title: 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.
authors: Department of Internal Medicine and Gastroenterology, Gemelli Hospital, Rome, Italy.
authors: Maria Ausiliatrice
authors: MA
authors: Puglisi
authors: Institute of Translational Pharmacology, National Research Council of Italy, Rome, Italy.
authors: Carlo
authors: C
authors: Cenciarelli
authors: Department of Internal Medicine and Gastroenterology, Gemelli Hospital, Rome, Italy.
authors: Valentina
authors: V
authors: Tesori
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Marianna
authors: M
authors: Cappellari
authors: Department of Anatomical Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.
authors: Maurizio
authors: M
authors: Martini
authors: Laboratory of Pharmacology, Division of Paediatric Oncology, Gemelli Hospital, Rome, Italy.
authors: Angela Maria
authors: AM
authors: Di Francesco
authors: Cytofluorimetry Laboratory, Bambino Gesù Paediatric Hospital, Rome, Italy.
authors: Ezio
authors: E
authors: Giorda
authors: Cytofluorimetry Laboratory, Bambino Gesù Paediatric Hospital, Rome, Italy.
authors: Rita
authors: R
authors: Carsetti
authors: Department of Haematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
authors: Lucia
authors: L
authors: Ricci-Vitiani
authors: Department of Internal Medicine and Gastroenterology, Gemelli Hospital, Rome, Italy.
authors: Antonio
authors: A
authors: Gasbarrini
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D018938:Caco-2 Cells; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D045325:HCT116 Cells; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D009569:Nitric Oxide; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: CD133; cancer stem cells; colon cancer; iNOS; nitric oxide