PMID- 25590623
OWN - NLM
STAT- MEDLINE
DCOM- 20151217
LR  - 20190223
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 1
DP  - 2015
TI  - Growth differentiation factor 15 (GDF-15) plasma levels increase during 
      bleomycin- and cisplatin-based treatment of testicular cancer patients and relate 
      to endothelial damage.
PG  - e0115372
LID - 10.1371/journal.pone.0115372 [doi]
LID - e0115372
AB  - INTRODUCTION: 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. 
      CONCLUSION: 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.
FAU - Altena, Renske
AU  - Altena R
AD  - Department of Medical Oncology, University of Groningen, University Medical 
      Centre Groningen, Groningen, the Netherlands.
FAU - Fehrmann, Rudolf S N
AU  - Fehrmann RS
AD  - 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.
FAU - Boer, Hink
AU  - Boer H
AD  - Department of Medical Oncology, University of Groningen, University Medical 
      Centre Groningen, Groningen, the Netherlands.
FAU - de Vries, Elisabeth G E
AU  - de Vries EG
AD  - Department of Medical Oncology, University of Groningen, University Medical 
      Centre Groningen, Groningen, the Netherlands.
FAU - Meijer, Coby
AU  - Meijer C
AD  - Department of Medical Oncology, University of Groningen, University Medical 
      Centre Groningen, Groningen, the Netherlands.
FAU - Gietema, Jourik A
AU  - Gietema JA
AD  - Department of Medical Oncology, University of Groningen, University Medical 
      Centre Groningen, Groningen, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150115
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATF3 protein, human)
RN  - 0 (Activating Transcription Factor 3)
RN  - 0 (Amphiregulin)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (GDF15 protein, human)
RN  - 0 (Growth Differentiation Factor 15)
RN  - 0 (von Willebrand Factor)
RN  - 11056-06-7 (Bleomycin)
RN  - Q20Q21Q62J (Cisplatin)
SB  - IM
MH  - Activating Transcription Factor 3/blood
MH  - Adolescent
MH  - Adult
MH  - Amphiregulin/blood
MH  - Antineoplastic Combined Chemotherapy Protocols/pharmacology/*therapeutic use
MH  - Biomarkers, Tumor/blood
MH  - Bleomycin/pharmacology/*therapeutic use
MH  - Cell Line
MH  - Cisplatin/pharmacology/*therapeutic use
MH  - Endothelial Cells/*drug effects/metabolism/pathology
MH  - Endothelium, Vascular/drug effects/metabolism/pathology
MH  - Growth Differentiation Factor 15/*blood
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Testicular Neoplasms/*blood/drug therapy/pathology
MH  - Young Adult
MH  - von Willebrand Factor/metabolism
PMC - PMC4295859
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/01/16 06:00
MHDA- 2015/12/19 06:00
PMCR- 2015/01/15
CRDT- 2015/01/16 06:00
PHST- 2014/05/27 00:00 [received]
PHST- 2014/11/21 00:00 [accepted]
PHST- 2015/01/16 06:00 [entrez]
PHST- 2015/01/16 06:00 [pubmed]
PHST- 2015/12/19 06:00 [medline]
PHST- 2015/01/15 00:00 [pmc-release]
AID - PONE-D-14-23498 [pii]
AID - 10.1371/journal.pone.0115372 [doi]
PST - epublish
SO  - PLoS One. 2015 Jan 15;10(1):e0115372. doi: 10.1371/journal.pone.0115372. 
      eCollection 2015.