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Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

ABSTRACT: Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow to identification of biomarkers and adaptation of chemotherapy delivery.

ORGANISM(S): Homo sapiens

PROVIDER: GSE32384 | GEO | 2012/03/01

SECONDARY ACCESSION(S): PRJNA147963

REPOSITORIES: GEO

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Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

Project description:Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can result in vascular liver lesions such as sinusoidal dilatations. Physiopathology remains unclear and variability between patients suggests that there is individual susceptibility. A better understanding of the molecular mechanisms of oxaliplatin liver toxicity may allow to identification of biomarkers and adaptation of chemotherapy delivery. non-tumor frozen liver samples were obtained from patients operated on for CRLM after an exclusive oxaliplatin-based chemotherapy. Gene-expression profiles were first analyzed by microarray on a selected population of 20 patients; 9 patients with severe sinusoidal dilatation (SD) after a short period of chemotherapy and 10 patients without any sinusoidal dilatation after a long period of chemotherapy. These were compared with a control group of 5 patients without any chemotherapy and lesions. This dataset is part of the TransQST collection.

2012-03-01 | E-GEOD-32384 | biostudies-arrayexpress

Transcription profiling by array of human liver to investigate pathways of Oxaliplatin Related Sinusoidal Obstruction

Project description: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. This dataset is part of the TransQST collection.

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Global proteome changes in liver tissue 6 weeks after FOLFOX treatment of colorectal cancer liver metastases.

Project description:Study: Oxaliplatin-based chemotherapy for colorectal liver metastasis is associated with sinusoidal injury of liver parenchyma and may result in increased morbidity after liver surgery. Preclinical and human liver parenchyma studies have proposed several pathways of oxaliplatin-induced injury, but the effects on protein level remains unknown. Protein expression in liver tissue from eight patients treated with FOLFOX and seven controls without treatment was analyzed by label-free liquid chromatography mass spectrometry. Conclusion: Six weeks after FOLFOX treatment less than 1% of identified proteins showed changes in expression. The changes were associated with DNA replication, cell cycle entry and innate immune response. We hypothesize that the changes are residual after recovery from FOLFOX treatment injury.

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Prevention of the Hepatic Sinusoidal Obstruction Syndrome by Means of Anticoagulants

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