New Oncogenic Drivers in Hepatocellular Carcinoma: Role of the RNA Binding Protein Hu antigen R

156 p. : graf.

Three-dimensional growth as multicellular spheroid activates the proangiogenic phenotype of colorectal carcinoma cells via LFA-1-dependent VEGF: implications on hepatic micrometastasis

Background: The recruitment of vascular stromal and endothelial cells is an early event occurring during cancer cell growth at premetastatic niches, but how the microenvironment created by the initial three-dimensional (3D) growth of cancer cells affects their angiogenesis-stimulating potential is unclear. Methods: The proangiogenic profile of CT26 murine colorectal carcinoma cells was studied in seven-day cultured 3D-spheroids of <300 mu m in diameter, produced by the hanging-drop method to mimic the microenvironment of avascular micrometastases prior to hypoxia occurrence. Results: Spheroid-derived CT26 cells increased vascular endothelial growth factor (VEGF) secretion by 70%, which in turn increased the in vitro migration of primary cultured hepatic sinusoidal endothelium (HSE) cells by 2-fold. More importantly, spheroid-derived CT26 cells increased lymphocyte function associated antigen (LFA)-1-expressing cell fraction by 3-fold; and soluble intercellular adhesion molecule (ICAM)-1, given to spheroid-cultured CT26 cells, further increased VEGF secretion by 90%, via cyclooxygenase (COX)-2-dependent mechanism. Consistent with these findings, CT26 cancer cells significantly increased LFA-1 expression in non-hypoxic avascular micrometastases at their earliest inception within hepatic lobules in vivo; and angiogenesis also markedly increased in both subcutaneous tumors and hepatic metastases produced by spheroid-derived CT26 cells. Conclusion: 3D-growth per se enriched the proangiogenic phenotype of cancer cells growing as multicellular spheroids or as subclinical hepatic micrometastases. The contribution of integrin LFA-1 to VEGF secretion via COX-2 was a micro environmental-related mechanism leading to the pro-angiogenic activation of soluble ICAM-1-activated colorectal carcinoma cells. This mechanism may represent a new target for specific therapeutic strategies designed to block colorectal cancer cell growth at a subclinical micrometastatic stage within the liver.

La aplicación empresarial del marketing viral y el efecto boca-oreja electrónico. Opiniones de las empresas

[ES] La práctica tradicional del boca-oreja, natural desde hace años como modo de publicidad efectiva sin recurrir a grandes inversiones ni contrataciones en medios masivos se ha convertido en una nueva posibilidad de marketing con la llegada de las nuevas tecnologías e Internet. Así ha aparecido una nueva estrategia de marketing que consiste en explotar las redes sociales preexistentes para producir incrementos exponenciales en conocimiento de marca, denominada marketing viral. El efecto "boca-oreja online" que genera es una herramienta poderosa para las empresas, aunque su verdadero potencial está aún por descubrir. El objetivo del presente trabajo de investigación es analizar este fenómeno a través de una amplia revisión bibliográfica del término, así como un estudio empírico consistente en una entrevista en profundidad realizada a una muestra de importantes empresas españolas. Los resultados indican que el marketing viral puede ser empleado para el beneficio, tanto de grandes empresas con grandes presupuestos, como de pequeños negocios. Las experiencias exitosas de su utilización demuestran que, cuando se usa integrado en el resto de estrategias comerciales de la empresa, puede mejorar la recomendación de la marca e incrementar su notoriedad en el mercado. El marketing viral puede ser ventajoso a la hora de lanzar un nuevo producto al mercado, sin embargo, la efectividad y la medición de las campañas son vistas por muchos académicos y profesionales como un punto débil de la estrategia.

Interacciones entre las células madre pluripotentes del carcinoma embrionario y las células mioides peritubulares del testículo

112 p.+ anexos

Snail heterogeneity in clear cell renal cell carcinoma

Background: Intratumor heterogeneity may be responsible of the unpredictable aggressive clinical behavior that some clear cell renal cell carcinomas display. This clinical uncertainty may be caused by insufficient sampling, leaving out of histological analysis foci of high grade tumor areas. Although molecular approaches are providing important information on renal intratumor heterogeneity, a focus on this topic from the practicing pathologist' perspective is still pending. Methods: Four distant tumor areas of 40 organ-confined clear cell renal cell carcinomas were selected for histopathological and immunohistochemical evaluation. Tumor size, cell type (clear/granular), Fuhrman's grade, Staging, as well as immunostaining with Snail, ZEB1, Twist, Vimentin, E-cadherin, beta-catenin, PTEN, p-Akt, p110 alpha, and SETD2, were analyzed for intratumor heterogeneity using a classification and regression tree algorithm. Results: Cell type and Fuhrman's grade were heterogeneous in 12.5 and 60 % of the tumors, respectively. If cell type was homogeneous (clear cell) then the tumors were low-grade in 88.57 % of cases. Immunostaining heterogeneity was significant in the series and oscillated between 15 % for p110a and 80 % for Snail. When Snail immunostaining was homogeneous the tumor was histologically homogeneous in 100 % of cases. If Snail was heterogeneous, the tumor was heterogeneous in 75 % of the cases. Average tumor diameter was 4.3 cm. Tumors larger than 3.7 cm were heterogeneous for Vimentin immunostaining in 72.5 % of cases. Tumors displaying negative immunostaining for both ZEB1 and Twist were low grade in 100 % of the cases. Conclusions: Intratumor heterogeneity is a common event in clear cell renal cell carcinoma, which can be monitored by immunohistochemistry in routine practice. Snail seems to be particularly useful in the identification of intratumor heterogeneity. The suitability of current sampling protocols in renal cancer is discussed.