Endometrioid or type-I endometrial carcinoma (EC) develops from hyperproliferative glandular pathologies. Inactivation of the tumor suppressor gene PTEN is frequently associated with type-I EC. Using a previously characterized Pten heterozygous (Pten+/−) mouse model, this study investigates the three-dimensional (3D) telomere profiles during progression from hyperplastic lesions to EC to test the hypothesis that altered 3D telomere profiles can be detected prior to Pten loss in early hyperproliferative lesions. We used immunohistochemistry and 3D-telomere fluorescent in-situ hybridization to investigate Pten expression, telomere length and signal distribution, average number and spatial distribution of telomeres and formation of telomere aggregates in uterine glandular epithelial cells from wildtype and Pten+/− mice. Pten showed nuclear and cytoplasmic localization in WT, predominantly cytoplasmic staining in simple hyperplasia (SH) and was markedly reduced in atypical hyperplasia (AH). Telomere length in glandular epithelial cells does not shorten with age. The average number of telomeres per nucleus was not different in WT and Pten+/− mice indicating the lack of substantial numeric chromosome aberrations during EC development. We observed telomere aggregates in lesions of AH and EC. SH lesions in Pten+/− mice differed from normal glandular epithelium by an increased relative number of shorter telomeres and by a telomere signal distribution indicative of a heterogeneous cell population. Our study revealed that alterations in the nuclear 3D telomere architecture are present in early proliferative lesions of mouse uterine tissues indicative of EC development. The changes in telomere length distribution and nuclear signal distribution precede the loss of Pten. © 2013 Wiley Periodicals, Inc.
Endometrial carcinoma (EC) is the most common malignancy of the female genital tract. Type I (endometrioid) EC is associated with elevated estrogen signaling. One of the earliest genetic events in human type I EC is loss of the tumor suppressor gene PTEN. Loss of PTEN allows unrestrained activation of the AKT kinase, which, in turn, regulates such key processes as proliferation, survival, cell size, and mRNA translation. We have previously shown, using a Pten+/− mouse model, that the neoplastic lesions develop even in the absence of estrogen, suggesting that there might exist a functional and physiological link between loss of Pten and hormone-independent increased estrogen receptor activity. Previous studies have suggested that AKT can phosphorylate and activate estrogen receptor alpha (ERα) at Ser167, promoting the activation of this nuclear receptor both in vivo and in vitro, even in the absence of ligand. In order to define in vivo the role of ERα phosphorylation on Ser167 in normal endometrial physiology and during neoplastic transformation, we have designed a knock-in approach to introduce the S167A mutation in the mouse germline (ERαA/A). These mice are viable and fertile. We bred ERαA/A mice to Pten+/− mice to test whether ERα phosphorylation on Ser167 is required for the development of endometrial hyperplasia and carcinoma. We found that, at the age of 6 months, the uterus weight of ERαA/A/Pten+/− mice was significantly reduced compared to that of Pten+/− mice. To elucidate whether inhibition of ERα phosphorylation on Ser167 affects cell cycle progression, we analyzed BrdU incorporation in primary cultures of control and ERαA/A endometrial epithelial cells, and found that impairment of ERα phosphorylation on Ser167 leads to a significant reduction of the number of actively proliferating cells. In order to understand the molecular mechanisms responsible for this cell cycle impairment, we analyzed by real-time PCR the expression levels of cell cycle-related genes in the uterus of control and ERαA/A mice. Surprisingly, our results indicate that many genes related with the G2/M phase of the cell cycle, like Ccna2 or Ccnb1, and spindle formation, like Plk1 or Tpx2, are deregulated in ERαA/A uteri, compared to wild-type controls. In conclusion, our results indicate that ERα phosphorylation on Ser167 is an obligatory pathway for the development of endometrial lesions consequent to loss of Pten in endometrial cancer, at least in part by affecting the expression of cell cycle genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3085. doi:1538-7445.AM2012-3085
IMCgp100, a first in class immunotherapy, is a T cell redirecting bispecific biologic comprising an affinity enhanced T-cell receptor specific for gp100 and an anti-CD3 scFV. Phase I/IIa data supported a favourable safety profile and durable responses in cutaneous and uveal melanoma (CM and UM) were observed. To complement the clinical studies we have developed a comprehensive biomarker strategy, which includes analysis of markers in both the tumour and periphery, to aid our understanding of pharmacodynamics, patient response and potential mechanisms of resistance. The data obtained provide evidence of the pharmacodynamic effects of chemokine/cytokine release, in both the tumor and periphery, and lymphocyte infiltration into tumors over 2 days post dose. Changes in the levels of certain chemokines following the first dose of IMCgp100 were associated with tumor shrinkage. In addition, biological differences in marker responses were also seen between CM and UM patients. The biomarker strategy developed forms the basis for the on-going Ph II development of IMCgp100 in CM and UM and for other ImmTAC molecules, both as single agents and in combination, for the treatment of solid tumours. Citation Format: Cheryl McAlpine, Sandra Herrero Gonzalez, Lindsay Bawden, David Krige, William Shingler, Andy Johnson, Sanjay Patel, Debbie Parker, Christina M. Coughlin, Namir J. Hassan, Bent K. Jakobsen. Biomarker Strategy To Guide Clinical Development Of ImmTAC™ molecules , A Novel Class Of Bispecific T Cell Engaging Biologic Drugs. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A35.
Globalmente podemos considerar la existencia de tres tipos de uniones intercelulares (Esquema 2): las uniones estrechas o tight junctions, los desmosomas y las uniones comunicantes o gap junctions.Las uniones estrechas son regiones diferenciadas de la membrana plasmática que sellan el espacio intercelular. Su función principal es impedir el transporte paracelular. Por otro lado, la adhesión mecánica entre célula y célula se mantiene, fundamentalmente, gracias a los desmosomas, confiriendo así, rigidez al tejido. Unión estrecha o tight junction Desmosoma Unión comunicante o gap junction Esquema 2. Uniones intercelulares Oligodendrocito o Microglía Neurona Astrocito Capilar sanguíneo Células ependimales Ventrículo cerebral Vaina de mielina Corte de una vaina de mielina Esquema 1. Interacciones entre células gliales y neuronas en el sistema nervioso. AraC: citosina b arabinofuranósido. AA: ácido araquidónico. DHEA: dehidroepiandosterona. AGA: ácido 18-a-glicirretínico. ET-1: endotelina-1. Modificado de Tabernero y col. (2001). En el cerebro, las isoformas ET-1 y ET-3 son producidas por varios tipos de células, incluyendo los astrocitos (Ehrenreich et al. 1991; Giaume and Venance 1998), ciertas neuronas (Fuxe et al. 1991) y las células endoteliales (Yoshimoto et al. 1990), existiendo sitios de unión de alta afinidad para estos péptidos. En los astrocitos, las ETs inducen cambios en la concentración de varios segundos mensajeros, conocidos por su implicación en la regulación de los canales de las uniones comunicantes. En estos cambios se incluyen (Giaume et al. 1992): 1.1.4.2. Carbenoxolona La CBX es un derivado soluble del AGA, concretamente es la sal disódica del 3β-Ohemisuccinato. Los derivados del AGA se han utilizado para estudiar el papel de las uniones comunicantes en el control del crecimiento de fibroblastos (Martin et al. 1991), la diferenciación de mioblastos (Mege et al. 1994) y la maduración de los oocitos (Downs 1995). Algunos autores proponen que los derivados del ácido glicirretínico, como la CBX, inhiben las uniones comunicantes al unirse directamente a las conexinas e inducir, de este modo el cierre del canal (Davidson and Baumgarten 1988; Spray and Burt 1990). En este sentido, existen indicios que avalan la teoría de que estos compuestos se intercalan en la membrana plasmática y se unen a los conexones de las uniones comunicantes, induciendo un cambio conformacional que resulta en el cierre del canal (Davidson and Baumgarten 1988; Goldberg et al. 1996), sin afectar a la síntesis de proteínas ni a su localización (Goldberg et al. 1996).Los estudios realizados en nuestro laboratorio han puesto de manifiesto que la CBX produce un aumento de la expresión de los transportadores de glucosa GLUT-1 y GLUT-3 y de la hexokinasa I y II, lo que conlleva un incremento en la captación de glucosa por los astrocitos (Herrero-Gonzalez et al. 2009; Sanchez-Alvarez et al. 2004). Además, se ha demostrado que la CBX produce un aumento de la expresión de la proteína Ki-67 y de las ciclinas D1 y D3 (Herrero-Gonzalez et al...
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