title: Gene expression changes in melanoma metastases in response to high-dose chemotherapy during isolated limb perfusion.
abstract: Despite recent advances in melanoma therapy, disseminated melanoma still lacks effective treatment, and recurrence of the tumor frequently occurs, even after high-dose chemotherapy. The mechanisms responsible for this chemoresistance or for the formation of new relapses remain poorly understood. Using a human 'model', in which the isolated limb is perfused with high doses of the chemotherapeutic melphalan (ILP), we identified a five-gene set (ATF3, CYR61, IER5, IL6, and PTGS2) of stress-induced genes that was consistently upregulated after ILP in all in-transit metastatic melanoma samples as well as in three melphalan-treated melanoma cell lines. Early post-ILP relapses retained these elevated expressions, whereas the expression of these genes returned to their original levels in late post-ILP recurrences. In addition, we identified upregulation of these genes in the A375 cell line's side population (SP) and melanospheres, established methods to enrich for candidate cancer stem cells (CSCs), which are considered chemoresistant and tumorigenic, and thus proposed to be responsible for tumor relapse. Our data identify an immediate and short-term upregulation of early stress-responsive genes that are potentially linked to chemoresistance and CSCs.
authors.affiliation: Translational Cell & Tissue Research, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium. jasper.wouters@med.kuleuven.be
authors.forename: Jasper
authors.initials: J
authors.lastname: Wouters
authors.forename: Marguerite
authors.initials: M
authors.lastname: Stas
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.forename: Kathleen
authors.initials: K
authors.lastname: Van den Eynde
authors.forename: Hugo
authors.initials: H
authors.lastname: Vankelecom
authors.forename: Joost J
authors.initials: JJ
authors.lastname: van den Oord
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D010478:Chemotherapy, Cancer, Regional Perfusion; D004305:Dose-Response Relationship, Drug; D005121:Extremities / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy; D020411:Oligonucleotide Array Sequence Analysis; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D058985:Side-Population Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D008558:Melphalan