title: Melanoma cells influence the differentiation pattern of human epidermal keratinocytes.
abstract: BACKGROUND
  Nodular melanoma is one of the most life threatening tumors with still poor therapeutic outcome. Similarly to other tumors, permissive microenvironment is essential for melanoma progression. Features of this microenvironment are arising from molecular crosstalk between the melanoma cells (MC) and the surrounding cell populations in the context of skin tissue. Here, we study the effect of melanoma cells on human primary keratinocytes (HPK). Presence of MC is as an important modulator of the tumor microenvironment and we compare it to the effect of nonmalignant lowly differentiated cells also originating from neural crest (NCSC).
  
  
  METHODS
  Comparative morphometrical and immunohistochemical analysis of epidermis surrounding nodular melanoma (n = 100) was performed. Data were compared to results of transcriptome profiling of in vitro models, in which HPK were co-cultured with MC, normal human melanocytes, and NCSC, respectively. Differentially expressed candidate genes were verified by RT-qPCR. Biological activity of candidate proteins was assessed on cultured HPK.
  
  
  RESULTS
  Epidermis surrounding nodular melanoma exhibits hyperplastic features in 90% of cases. This hyperplastic region exhibits aberrant suprabasal expression of keratin 14 accompanied by loss of keratin 10. We observe that MC and NCSC are able to increase expression of keratins 8, 14, 19, and vimentin in the co-cultured HPK. This in vitro finding partially correlates with pseudoepitheliomatous hyperplasia observed in melanoma biopsies. We provide evidence of FGF-2, CXCL-1, IL-8, and VEGF-A participation in the activity of melanoma cells on keratinocytes.
  
  
  CONCLUSIONS
  We conclude that the MC are able to influence locally the differentiation pattern of keratinocytes in vivo as well as in vitro. This interaction further highlights the role of intercellular interactions in melanoma. The reciprocal role of activated keratinocytes on biology of melanoma cells shall be verified in the future.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Kodet
authors.forename: Lukáš
authors.initials: L
authors.lastname: Lacina
authors.forename: Eliška
authors.initials: E
authors.lastname: Krejčí
authors.forename: Barbora
authors.initials: B
authors.lastname: Dvořánková
authors.forename: Miloš
authors.initials: M
authors.lastname: Grim
authors.forename: Jiří
authors.initials: J
authors.lastname: Štork
authors.forename: Daniela
authors.initials: D
authors.lastname: Kodetová
authors.forename: Čestmír
authors.initials: Č
authors.lastname: Vlček
authors.forename: Jana
authors.initials: J
authors.lastname: Šáchová
authors.forename: Michal
authors.initials: M
authors.lastname: Kolář
authors.affiliation: 1st Faculty of Medicine, Institute of Anatomy, Charles University in Prague, U Nemocnice 3, CZ-12800 Prague, Czech Republic. strnad@img.cas.cz.
authors.forename: Hynek
authors.initials: H
authors.lastname: Strnad
authors.forename: Karel
authors.initials: K
authors.lastname: Smetana
mesh_terms: D000328:Adult; D000368:Aged; D002450:Cell Communication; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D054360:Chemokine CXCL1 / Q000494:pharmacology; D000078404:Epidermal Cells; D004817:Epidermis / Q000473:pathology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D016209:Interleukin-8 / Q000494:pharmacology; D053550:Keratin-10 / Q000378:metabolism; D053547:Keratin-14 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009418:S100 Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D054360:Chemokine CXCL1; D016209:Interleukin-8; D053547:Keratin-14; D009418:S100 Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D053550:Keratin-10