El papel del microambiente tumoral y los fibroblastos asociados a cáncer en el desarrollo y la progresión del cáncer de mama / The role of tumor microenvironment and cancer-associated fibroblasts in breast cancer development and progression

Es bien sabido que el cáncer mamario es considerado un problema de salud a nivel mundial, la enorme tasa de mortalidad se debe a la recaída de la enfermedad, principalmente por la generación de resistencia a los diversos tratamientos. Hasta hace unos años, esta resistencia era atribuida a las mutaciones genéticas heredadas, sin embargo, evidencias recientes sugieren que el microambiente tumoral desempeña un papel clave en el desarrollo y la progresión del cáncer. La relación simbiótica entre las células tumorales y los fibroblastos asociados a cáncer (FAC), condicionan un ambiente propicio para el soporte estructural necesario, lleno de nutrientes que favorecen su crecimiento y progresión. Aquí se describe el papel que juega el microambiente tumoral y los FAC, desde su origen celular y activación, hasta los mecanismos de quimiorresistencia tumoral, además de los cambios epigenéticos y las proteínas involucradas, como las HDAC, que prometen ser blancos terapéuticos de nuevos fármacos dirigidos a su inhibición, al mitigar diversas vías que participan en la activación de los FAC o revertir su potencial promotor de tumores, lo que a su vez, mejoraría la calidad de vida de las pacientes. (AU)

It is well known that breast cancer is considered a worldwide health problem, the enormous mortality rate is due to the relapse of patients mostly due to the generation of resistance to various treatments. Until a few years ago, this resistance was attributed to inherited genetic mutations, however, recent evidence suggests that tumor microenvironment plays a key role in the development and progression of cancer. The symbiotic relationship between tumor cells and cancer-associated fibroblasts (CAF) provides an environment conducive to the necessary structural support, full of nutrients that favor their growth and progression. Here we describe the role played by the tumor microenvironment and CAF, from their cellular origin and activation to the mechanisms of tumor chemoresistance, in addition to the epigenetic changes and proteins involved, such as HDAC, which promise to be therapeutic targets for new drugs aimed at their inhibition, by mitigating various pathways involved in the activation of CAF or reversing their tumor-promoting potential, which in turn, would improve the quality of life of patients. (AU)

MiR-489 suppresses tumor growth and invasion by targeting HDAC7 in colorectal cancer

Purpose: The expression of miR-489 is linked to tumor development and progression; nevertheless, its role in tumor growth and invasion of colorectal cancer (CRC) and the underlying mechanism has not been clarified. Experimental design: We used quantitative RT-PCR to measure the expression of mature miR-489 in human colorectal tissues and the corresponding CRCs. Targets of miR-489 were predicted with TargetScan and substantiated by dual-luciferase reporter assay. Furthermore, we did in vitro and in vivo analysis with expression vectors and small interfering RNAs, to elucidate the precise role of miR-489 and its target gene histone deacetylase 7 (HDAC7) on cell proliferation, survival, and invasion. Results: Compared to the corresponding non-tumor tissues, miR-489 was frequently downregulated in CRC. By Kaplan-Meier analysis, we found that lower CRC recurrence free survival years in the group with elevated miR-489 expression than those with lower miR-489 expression. In addition, we examined that miR-489 obviously inhibited the migratory and invasive capability in CRC. In further study, we found that miR-489 targets the 3′-UTR of the HDAC7 transcript and downregulates its expression, and HDAC7 expression promoted tumor cell proliferation and invasion. We demonstrated that miR-489 suppresses tumor invasion and metastasis in CRC by targeting HDAC7. Conclusions: We identified that MiR-489 suppresses tumor growth and invasion in CRC by targeting HDAC7. The expression of miR-489 suggests CRC recurrence and metastasis, which shed crucial light on how miR-489 functions in CRC pathogenesis

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¿Hay un lugar para la teofilina en la EPOC? / Is There room for Theophylline in COPD?

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Valproic acid inhibits the angiogenic potential of cervical cancer cells via HIF-1alpha/VEGF signals

Purpose. Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, the investigation about the molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The objective of the present study is to investigate the effects of valproic acid (VPA), a histone deacetylase inhibitor, on the angiogenesis of cervical cancer. Methods. The effects and mechanisms of VPA on in vitro angiogenesis and vascular endothelial growth factor (VEGF) expression of human cervical cancer HeLa and SiHa cells were investigated. Results. Our present study reveals that 1 mM VPA can significantly inhibit the in vitro angiogenic potential and VEGF expression of human cervical cancer HeLa and SiHa cells. Further, the transcription and protein levels of hypoxia inducible factor-1α (HIF-1α), and not HIF-1β, are significantly inhibited in VPA-treated cervical cancer cells. Over expression of HIF-1α can obviously reverse VPA-induced VEGF down regulation. VPA-treatment decreases the activation of Akt and ERK1/2 in both HeLa and SiHa cells in a time-dependent manner. The inhibitor of Akt (LY 294002) or ERK1/2 (PD98059) can inhibit VEGF alone and cooperatively reinforce the suppression effects of VPA on HIF-1α and VEGF expression. Conclusion. Collectively, our data reveal that the inhibition of PI3K/Akt and ERK1/2 signals are involved in VPA-induced HIF-1α and VEGF suppression of cervical cancer cells (AU)

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Nuevos fármacos en el tratamiento de los linfomas cutáneos de células T / New drugs in the therapy of T-cell cutaneous lymphoma

No existe actualmente ningún tratamiento curativo de los linfomas cutáneos en estadios avanzados. Históricamente estos pacientes han sido sometidosa esquemas de quimioterapia utilizados en linfomas sistémicos generalmente muy tóxicos, y de beneficios muy limitados. Gracias al crecienteconocimiento de la etiopatogenia de los linfomas cutáneos se han podido identificar dianas terapéuticas y desarrollar nuevas moléculas que se estánprobando en la actualidad con resultados esperanzadores. Este el caso de los inhibidores de las histonas desacetilasas (IHDAC) y los nuevos anticuerposmonoclonales, entre otros. De la misma forma ha podido observarse que fármacos útiles en otros tumores, como gemcitabina, bortezomib odoxorubicina liposomal, también son activos en los LCP-T, al menos, en estudios preliminares. En los últimos años se están añadiendo a nuestro arsenalnuevos medicamentos y estrategias terapéuticas encaminadas a cambiar la historia natural de esta enfermedad. En este artículo revisamos los avancesterapéuticos en este campo (AU)

There is currently no curative treatment of cutaneous lymphomas in advanced stages. Historically these patients have been treated with chemotherapyregimens used in systemic lymphomas usually very toxic and with limited benefits. With the growing knowledge about the pathogenesis of cutaneouslymphomas it has been able to identify therapeutic targets and to develop new molecules that currently are being tested with promising results. This isthe case of histone deacetylase inhibitors (IHDAC) and the new monoclonal antibodies, among others. In the same way it has been found that usefuldrugs in other tumors, such as gemcitabine, bortezomib and liposomal doxorubicin are also active in the LCP-T, at least in preliminary studies. In thelast years, new drugs and therapeutic strategies are being added to our arsenal with the purpose of changing the natural history of this disease. In thisarticle we review the therapeutic advances in this field (AU)

Las terapias epigenéticas, más allá de los biológicos en el tratamiento de la artritis reumatoide / Epigenetic therapies, a step beyond biologics for rheumatoid arthritis

La artritis reumatoide ha experimentado en la última década una revolución terapéutica, derivada del conocimiento de los procesos patogénicos y favorecida por el desarrollo de la tecnología necesaria para distribuir tratamientos moleculares. Las nuevas terapias permiten diferenciar subtipos de pacientes según la respuesta clínica y además mejoran nuestra comprensión de la enfermedad. Ello hace vaticinar la llegada de nuevas generaciones de moléculas para un tratamiento individualizado. Uno de los campos hacia donde se dirigen las investigaciones es la epigenética. Los mecanismos de regulación epigenéticos son interruptores que deciden cuándo y cómo expresar determinados genes en cada célula. Actuando como vigilantes de una expresión génica inapropiada, protegen al organismo del desarrollo de tumores. La principal ventaja de los tratamientos epigenéticos podría ser su selectividad por las células que muestran patrones epigenéticos alterados, por lo que el reto es identificar estas alteraciones entre los pacientes con artritis reumatoide. Aunque debe establecerse su perfil de seguridad, parece probable el uso de terapias epigenéticas en las enfermedades autoinmunes (AU)

Over the last decade, the management of rheumatoid arthritis has evolved as a result of both the understanding of disease-related processes and the availability of the necessary high-throughput technology to provide patients with molecule-based therapies. New therapies allow the classification of patients into subsets as regards clinical response, at the same time adding to our knowledge of rheumatoid arthritis pathogenesis. New generations of molecules will likely soon be ready for “a la carte” treatment of patients. A promising field of research is epigenetics. Epigenetic regulatory mechanisms switch on and off the transcription of specific genes in individual cells. Acting as observers on non-adequate gene expression, these mechanisms yield protection against the development of tumours. The major achievement of epigenetic therapies could be their selective action on cells with altered epigenetic programs, and it is our challenge to recognize these alterations among patients with rheumatoid arthritis. Although safety concerns may arise, epigenetic drugs will likely be used to treat autoimmune diseases (AU)

Estructura y función del ADN y de los genes II. Tipos de alteraciones de la función del gen por procesos epigenéticos / Structure and function of DNA and of the genes II. Types of alterations of the gene function through epigenetic processes

El tipo de cambios en la función del gen que vamos a resumir en este artículo, no se deben a alteraciones en la estructura del ADN, en ninguno de sus niveles de resolución (mutaciones, pérdidas y ganancias de material, tanto invisibles como visibles por citogenética). Son cambios producidos por procesos epigenéticos, que sin alterar la estructura de la molécula de ADN, si alteran su función (AU)

The type of changes in the gene function we are going to summarize in this article are not due to alterations in DNA structure, in any of their resolution levels (mutations, material loss and gains, both invisible and visible by cytogenetic). They are changes produced by epigenetic processes, which although they do not alter the DNA molecular structure, they do alter its function (AU)