title: Melanocytes Affect Nodal Expression and Signaling in Melanoma Cells: A Lesson from Pediatric Large Congenital Melanocytic Nevi.
abstract: Expression of Nodal, a Transforming Growth Factor-beta (TGF-β) related growth factor, is associated with aggressive melanoma. Nodal expression in adult dysplastic nevi may predict the development of aggressive melanoma in some patients. A subset of pediatric patients diagnosed with giant or large congenital melanocytic nevi (LCMN) has shown increased risk for development of melanoma. Here, we investigate whether Nodal expression can help identify the rare cases of LCMN that develop melanoma and shed light on why the majority of these patients do not. Immunohistochemistry (IHC) staining results show varying degree of Nodal expression in pediatric dysplastic nevi and LCMN. Moreover, median scores from Nodal IHC expression analysis were not significantly different between these two groups. Additionally, none of the LCMN patients in this study developed melanoma, regardless of Nodal IHC levels. Co-culture experiments revealed reduced tumor growth and lower levels of Nodal and its signaling molecules P-SMAD2 and P-ERK1/2 when melanoma cells were grown in vivo or in vitro with normal melanocytes. The same was observed in melanoma cells cultured with melanocyte conditioned media containing pigmented melanocyte derived melanosomes (MDM). Since MDM contain molecules capable of inactivating radical oxygen species, to investigate potential anti-oxidant effect of MDM on Nodal expression and signaling in melanoma, melanoma cells were treated with either N-acetyl-l-cysteine (NAC), a component of the anti-oxidant glutathione or synthetic melanin, which in addition to providing pigmentation can also exert free radical scavenging activity. Melanoma cells treated with NAC or synthetic melanin showed reduced levels of Nodal, P-SMAD2 and P-ERK1/2 compared to untreated melanoma cells. Thus, the potential role for Nodal in melanoma development in LCMN is less evident than in adult dysplastic nevi possibly due to melanocyte cross-talk in LCMN capable of offsetting or delaying the pro-melanoma effects of Nodal via anti-oxidant effects of MDM.
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. nmargaryan@luriechildrens.org.
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. agilgur@luriechildrens.org.
authors.forename: Alina
authors.initials: A
authors.lastname: Gilgur
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. eseftor@luriechildrens.org.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. chad-purnell@northwestern.edu.
authors.forename: Chad
authors.initials: C
authors.lastname: Purnell
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. narva@luriechildrens.org.
authors.forename: Nicoleta C
authors.initials: NC
authors.lastname: Arva
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. argosain@luriechildrens.org.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Gosain
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. m-hendrix@northwestern.edu.
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.affiliation: Stanley Manne Children's Research Institute, Ann &amp; Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. lstrizzi@luriechildrens.org.
authors.forename: Luigi
authors.initials: L
authors.lastname: Strizzi
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D006801:Humans; D008543:Melanins / Q000494:pharmacology; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism*; D008545:Melanoma / Q000151:congenital / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D055457:Nodal Protein / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism
chemical_list: D008543:Melanins; C526007:NODAL protein, human; D055457:Nodal Protein; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000111:Acetylcysteine
keywords: Nodal; anti-oxidants; melanocytes; melanoma; melanosomes; pediatric nevi