RT Journal Article
T1 A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer.
A1 Peñarando, Jon
A1 Lopez-Sanchez, Laura M
A1 Mena, Rafael
A1 Guil-Luna, Silvia
A1 Conde, Francisco
A1 Hernandez, Vanessa
A1 Toledano, Marta
A1 Gudiño, Victoria
A1 Raponi, Michela
A1 Billard, Caroline
A1 Villar, Carlos
A1 Diaz, Cesar
A1 Gomez-Barbadillo, Jose
A1 De la Haba-Rodriguez, Juan
A1 Myant, Kevin
A1 Aranda, Enrique
A1 Rodriguez-Ariza, Antonio
K1 Apc
K1 Mesenchymal
K1 Nitric oxide
K1 Stem cell
K1 eNOS
AB Nitric oxide (NO) has been highlighted as an important agent in cancer-related events. Although the inducible nitric oxide synthase (iNOS) isoform has received most attention, recent studies in the literature indicate that the endothelial isoenzyme (eNOS) can also modulate different tumor processes including resistance, angiogenesis, invasion, and metastasis. However, the role of eNOS in cancer stem cell (CSC) biology and mesenchymal tumors is unknown. Here, we show that eNOS was significantly upregulated in VilCre ERT2 Apc fl/+ and VilCre ERT2 Apc fl/fl mouse intestinal tissue, with intense immunostaining in hyperproliferative crypts. Similarly, the more invasive VilCre ERT2 Apc fl/+ Pten fl/+ mouse model showed an overexpression of eNOS in intestinal tumors whereas this isoform was not expressed in normal tissue. However, none of the three models showed iNOS expression. Notably, when 40 human colorectal tumors were classified into different clinically relevant molecular subtypes, high eNOS expression was found in the poor relapse-free and overall survival mesenchymal subtype, whereas iNOS was absent. Furthermore, Apc fl/fl organoids overexpressed eNOS compared with wild-type organoids and NO depletion with the scavenger carboxy-PTIO (c-PTIO) decreased the proliferation and the expression of stem-cell markers, such as Lgr5, Troy, Vav3, and Slc14a1, in these intestinal organoids. Moreover, specific NO depletion also decreased the expression of CSC-related proteins in human colorectal cancer cells such as β-catenin and Bmi1, impairing the CSC phenotype. To rule out the contribution of iNOS in this effect, we established an iNOS-knockdown colorectal cancer cell line. NO-depleted cells showed a decreased capacity to form tumors and c-PTIO treatment in vivo showed an antitumoral effect in a xenograft mouse model. Our data support that eNOS upregulation occurs after Apc loss, emerging as an unexpected potential new target in poor-prognosis mesenchymal colorectal tumors, where NO scavenging could represent an interesting therapeutic alternative to targeting the CSC subpopulation.
PB BioMed Central
YR 2017
FD 2017-12-14
LK http://hdl.handle.net/10668/12002
UL http://hdl.handle.net/10668/12002
LA en
NO Peñarando J, López-Sánchez LM, Mena R, Guil-Luna S, Conde F, Hernández V, et al. A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer. BMC Biol. 2018 Jan 10;16(1):3
NO We would like to acknowledge the following founding sources: Instituto de Salud Carlos III through the projects PI13/00553 and PI16/01508 (co-funded by the European Regional Development Fund/European Social Fund) “Investing in your future”). ARA was funded with a researcher contract through the program “Nicolás Monardes” from Junta de Andalucia. We also acknowledge the technical help of Álvaro Jiménez and Esther Peralbo from the Genomics and Microscopy Units at the IMIBIC.
DS RISalud
RD Apr 14, 2025