NOTCH keeps bladder cancer at bay

Dysfunction in the NOTCH signaling pathway is frequently observed in human cancers. In some cancers, such as T cell lymphoblastic leukemia and lung adenocarcinoma, constitutive activation of NOTCH signaling promotes tumorigenesis. Conversely, other cancers, including myeloid leukemia and squamous cell carcinomas (SCCs) of different origins, are associated with loss of NOTCH function. Antonio Maraver, Pablo Fernandez-Marcos, and colleagues at the Spanish National Cancer Research Center determined that NOTCH1 and NOTCH2 mutations in human bladder cancers result in loss of NOTCH function. In murine models, loss of NOTCH signaling accelerated bladder cancer tumorigenesis and promoted the formation of SCC with mesenchymal features, a particularly aggressive form of bladder cancer. NOTCH signaling promoted expression of the transcription factor HES1, which prevents epithelial-mesenchymal transition (EMT). Moreover, evaluation of human bladder cancers revealed that tumors with low levels of HES1 exhibited greater EMT and invasive features. Together, these results indicate that NOTCH serves as tumor suppressor in the bladder; therefore, inactivation of this pathway promotes  EMT in squamous bladder cancer cells. The accompanying image shows a hematoxylin and eosin stained section of a bladder SCC. 

Published January 9, 2015, by Corinne Williams

Related articles

NOTCH pathway inactivation promotes bladder cancer progression
Antonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, Manuel Serrano
Antonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, Manuel Serrano
View: Text | PDF
Research Article

NOTCH pathway inactivation promotes bladder cancer progression

Abstract

NOTCH signaling suppresses tumor growth and proliferation in several types of stratified epithelia. Here, we show that missense mutations in NOTCH1 and NOTCH2 found in human bladder cancers result in loss of function. In murine models, genetic ablation of the NOTCH pathway accelerated bladder tumorigenesis and promoted the formation of squamous cell carcinomas, with areas of mesenchymal features. Using bladder cancer cells, we determined that the NOTCH pathway stabilizes the epithelial phenotype through its effector HES1 and, consequently, loss of NOTCH activity favors the process of epithelial-mesenchymal transition. Evaluation of human bladder cancer samples revealed that tumors with low levels of HES1 present mesenchymal features and are more aggressive. Together, our results indicate that NOTCH serves as a tumor suppressor in the bladder and that loss of this pathway promotes mesenchymal and invasive features.

Authors

Antonio Maraver, Pablo J. Fernandez-Marcos, Timothy P. Cash, Marinela Mendez-Pertuz, Marta Dueñas, Paolo Maietta, Paola Martinelli, Maribel Muñoz-Martin, Mónica Martínez-Fernández, Marta Cañamero, Giovanna Roncador, Jorge L. Martinez-Torrecuadrada, Dimitrios Grivas, Jose Luis de la Pompa, Alfonso Valencia, Jesús M. Paramio, Francisco X. Real, Manuel Serrano

×
Advertisement