A role for endothelial nitric oxide synthase in intestinal stem cell proliferation and mesenchymal colorectal cancer

• DOI: 10.1186/s12915-017-0472-5
• Publication Date: 2018-01-10T15:05:42Z
• Authors: Jon Peñarando; Laura M. López-Sá...; Rafael Mena; Silvia Guil-Luna; Francisco Conde; Vanessa Hernández; Marta Toledano; Victoria Gudiño; Michela Raponi; Caroline Billard; Carlos Villar; César Díaz; José Gómez-Barbad...; Juan De la Haba-R...; Kevin Myant; Enrique Aranda; Antonio Rodríguez...
• Keywords: LGR5; Stem cell marker

Nitric oxide (NO) has been highlighted as an important agent in cancer-related events. Although the inducible nitric synthase (iNOS) isoform received most attention, recent studies literature indicate that endothelial isoenzyme (eNOS) can also modulate different tumor processes including resistance, angiogenesis, invasion, and metastasis. However, role of eNOS cancer stem cell (CSC) biology mesenchymal tumors is unknown. Here, we show was significantly upregulated VilCre ERT2 Apc fl/+ fl/fl mouse intestinal tissue, with intense immunostaining hyperproliferative crypts. Similarly, more invasive Pten model showed overexpression whereas this not expressed normal tissue. none three models iNOS expression. Notably, when 40 human colorectal were classified into clinically relevant molecular subtypes, high expression found poor relapse-free overall survival subtype, absent. Furthermore, organoids overexpressed compared wild-type NO depletion scavenger carboxy-PTIO (c-PTIO) decreased proliferation stem-cell markers, such Lgr5, Troy, Vav3, Slc14a1, these organoids. Moreover, specific CSC-related proteins cells β-catenin Bmi1, impairing CSC phenotype. To rule out contribution effect, established iNOS-knockdown line. NO-depleted a capacity to form c-PTIO treatment vivo antitumoral effect xenograft model. Our data support upregulation occurs after loss, emerging unexpected potential new target poor-prognosis tumors, where scavenging could represent interesting therapeutic alternative targeting subpopulation.