Nueva era de la medicina basada en las células madre mesenquimales: bases, retos y perspectivas / New era of mesenchymal stem cell-based medicine: Basis, challenges and prospects

Las células madre de origen mesenquimal (CMM) suscitan un interés especial debido a sus propiedades regenerativas, antiinflamatorias, antiapoptóticas, contra el estrés oxidativo, antitumorales o antimicrobianas. Sin embargo, su implementación en clínica se topa con inconvenientes de la terapia celular como la incompatibilidad inmunológica, la formación de tumores, la posible transmisión de infecciones, la entrada en senescencia celular y la difícil evaluación de seguridad, dosis y potencia; así como complejas condiciones de almacenamiento, elevado coste económico o uso clínico poco práctico. Considerando que los efectos positivos de las CMM se deben, en gran medida, a los efectos paracrinos mediados por el conjunto de sustancias que segregan (factores de crecimiento, citoquinas, quimiocinas o microvesículas), la obtención in vitro de esos productos biológicos posibilita una medicina regenerativa libre de células sin los inconvenientes de la terapia celular. No obstante, esa nueva innovación terapéutica implica retos, como el reconocimiento de la heterogeneidad biológica de las CMM y la optimización y estandarización de su secretoma (AU)

Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome (AU)

New era of mesenchymal stem cell-based medicine: basis, challenges and prospects.

Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome.

Metaloproteinasa 11, potencial marcador y diana molecular en cáncer de próstata avanzado y resistente a la castración. Estudio en cultivo de fibroblastos peritumorales / Metalloproteinase 11, potential marker and molecular target in advanced and castration-resistant prostate cancer. Culture study of peritumoral fibroblasts

Objetivo: Analizar el comportamiento de la metaloprotesa 11 (MMP11) en fibroblastos cultivados procedentes de tumores prostáticos humanos con diferentes características clinicopatológicas. Material y métodos: Para este estudio se analizaron muestras de biopsias de próstata obtenidas por vía transrectal de tumores con diferentes características, tratados o no con privación androgénica (PA). Tras la optimización del método de cultivo, se aislaron y cultivaron los fibroblastos para realizar el estudio (PCR) del ARNm de MMP11. Resultados: Se estudiaron finalmente 37 casos: 5 muestras de hiperplasia benigna de próstata, 14 casos con neoplasias localizadas (7 de alto riesgo según la clasificación de D’Amico), 5 con tumores con metástasis óseas y 13 tratados con PA, de los que 6 cumplían los requisitos para ser definidos como resistentes a la castración. En los tumores sin PA, la expresión de MMP11 fue significativamente mayor (p = 0,001) en los fibroblastos de tumores de grados más altos. Se encontró una correlación significativa (p = 0,001) entre PSA y expresión de MMP11 fibroblástica y un aumento significativo de la expresión de MMP11 en los tumores metastásicos. En los tumores con PA se objetivó una expresión significativamente mayor de MMP11 en pacientes resistentes a la castración que en los sensibles a esta (p = 0,003). Conclusión: En tumores de próstata avanzados o en fases de mayor agresividad tumoral, la producción de MMP11 por los fibroblastos resulta significativamente mayor que en tumores no metastásicos o en fases de sensibilidad a la PA

Objective: To analyze the expression of metalloprotein 11 (MMP11) in cultured fibroblasts obtained from human prostate tumors with different clinical and pathological characteristics. Material and methods: For this study we analyzed samples of transrectal prostate biopsies from tumors with different characteristics, treated with or whithout androgen deprivation (AD). After optimization of the culture method, fibroblasts were isolated and cultured to perform the study (PCR) of MMP11 mRNA. Results: Finally, 37 cases were studied: 5 samples of benign prostatic hyperplasia, 14 cases with localized neoplasms (7 high-risk according to the D’Amico classification), 5 with metastasic tumors (bone metastases), and 13 treated with AD therapy, of which 6 fulfilled the requirements to be defined as resistant to castration. In tumors without AD therapy, MMP11 expression was significantly higher (P= .001) in fibroblasts of higher grade tumors. A significant (P= .001) correlation was found between PSA and expression of MMP11 in fibroblast s and a significant increase of MMP11 expression in metastatic tumors. In tumors with AD therapy, a significantly greater expression of MMP11 was observed in resistant to castration patients than in those sensitive to castration (P= .003). Conclusion: In advanced prostate tumors or in stages of increased tumor aggressiveness, the production of MMP11 by fibroblasts is significantly greater than in non-metastatic tumors or in AD sensitive tumors

Metalloproteinase 11, potential marker and molecular target in advanced and castration-resistant prostate cancer. Culture study of peritumoral fibroblasts. / Metaloproteinasa 11, potencial marcador y diana molecular en cáncer de próstata avanzado y resistente a la castración. Estudio en cultivo de fibroblastos peritumorales.

OBJECTIVE: To analyze the expression of metalloprotein 11 (MMP11) in cultured fibroblasts obtained from human prostate tumors with different clinical and pathological characteristics. MATERIAL AND METHODS: For this study we analyzed samples of transrectal prostate biopsies from tumors with different characteristics, treated with or whithout androgen deprivation (AD). After optimization of the culture method, fibroblasts were isolated and cultured to perform the study (PCR) of MMP11 mRNA. RESULTS: Finally, 37 cases were studied: 5 samples of benign prostatic hyperplasia, 14 cases with localized neoplasms (7 high-risk according to the D'Amico classification), 5 with metastasic tumors (bone metastases), and 13 treated with AD therapy, of which 6 fulfilled the requirements to be defined as resistant to castration. In tumors without AD therapy, MMP11 expression was significantly higher (P=.001) in fibroblasts of higher grade tumors. A significant (P=.001) correlation was found between PSA and expression of MMP11 in fibroblast s and a significant increase of MMP11 expression in metastatic tumors. In tumors with AD therapy, a significantly greater expression of MMP11 was observed in resistant to castration patients than in those sensitive to castration (P=.003). CONCLUSION: In advanced prostate tumors or in stages of increased tumor aggressiveness, the production of MMP11 by fibroblasts is significantly greater than in non-metastatic tumors or in AD sensitive tumors.

Expression of TLR3, 4, 7 and 9 in cutaneous malignant melanoma: relationship with clinicopathological characteristics and prognosis.

Toll-like receptors (TLRs) have achieved an extraordinary amount of interest in cancer research due to their role in tumor progression. The aim of this study was to investigate the expression and clinical relevance of TLR3, 4, 7 and 9 in cutaneous malignant melanoma (CMM). The expression levels of TLR3, 4, 7 and 9 were analyzed in tumors from 30 patients with CMM. The analysis was performed by immunohistochemistry, and the results were correlated with various clinicopathological findings and with relapse-free survival. Our results indicate that there was a wide variability in the immunostaining score values for each receptor. Positive staining for TLRs was generally found in tumor cells, especially for TLR4 and TLR9. Nevertheless, a significant percentage of tumors also showed TLR4 expression in mononuclear inflammatory cells (62.1 %) and in fibroblast-like cells (34.5 %). Our results showed no significant association between score values for each TLR and clinicopathological characteristics of patients. However, our results demonstrated that high TLR4 expression was significantly associated with a shortened relapse-free survival (p = 0.001). Therefore, TLR4 expression may be a new prognostic factor of unfavorable evolution in cutaneous malignant melanoma.

Matrix Metalloproteinases and Bladder Cancer: What is New?

Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPs might permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011.