High Nitric Oxide production, secondary to high inducible-nitric oxide synthase expression, is essential in regulating tumor initiating properties of colon cancer stem cells. (Abstract/Poster in convegno)

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Label
  • High Nitric Oxide production, secondary to high inducible-nitric oxide synthase expression, is essential in regulating tumor initiating properties of colon cancer stem cells. (Abstract/Poster in convegno) (literal)
Anno
  • 2014-01-01T00:00:00+01:00 (literal)
Alternative label
  • 1Puglisi A., 2Tesori V., 3 Ricci-Vitiani L., 3Cappellari M., 4Cenciarelli C., 5Martini M., 6Giorda E., 6Carsetti R., 2Gasbarrini G., 7Pani GB., 1Gasbarrini A. (2014)
    High Nitric Oxide production, secondary to high inducible-nitric oxide synthase expression, is essential in regulating tumor initiating properties of colon cancer stem cells.
    in UEG Week, Vienna, Austria, 18-22 October, 2014
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • 1Puglisi A., 2Tesori V., 3 Ricci-Vitiani L., 3Cappellari M., 4Cenciarelli C., 5Martini M., 6Giorda E., 6Carsetti R., 2Gasbarrini G., 7Pani GB., 1Gasbarrini A. (literal)
Note
  • Poster (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • 1Internal Medicine and Gastroenterology, GEMELLI HOSPITAL, ROME, 2Medical Research Foundation ONLUS, Bologna, 3Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità , 4Institute ofTranslational Pharmacology, National Research Council , 5Anatomic Pathology , GEMELLI HOSPITAL, 6Cytofluorimetry Laboratory, Bambino Gesù Pediatric Hospital, 7General Pathology, GEMELLI HOSPITAL, ROME, Italy (literal)
Titolo
  • High Nitric Oxide production, secondary to high inducible-nitric oxide synthase expression, is essential in regulating tumor initiating properties of colon cancer stem cells. (literal)
Abstract
  • INTRODUCTION Several studies have indicated that continuous exposure to high concentrations of Nitric Oxide (NO), produced by inducibile-NO synthase (iNOS), promote neoplastic transformation in many human cancers and especially in colon cancer (CC). Recently, it has also been suggested that high NO synthesis is a distinctive feature of \"cancer stem cells\" (CSC), a tumor subpopulation with self-renewal capacity, that may be identified by the expression of the CD133 surface marker. AIMS & METHODS Aims of this study were to explore the contribution of NO in the definition of colon CSC features and evaluate potential strategies to treat CC by modulating NO production. By immunohistochemistry analysis we evaluated iNOS and CD133 expression in 30 samples of human CC. Using the DAF-2DA detection system, we assayed the production of intracellular NO in 5 colon CSC lines obtained from human CC tissues. By FACS sorter, we purified the NOhigh and NOlow fractions from all colon CSC lines. We compared the tumorigenic potential of both cell fractions by in vitro and in vivo assays. To tested the potential antitumor effects of iNOS modulation, we treated colon CSCs with the selective iNOS inhibitor 1400W or we stably transfected these cells with two distinct iNOS-directed short-harpin RNA(shRNAs). RESULTS NOhigh CSCs display an overespression of stem cell markers and higher expression levels of iNOS than NOlow cells. Interestingly, immunohistochemistry analysis confirmed that, regardless of tumor differentiation grade and TNM stage, there was a significant association between iNOS overexpression and higher expression level of the stem cell marker CD133, in human CC. Moreover, we demonstrated, by in vitro and in vivo assays, that NOhigh cells displayed higher tumorigenic abilities than NOlow fractions. The blockade of endogenous NO availability using a specific iNOS inhibitor and genetic knock-down of iNOS resulted in a significant reduction of colon CSC growth and tumorigenic capacity: a lower capacity to give rise to colonies in soft agar, a dramatic decrease of invasivness and in vivo tumor growth (xenotransplantations in nude mice). These data confirmed an integral role for endogenous NO and iNOS activity in the biology of colon CSCs. Interestingly, analysis of the genes altered by iNOS-directed shRNA showed that the knockdown of iNOS expression was associated with a significant down regulation of a wide range of signaling pathways in colon CSCs, especially genes involved in stemness and tumor progression (such as CD133, BMI, b-Catenin and NF-kB pathway). CONCLUSION These findings have demonstrated for the first time 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 gathering new insights on the link between inflammation and colon tumorigenesis. (literal)
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