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Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation
Julie Agostini1, Stéphane Benoist, Marie Seman
1Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France.
Background & Aims:
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 the identification of biomarkers and adaptation of chemotherapy delivery.
Methods:
Between 1998 and 2009, 83 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 19 patients: 9 patients with severe sinusoidal dilatation 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. Twenty-two differentially-expressed (at least 1.5-fold difference in expression) genes were selected. These were validated using microfluidic quantitative RT-PCR in an independent set of 58 patients (28 with sinusoidal dilatation and 30 without sinusoidal dilatation).
Results:
Among the 22 selected genes, 12 were validated as being up-regulated in samples from patients with sinusoidal dilatation compared to patients without sinusoidal dilatation. Genes involved in angiogenesis (VEGFD, THY-1, GPNMB) and cellular adhesion (VWF, CDH13, THBS2), and extracellular matrix components (COL1A1, COL4A1, SLCO1A2) were over-represented in patients with sinusoidal dilatation.
Conclusions:
This molecular signature confirms the involvement of angiogenesis and coagulation in sinusoidal injuries induced by oxaliplatin and reinforces a potential protective role of bevacizumab and aspirin, as suggested in retrospective clinical studies.
Insights
Oxaliplatin chemotherapy for colorectal liver metastases can cause liver damage. This study identified specific genes related to angiogenesis and coagulation, suggesting potential protective roles for bevacizumab and aspirin.
Area of Science:
- Hepatology
- Oncology
- Molecular Biology
Background:
- Oxaliplatin-based chemotherapy for colorectal liver metastases (CRLM) can lead to vascular liver lesions, specifically sinusoidal dilatations.
- The exact physiopathology of oxaliplatin-induced liver toxicity is not fully understood, and patient variability suggests individual susceptibility.
- Identifying molecular mechanisms of liver toxicity could lead to biomarkers and tailored chemotherapy delivery.
Purpose of the Study:
- To investigate the molecular mechanisms underlying oxaliplatin-induced liver toxicity in patients with CRLM.
- To identify potential biomarkers for predicting or monitoring oxaliplatin liver toxicity.
- To explore the role of angiogenesis and coagulation in oxaliplatin-induced sinusoidal injuries.
Main Methods:
- Gene-expression profiling using microarrays on liver samples from patients with and without sinusoidal dilatation after oxaliplatin chemotherapy.
- Validation of differentially expressed genes using microfluidic quantitative RT-PCR in an independent cohort.
- Comparison with a control group of patients who did not receive chemotherapy.
Main Results:
- Twelve out of 22 selected genes were validated as upregulated in patients with sinusoidal dilatation.
- Over-represented genes were associated with angiogenesis (e.g., VEGFD, THY-1, GPNMB), cellular adhesion (e.g., VWF, CDH13, THBS2), and extracellular matrix components (e.g., COL1A1, COL4A1, SLCO1A2).
Conclusions:
- The identified molecular signature implicates angiogenesis and coagulation pathways in oxaliplatin-induced sinusoidal liver injuries.
- These findings support the potential protective effects of bevacizumab and aspirin against oxaliplatin liver toxicity, as suggested by prior clinical studies.
