High nitric oxide production, secondary to inducible nitric oxide synthase expression, is essential for regulation of the tumour‐initiating properties of colon cancer stem cells

Abstract

Chronic inflammation is a leading cause of neoplastic transformation in many human cancers and especially in colon cancer (CC), in part due to tumour promotion by nitric oxide (NO) generated at inflammatory sites. It has also been suggested that high NO synthesis, secondary to inducible NO synthase (iNOS) expression, is a distinctive feature of cancer stem cells (CSCs), a small subset of tumour cells with self-renewal capacity. In this study we explored the contribution of NO to the development of colon CSC features and evaluated potential strategies to treat CC by modulating NO production. Our data show an integral role for endogenous NO and iNOS activity in the biology of colon CSCs. Indeed, colon CSCs with high endogenous NO production (NO(high)) displayed higher tumourigenic abilities than NO(low) fractions. The blockade of endogenous NO availability, using either a specific iNOS inhibitor or a genetic knock-down of iNOS, resulted in a significant reduction of colon CSC tumourigenic capacities in vitro and in vivo. Interestingly, analysis of genes altered by iNOS-directed shRNA showed that the knockdown of iNOS expression was associated with a significant down-regulation of signalling pathways involved in stemness and tumour progression in colon CSCs. These findings confirm that endogenous NO plays an important role in defining the stemness properties of colon CSCs through cross-regulation of several cellular signalling pathways. This discovery could shed light on the mechanisms by which NO induces the growth and invasiveness of CC, providing new insights into the link between inflammation and colon tumourigenesis.

The interference of Notch1 target Hes1 affects cell growth, differentiation and invasiveness of glioblastoma stem cells through modulation of multiple oncogenic targets

“…Elevated NO synthase 2 (NOS2) expression correlates with decreased survival in human glioma patients [46]. Previously, we and others have demonstrated that NOS2 inhibition slowed colon and glioma stem cells growth in vivo animal models [47, 46]. Accordingly, we report that targeting Hes1 downregulates NOS2, IL1B, IL6 and NF-κB2 mRNA levels.…”

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

“…Another important oncogenic pathway in cancer promoted by NO to induce proliferation and migration is the Wnt/β-catenin pathway, as suggested by the activation of Wnt target genes following the overexpression of iNOS in cultured human colon and breast cancer cells (Du et al, 2013). Interestingly, NO can also support tumor-forming cancer stem cells (CSCs), as NO produced in cultured human colon CSCs was found to drive stemness-related signaling pathways, central to colon tumor initiation and progression (Puglisi et al, 2015). In contrast to the role that NO plays in supporting oncogenic pathways in cancer, NO also exhibits an anti-proliferative role by suppressing oncogenic pathways or by activating tumor-suppressing ones.…”

Nitric Oxide: The Forgotten Child of Tumor Metabolism

“…NOS2 expression in these patients greatly increases their risk of developing colon cancer [24]. Additionally, colorectal cancer stem cells are dependent on NO synthesis and NOS expression for tumor initiation [25]. However, early stage colon cancer patients have been shown to have low NOS2 in their colonic epithelium.…”