Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

Agostini, Julie; Benoist, Stéphane; Seman, Marie; Julié, Catherine; Imbeaud, Sandrine; Letourneur, Franck; Cagnard, Nicolas; Rougier, Philippe; Brouquet, Antoine; Zucman-Rossi, Jessica; Laurent-Puig, Pierre

doi:10.1016/j.jhep.2011.10.023

« Previous Next »Journal of Hepatology
Volume 56, Issue 4 , Pages 869-876, April 2012

Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

Julie Agostini
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France
Stéphane Benoist
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France
- Assistance-Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Department of Surgery, Boulogne, France
Marie Seman
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France
Catherine Julié
- Assistance-Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Department of Pathology, Boulogne, France
Sandrine Imbeaud
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S674, Paris, France
Franck Letourneur
- Institut Cochin, INSERM U1016, Paris, France
Nicolas Cagnard
- Institut Cochin, INSERM U1016, Paris, France
Philippe Rougier
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France
Antoine Brouquet
- Assistance-Publique-Hôpitaux de Paris, Hôpital Ambroise Paré, Department of Surgery, Boulogne, France
Jessica Zucman-Rossi
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S674, Paris, France
Pierre Laurent-Puig
- Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France
- Corresponding author. Address: UMR-S INSERM 775, Paris Descartes University, 45 rue des Saints-Pères, 75006 Paris, France. Tel.: +33 1 42 86 20 81; fax: +33 1 42 86 20 72.

Received 7 July 2011; received in revised form 4 October 2011; accepted 19 October 2011. published online 26 December 2011.

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.

Keywords: Sinusoidal dilatation, Oxaliplatin, Colorectal liver metastases, Molecular pathways