RESUMEN

Skin is usually the first and most affected organ involved in graft-versus-host disease (GvHD), and treatment is still a clinical challenge. Although the need for skin-directed treatments such as physical treatments and topical medications are generally agreed on, what the gold standard treatment strategy should be remains open to debate. The aim of this scoping review was to synthesize the current knowledge on the topical and physical treatments of cutaneous GvHD in haematopoietic stem cell transplantation patients and to highlight the best evidence available so as to reduce the gap between 'what is known' and 'what is done' in the clinical practice. Twenty-eight studies were included in this qualitative synthesis. Photo-biomodulation with psoralen was not included in this review. Phototherapy (ultraviolet A or B or narrowband B) was the physical treatment most described in the literature in both acute GvHD and chronic GvHD. Topical calcineurin inhibitors such as tacrolimus ointment and pimecrolimus cream as well as corticosteroid creams such as clobetasol and triamcinolone are mainly used in case of chronic GvHD. In all of the studies included in the review, topical treatments were always associated with systemic therapy. None of the topical interventions identified in our review provided strong evidence supporting its use, and the topical approaches seemed to have an adjuvant role in the treatment of cutaneous GvHD.

Asunto(s)

Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedades de la Piel , Inhibidores de la Calcineurina/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Fototerapia , Piel , Enfermedades de la Piel/tratamiento farmacológico

RESUMEN

Clinical management of malignant pleural mesothelioma (MPM) is very challenging because of the uncommon resistance of this tumor to chemotherapy. We report here increased expression of macrophage colony-stimulating-factor-1-receptor (M-CSF/CSF-1R) mRNA in mesothelioma versus normal tissue specimens and demonstrate that CSF-1R expression identifies chemoresistant cells of mesothelial nature in both primary cultures and mesothelioma cell lines. By using RNAi or ligand trapping, we demonstrate that the chemoresistance properties of those cells depend on autocrine CSF-1R signaling. At the single-cell level, the isolated CSF-1R(pos) cells exhibit a complex repertoire of pluripotency, epithelial-mesenchymal transition and detoxifying factors, which define a clonogenic, chemoresistant, precursor-like cell sub-population. The simple activation of CSF-1R in untransformed mesothelial cells is sufficient to confer clonogenicity and resistance to pemetrexed, hallmarks of mesothelioma. In addition, this induced a gene expression profile highly mimicking that observed in the MPM cells endogenously expressing the receptor and the ligands, suggesting that CSF-1R expression is mainly responsible for the phenotype of the identified cell sub-populations. The survival of CSF1R(pos) cells requires active AKT (v-akt murine thymoma viral oncogene homolog 1) signaling, which contributed to increased levels of nuclear, transcriptionally competent ß-catenin. Inhibition of AKT reduced the transcriptional activity of ß-catenin-dependent reporters and sensitized the cells to senescence-induced clonogenic death after pemetrexed treatment. This work expands what is known on the non-macrophage functions of CSF-1R and its role in solid tumors, and suggests that CSF-1R signaling may have a critical pathogenic role in a prototypical, inflammation-related cancer such as MPM and therefore may represent a promising target for therapeutic intervention.

Asunto(s)

Comunicación Autocrina , Resistencia a Antineoplásicos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Mesotelioma/metabolismo , Mesotelioma/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Factor Estimulante de Colonias de Macrófagos/metabolismo , Comunicación Autocrina/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Transformación Celular Neoplásica/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glutamatos , Guanina/análogos & derivados , Humanos , Interleucinas/farmacología , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Factor Estimulante de Colonias de Macrófagos/farmacología , Mesotelioma/enzimología , Mesotelioma/genética , Mesotelioma Maligno , Pemetrexed , Receptor de Factor Estimulante de Colonias de Macrófagos/genética

RESUMEN

We identified a discrete number of microRNAs differentially expressed in benign or malignant mesothelial tissues. We focused on mir-145 whose levels were significantly downregulated in malignant mesothelial tissues and malignant pleural mesothelioma (MPM) cell lines as compared to benign tissues (pleura, peritoneum or cysts). We show that promoter hyper-methylation caused very low levels in MPM cell lines and specimens. Treatment of MPM cell lines with mir-145 agonists negatively modulated some protumorigenic properties of MPM cells, such as clonogenicity, cell migration and resistance to pemetrexed treatment. The main effector mechanism of the clonogenic death induced by mir-145 was that of accelerated senescence. We found that mir-145 targeted OCT4 via specific binding to its 3'-UTR. Increased intracellular levels of mir-145 decreased the levels of OCT4 and its target gene ZEB1, thereby counteracting the increase of OCT4 induced by pemetrexed treatment which is known to favor the development of chemoresistant cells. In line with this, reintroduction of OCT4 into mimic-145 treated cells counteracted the effects on clonogenicity and replicative senescence. This further supports the relevance of the mir-145-OCT4 interaction for the survival of MPM cells. The potential use of mir-145 expression levels to classify benign vs malignant mesothelial tissues and the differences between pemetrexed-induced senescence and that induced by the re-expression of mir-145 are discussed.

Asunto(s)

Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Mesotelioma/genética , MicroARNs/genética , Neoplasias Pleurales/genética , Regiones no Traducidas 3'/genética , Animales , Antineoplásicos/farmacología , Secuencia de Bases , Línea Celular , Línea Celular Tumoral , Movimiento Celular/genética , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Senescencia Celular/genética , Metilación de ADN , Regulación hacia Abajo , Técnicas de Silenciamiento del Gen , Glutamatos/farmacología , Guanina/análogos & derivados , Guanina/farmacología , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Mesotelioma/metabolismo , Mesotelioma/patología , Mesotelioma Maligno , Ratones SCID , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Pemetrexed , Neoplasias Pleurales/metabolismo , Neoplasias Pleurales/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Ácido Nucleico

RESUMEN

Werner syndrome (WS) results from dysfunction of the WRN protein, and is associated with premature aging and early death. Here we report that loss of WRN function elicits accumulation of the Yes-associated protein (YAP protein), a major effector of the Hippo tumor suppressor pathway, both experimentally and in WS-derived fibroblasts. YAP upregulation correlates with slower cell proliferation and accelerated senescence, which are partially mediated by the formation of a complex between YAP and the PML protein, whose activity promotes p53 activation. The ATM kinase is necessary for YAP and PML accumulation in WRN-depleted cells. Notably, the depletion of either YAP or PML partially impairs the induction of senescence following WRN loss. Altogether, our findings reveal that loss of WRN activity triggers the activation of an ATM-YAP-PML-p53 axis, thereby accelerating cellular senescence. The latter has features of SASP (senescence-associated secretory phenotype), whose protumorigenic properties are potentiated by YAP, PML and p53 depletion.

Asunto(s)

Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Exodesoxirribonucleasas/metabolismo , Proteínas Nucleares/metabolismo , RecQ Helicasas/metabolismo , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Proteínas de Ciclo Celular , Senescencia Celular/fisiología , Exodesoxirribonucleasas/deficiencia , Células HCT116 , Células HEK293 , Humanos , Células MCF-7 , Proteína de la Leucemia Promielocítica , RecQ Helicasas/deficiencia , Transducción de Señal , Transfección , Helicasa del Síndrome de Werner , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo

RESUMEN

Here we show that pemetrexed-treated mesothelioma cells undergo accelerated senescence. This is characterized by the secretion of proinflammatory and mitogenic cytokines, reminiscent of an SASP (senescence-associated secretory phenotype). Conditioned media from senescent MPM (malignant pleural mesothelioma) cells trigger the emergence of EMT (epithelial-to-mesenchymal)-like, clonogenic and chemoresistant cell subpopulations, expressing high levels of ALDH (aldehyde dehydrogenase) activity (ALDH(bright) cells). We show by fluorescence-activated cell sorting of purified ALDH(bright) and ALDH(low) cells, that both cell-autonomous and cell-non-autonomous mechanisms converge to maintain the SASP-induced, EMT-like cell subpopulations. Chemoresistant ALDH(bright) cells exist within primary MPM specimens and enrichment for ALDH(bright) cells correlates with an earlier tumor onset into NOD/SCID mice. We show that RAS(v12) expression induces SASP-like changes in untransformed human mesothelial cells, and that p53 ablation increases the effect of RAS(v12) expression. We identify STAT3 activation as a crucial event downstream to SASP signaling. In fact, small hairpin RNA-mediated ablation of STAT3 deeply attenuates the induction of EMT genes and the increase of ALDH(bright) cells induced by SASP-cytokines. This strongly affects the chemoresistance of MPM cells in vitro and leads to anticancer effects in vivo.

Asunto(s)

Senescencia Celular , Resistencia a Antineoplásicos , Mesotelioma/patología , Fenotipo , Aldehído Deshidrogenasa/metabolismo , Animales , Recuento de Células , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Transformación Celular Neoplásica/efectos de los fármacos , Senescencia Celular/efectos de los fármacos , Medios de Cultivo Condicionados/metabolismo , Citocinas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Genes ras/genética , Glutamatos/farmacología , Guanina/análogos & derivados , Guanina/farmacología , Humanos , Masculino , Mesodermo/efectos de los fármacos , Mesodermo/patología , Mesotelioma/genética , Mesotelioma/metabolismo , Ratones , Mitógenos/metabolismo , Pemetrexed , ARN Interferente Pequeño/genética , Factor de Transcripción STAT3/deficiencia , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos

RESUMEN

The tumour suppressor p53 induces cellular senescence in response to oncogenic signals. p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation. The mechanism of p53 activation by oncogenes remains largely unknown. Here we report that the tumour suppressor PML regulates the p53 response to oncogenic signals. We found that oncogenic Ras upregulates PML expression, and overexpression of PML induces senescence in a p53-dependent manner. p53 is acetylated at lysine 382 upon Ras expression, an event that is essential for its biological function. Ras induces re-localization of p53 and the CBP acetyltransferase within the PML nuclear bodies and induces the formation of a trimeric p53-PML-CBP complex. Lastly, Ras-induced p53 acetylation, p53-CBP complex stabilization and senescence are lost in PML-/- fibroblasts. Our data establish a link between PML and p53 and indicate that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression.

Asunto(s)

Senescencia Celular/fisiología , Genes ras , Proteínas de Neoplasias/fisiología , Factores de Transcripción/fisiología , Proteína p53 Supresora de Tumor/metabolismo , Acetilación , Animales , Núcleo Celular/metabolismo , Senescencia Celular/genética , Humanos , Lisina/metabolismo , Ratones , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Nucleares/fisiología , Proteína de la Leucemia Promielocítica , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor , Regulación hacia Arriba

RESUMEN

RAR and AML1 transcription factors are found in leukemias as fusion proteins with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is required to block hematopoietic differentiation. We show that PML-RAR and AML1-ETO exist in vivo within high molecular weight (HMW) nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of N-CoR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results show that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.

Asunto(s)

Transformación Celular Neoplásica , Leucemia/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Factores de Transcripción/metabolismo , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Histona Desacetilasas/metabolismo , Humanos , Leucemia/etiología , Leucemia Mieloide/etiología , Leucemia Mieloide/genética , Leucemia Promielocítica Aguda/etiología , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/metabolismo , Co-Represor 1 de Receptor Nuclear , Fragmentos de Péptidos/metabolismo , Unión Proteica , Estructura Cuaternaria de Proteína , Proteína 1 Compañera de Translocación de RUNX1 , Proteínas Represoras/metabolismo , Elementos de Respuesta , Transcripción Genética , Tretinoina

Asunto(s)

Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Animales , Diferenciación Celular/genética , Supervivencia Celular/genética , Cromosomas Humanos Par 15/genética , Cromosomas Humanos Par 15/ultraestructura , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 17/ultraestructura , Regulación Leucémica de la Expresión Génica/genética , Células Madre Hematopoyéticas/patología , Humanos , Leucemia Promielocítica Aguda/patología , Ratones , Ratones Transgénicos , Proteínas de Neoplasias/fisiología , Proteínas de Fusión Oncogénica/fisiología , Transcripción Genética/genética , Translocación Genética

RESUMEN

The transforming proteins of acute promyelocytic leukaemias (APL) are fusions of the promyelocytic leukaemia (PML) and the promyelocytic leukaemia zinc-finger (PLZF) proteins with retinoic acid receptor-alpha (RARalpha). These proteins retain the RARalpha DNA- and retinoic acid (RA)-binding domains, and their ability to block haematopoietic differentiation depends on the RARalpha DNA-binding domain. Thus RA-target genes are downstream effectors. However, treatment with RA induces differentiation of leukaemic blast cells and disease remission in PML-RARalpha APLs, whereas PLZF-RARa APLs are resistant to RA. Transcriptional regulation by RARs involves modifications of chromatin by histone deacetylases, which are recruited to RA-target genes by nuclear co-repressors. Here we show that both PML-RARalpha and PLZF-RARalpha fusion proteins recruit the nuclear co-repressor (N-CoR)-histone deacetylase complex through the RARalpha CoR box. PLZF-RARalpha contains a second, RA-resistant binding site in the PLZF amino-terminal region. High doses of RA release histone deacetylase activity from PML-RARalpha, but not from PLZF-RARalpha. Mutation of the N-CoR binding site abolishes the ability of PML-RARalpha to block differentiation, whereas inhibition of histone deacetylase activity switches the transcriptional and biological effects of PLZF-RARalpha from being an inhibitor to an activator of the RA signalling pathway. Therefore, recruitment of histone deacetylase is crucial to the transforming potential of APL fusion proteins, and the different effects of RA on the stability of the PML-RARalpha and PLZF-RARalpha co-repressor complexes determines the differential response of APLs to RA.

Asunto(s)

Proteínas de Unión al ADN/fisiología , Histona Desacetilasas/fisiología , Leucemia Promielocítica Aguda/enzimología , Proteínas de Neoplasias/fisiología , Proteínas de Fusión Oncogénica/fisiología , Receptores de Ácido Retinoico/fisiología , Factores de Transcripción/fisiología , Sitios de Unión , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Línea Celular , Clonación Molecular , Proteínas de Unión al ADN/genética , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas , Histona Desacetilasas/genética , Ácidos Hidroxámicos/farmacología , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/metabolismo , Mutagénesis , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Proteínas Nucleares/fisiología , Co-Represor 1 de Receptor Nuclear , Proteínas de Fusión Oncogénica/genética , Unión Proteica , Receptores de Ácido Retinoico/genética , Proteínas Represoras/genética , Proteínas Represoras/fisiología , Receptor alfa de Ácido Retinoico , Factores de Transcripción/genética , Tretinoina/farmacología , Proteínas Supresoras de Tumor