title: Metastatic lesions with and without interleukin-18-dependent genes in advanced-stage melanoma patients.
abstract: IL-18 is an immune-stimulating cytokine that promotes experimental melanoma metastasis via vascular endothelial growth factor (VEGF)-induced very late antigen (VLA)-4. We studied genes associated with the ability of melanoma cells to allow metastasis under IL-18 effects, and we verified their expression in metastatic lesions from patients with melanoma. Human melanoma cell lines with and without the IL-18 receptor (IL-18R)/VEGF/VLA-4-expressing phenotype were identified, and their metastatic potential was studied in nude mice. RNA from untreated and IL-18-treated melanoma phenotypes was hybridized to a cDNA microarray, and their signature genes were studied. RNA from primary and metastatic lesions from patients with melanoma was hybridized to a cDNA microarray to identify lesions with the transcript patterns of melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype. IL-18R/VEGF/VLA-4-expressing A375 and 1182 melanoma cells produced a higher metastasis number than 526 and 624.28 melanoma cells, not using this prometastatic pathway. Melanoma cells with and without the IL-18R/VEGF/VLA-4 phenotype had distinct transcript patterns. However, the type I transcriptional cluster, including cutaneous and lymph node metastases, but not the type II cluster, not including cutaneous metastases, had signature genes from IL-18-treated melanoma cells with, but not without, the IL-18R/VEGF/VLA-4 phenotype. Metastatic melanoma lesions with and without IL-18-dependent genes were identified, suggesting that melanoma metastasis developed via inflammation-dependent and inflammation-independent mechanisms. Signature genes from melanomas with and without the IL-18R/VEGF/VLA-4 phenotype may serve as diagnostic biomarkers of melanoma predisposition to prometastatic effects of IL-18.
authors.affiliation: Department of Cellular Biology and Histology, Basque Country University School of Medicine and Dentistry, Leioa, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Crende
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.forename: María
authors.initials: M
authors.lastname: Valcárcel
authors.forename: Teresa
authors.initials: T
authors.lastname: Carrascal
authors.forename: Pia
authors.initials: P
authors.lastname: Riestra
authors.forename: Jose A
authors.initials: JA
authors.lastname: López-Guerrero
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Fernando
authors.initials: F
authors.lastname: Vidal-Vanaclocha
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018076:DNA, Complementary; D039041:Integrin alpha4beta1; D020382:Interleukin-18; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse