title: Growth differentiation factor 15 (GDF-15) plasma levels increase during bleomycin- and cisplatin-based treatment of testicular cancer patients and relate to endothelial damage.
abstract: BACKGROUND
  Chemotherapy-related endothelial damage contributes to the early development of cardiovascular morbidity in testicular cancer patients. We aimed to identify relevant mechanisms of and search for candidate biomarkers for this endothelial damage.
  
  
  METHODS
  Human micro-vascular endothelial cells (HMEC-1) were exposed to bleomycin or cisplatin with untreated samples as control. 18k cDNA microarrays were used. Gene expression differences were analysed at single gene level and in gene sets clustered in biological pathways and validated by qRT-PCR. Protein levels of a candidate biomarker were measured in testicular cancer patient plasma before, during and after bleomycin-etoposide-cisplatin chemotherapy, and related to endothelial damage biomarkers (von Willebrand Factor (vWF), high-sensitivity C-Reactive Protein (hsCRP)).
  
  
  RESULTS
  Microarray data identified several genes with highly differential expression; e.g. Growth Differentiation Factor 15 (GDF-15), Activating Transcription Factor 3 (ATF3) and Amphiregulin (AREG). Pathway analysis revealed strong associations with 'p53' and 'Diabetes Mellitus' gene sets. Based on known function, we measured GDF-15 protein levels in 41 testicular patients during clinical follow-up. Pre-chemotherapy GDF-15 levels equalled controls. Throughout chemotherapy GDF-15, vWF and hsCRP levels increased, and were correlated at different time-points.
  
  
  CONCLUSIONS
  An unbiased approach in a preclinical model revealed genes related to chemotherapy-induced endothelial damage, like GDF-15. The increases in plasma GDF-15 levels in testicular cancer patients during chemotherapy and its association with vWF and hsCRP suggest that GDF-15 is a potentially useful biomarker related to endothelial damage.
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Renske
authors.initials: R
authors.lastname: Altena
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands; Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Rudolf S N
authors.initials: RS
authors.lastname: Fehrmann
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Hink
authors.initials: H
authors.lastname: Boer
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Elisabeth G E
authors.initials: EG
authors.lastname: de Vries
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Coby
authors.initials: C
authors.lastname: Meijer
authors.affiliation: Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.
authors.forename: Jourik A
authors.initials: JA
authors.lastname: Gietema
mesh_terms: D051700:Activating Transcription Factor 3 / Q000097:blood; D000293:Adolescent; D000328:Adult; D066258:Amphiregulin / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001761:Bleomycin / Q000494:pharmacology / Q000627:therapeutic use*; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055436:Growth Differentiation Factor 15 / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013736:Testicular Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; D066258:Amphiregulin; D014408:Biomarkers, Tumor; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D014841:von Willebrand Factor; D001761:Bleomycin; D002945:Cisplatin