title: Gene expression profiling provides insights into pathways of oxaliplatin-related sinusoidal obstruction syndrome in humans.
abstract: Sinusoidal obstruction syndrome (SOS; formerly veno-occlusive disease) is a well-established complication of hematopoietic stem cell transplantation, pyrrolizidine alkaloid intoxication, and widely used chemotherapeutic agents such as oxaliplatin. It is associated with substantial morbidity and mortality. Pathogenesis of SOS in humans is poorly understood. To explore its molecular mechanisms, we used Affymetrix U133 Plus 2.0 microarrays to investigate the gene expression profile of 11 human livers with oxaliplatin-related SOS and compared it to 12 matched controls. Hierarchical clustering analysis showed that profiles from SOS and controls formed distinct clusters. To identify functional networks and gene ontologies, data were analyzed by the Ingenuity Pathway Analysis Tool. A total of 913 genes were differentially expressed in SOS: 613 being upregulated and 300 downregulated. Reverse transcriptase-PCR results showed excellent concordance with microarray data. Pathway analysis showed major gene upregulation in six pathways in SOS compared with controls: acute phase response (notably interleukin 6), coagulation system (Serpine1, THBD, and VWF), hepatic fibrosis/hepatic stellate cell activation (COL3a1, COL3a2, PDGF-A, TIMP1, and MMP2), and oxidative stress. Angiogenic factors (VEGF-C) and hypoxic factors (HIF1A) were upregulated. The most significant increase was seen in CCL20 mRNA. In conclusion, oxaliplatin-related SOS can be readily distinguished according to morphologic characteristics but also by a molecular signature. Global gene analysis provides new insights into mechanisms underlying chemotherapy-related hepatotoxicity in humans and potential targets relating to its diagnosis, prevention, and treatment. Activation of VEGF and coagulation (vWF) pathways could partially explain at a molecular level the clinical observations that bevacizumab and aspirin have a preventive effect in SOS.
authors.affiliation: Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, 1211 Geneva, Switzerland. laura.rubbia-brandt@hcuge.ch
authors.forename: Laura
authors.initials: L
authors.lastname: Rubbia-Brandt
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tauzin
authors.forename: Catherine
authors.initials: C
authors.lastname: Brezault
authors.forename: Céline
authors.initials: C
authors.lastname: Delucinge-Vivier
authors.forename: Patrick
authors.initials: P
authors.lastname: Descombes
authors.forename: Bertand
authors.initials: B
authors.lastname: Dousset
authors.forename: Pietro E
authors.initials: PE
authors.lastname: Majno
authors.forename: Gilles
authors.initials: G
authors.lastname: Mentha
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
mesh_terms: D054418:Chemokine CCL20 / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D046228:Microarray Analysis; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D042582:Vascular Endothelial Growth Factor C; D000077150:Oxaliplatin