Tumorales Cultivadas , Ubiquitina Tiolesterasa/antagonistas & inhibidores , Ubiquitina Tiolesterasa/metabolismo , Proteasas Ubiquitina-Específicas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Ribosomopathies are a group of rare diseases in which genetic mutations cause defects in either ribosome biogenesis or function, given specific phenotypes. Ribosomal proteins, and multiple other factors that are necessary for ribosome biogenesis (rRNA processing, assembly of subunits, export to cytoplasm), can be affected in ribosomopathies. Despite the need for ribosomes in all cell types, these diseases result mainly in tissue-specific impairments. Depending on the type of ribosomopathy and its pathogenicity, there are many potential therapeutic targets. The present manuscript will review our knowledge of ribosomopathies, discuss current treatments, and introduce the new therapeutic perspectives based on recent research. Diamond-Blackfan anemia, currently treated with blood transfusion prior to steroids, could be managed with a range of new compounds, acting mainly on anemia, such as L-leucine. Treacher Collins syndrome could be managed by various treatments, but it has recently been shown that proteasomal inhibition by MG132 or Bortezomib may improve cranial skeleton malformations. Developmental defects resulting from ribosomopathies could be also treated pharmacologically after birth. It might thus be possible to treat certain ribosomopathies without using multiple treatments such as surgery and transplants. Ribosomopathies remain an open field in the search for new therapeutic approaches based on our recent understanding of the role of ribosomes and progress in gene therapy for curing genetic disorders.
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Anemia de Diamond-Blackfan/terapia , Proteínas Ribosómicas/genética , Ribosomas/genética , Humanos , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismoRESUMEN
The formation of the skeleton occurs throughout the lives of vertebrates and is achieved through the balanced activities of two kinds of specialized bone cells: the bone-forming osteoblasts and the bone-resorbing osteoclasts. Impairment in the remodeling processes dramatically hampers the proper healing of fractures and can also result in malignant bone diseases such as osteosarcoma. MicroRNAs (miRNAs) are a class of small non-coding single-strand RNAs implicated in the control of various cellular activities such as proliferation, differentiation, and apoptosis. Their post-transcriptional regulatory role confers on them inhibitory functions toward specific target mRNAs. As miRNAs are involved in the differentiation program of precursor cells, it is now well established that this class of molecules also influences bone formation by affecting osteoblastic differentiation and the fate of osteoblasts. In response to various cell signals, the tumor-suppressor protein p53 activates a huge range of genes, whose miRNAs promote genomic-integrity maintenance, cell-cycle arrest, cell senescence, and apoptosis. Here, we review the role of three p53-related miRNAs, miR-34c, -125b, and -203, in the bone-remodeling context and, in particular, in osteoblastic differentiation. The second aim of this study is to deal with the potential implication of these miRNAs in osteosarcoma development and progression.
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Neoplasias Óseas/patología , Diferenciación Celular/genética , Transformación Celular Neoplásica/genética , MicroARNs/genética , Osteoblastos/patología , Osteosarcoma/genética , Osteosarcoma/patología , Proteína p53 Supresora de Tumor/metabolismo , Animales , Neoplasias Óseas/genética , Humanos , MicroARNs/metabolismo , Osteoblastos/metabolismoRESUMEN
Throughout life, bones are subjected to the so-called 'bone-remodeling' process, which is a balanced mechanism between the apposition and the resorption of bone. This remodeling process depends on the activities of bone-specialized cells, namely the osteoblasts and the osteoclasts. Any deregulation in this process results in bone-related pathologies, classified as either metabolic nonmalignant diseases (such as osteoporosis) or malignant primary bone sarcomas. As these pathologies are not characterized by common targetable genetic alterations, epigenetic strategies could be relevant and promising options. Recently, targeting epigenetic regulators such as the bromodomains and extraterminal domains (BET) readers have achieved success in numerous other pathologies, including cancers. In this review, we highlight the current state of the art in terms of the diverse implications of BET bromodomain proteins in the bone's biology and its defects. Consequently, their role in bone-related pathologies will also be developed, especially in the context of the primary bone sarcomas.
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Neoplasias Óseas/genética , Dominios Proteicos , Proteínas/fisiología , Acetilación , Neoplasias Óseas/metabolismo , Neoplasias Óseas/terapia , Epigénesis Genética , Histonas/metabolismo , Humanos , Osteoporosis/tratamiento farmacológico , Osteosarcoma/genética , Procesamiento Proteico-Postraduccional , Proteínas/antagonistas & inhibidores , Proteínas/química , Proteínas/metabolismo , Sarcoma de Ewing/genéticaRESUMEN
Osteosarcoma (OS) and Ewing's sarcoma (ES) are the most common malignant bone tumors in children and adolescents. In many cases, the prognosis remains very poor. The Sonic hedgehog (SHH) signaling pathway, strongly involved in the development of many cancers, regulate transcription via the transcriptional factors Gli1-3. In this context, RNAseq analysis of OS and ES cell lines reveals an increase of some major compounds of the SHH signaling cascade in ES cells, such as the transcriptional factor Gli1. This increase leads to an augmentation of the transcriptional response of Gli1 in ES cell lines, demonstrating a dysregulation of Gli1 signaling in ES cells and thus the rationale for targeting Gli1 in ES. The use of a preclinical model of ES demonstrates that GANT61, an inhibitor of the transcriptional factor Gli1, reduces ES primary tumor growth. In vitro experiments show that GANT61 decreases the viability of ES cell, mainly through its ability to induce caspase-3/7-dependent cell apoptosis. Taken together, these results demonstrates that GANT61 may be a promising therapeutic strategy for inhibiting the progression of primary ES tumors.
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BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumour. Unfortunately, no new treatments are approved and over the last 30 years the survival rate remains only 30% at 5 years for poor responders justifying an urgent need of new therapies. The Mutt homolog 1 (MTH1) enzyme prevents incorporation of oxidized nucleotides into DNA and recently developed MTH1 inhibitors may offer therapeutic potential as MTH1 is overexpressed in various cancers. METHODS: The aim of this study was to evaluate the therapeutic benefits of targeting MTH1 with two chemical inhibitors, TH588 and TH1579 on human osteosarcoma cells. Preclinical efficacy of TH1579 was assessed in human osteosarcoma xenograft model on tumour growth and development of pulmonary metastases. FINDINGS: MTH1 is overexpressed in OS patients and tumour cell lines, compared to mesenchymal stem cells. In vitro, chemical inhibition of MTH1 by TH588 and TH1579 decreases OS cells viability, impairs their cell cycle and increases apoptosis in OS cells. TH1579 was confirmed to bind MTH1 by CETSA in OS model. Moreover, 90â¯mg/kg of TH1579 reduces in vivo tumour growth by 80.5% compared to non-treated group at day 48. This result was associated with the increase in 8-oxo-dG integration into tumour cells DNA and the increase of apoptosis. Additionally, TH1579 also reduces the number of pulmonary metastases. INTERPRETATION: All these results strongly provide a pre-clinical proof-of-principle that TH1579 could be a therapeutic option for patients with osteosarcoma. FUNDING: This study was supported by La Ligue Contre le Cancer, la SFCE and Enfants Cancers Santé.