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2831645 
Journal Article 
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 
Ausiliatrice Puglisi, M; Cenciarelli, C; Tesori, V; Cappellari, M; Martini, M; Di Francesco, AM; Giorda, E; Carsetti, R; Ricci-Vitiani, L; Gasbarrini, A 
2015 
Yes 
Journal of Pathology
ISSN: 0022-3417
EISSN: 1096-9896 
236 
4 
479-490 
English 
25875314 
WOS:000358302900009 
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 signaling 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 signaling 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. 
cancer stem cells; nitric oxide; iNOS; CD133; colon cancer