Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

• DOI: 10.1016/j.jhep.2011.10.023
• Publication Date: 2011-12-24T07:51:01Z
• Authors: Julie Agostini; Stéphane Benoist; Marie Seman; Catherine Julié; Sandrine Imbeaud; Franck Letourneur; Nicolas Cagnard; Philippe Rougier; Antoine Brouquet; Jessica Zucman-Rossi; Pierre Laurent-Puig
• Keywords: Male; Neovascularization, Pathologic; Organoplatinum Compounds; Gene Expression Profiling; Liver Neoplasms; Antineoplastic Agents; Middle Aged; Extracellular Matrix; 3. Good health; Oxaliplatin; 03 medical and health sciences; 0302 clinical medicine; Liver; Case-Control Studies; Cell Adhesion; Humans; Female; Vascular Diseases; Colorectal Neoplasms; Dilatation, Pathologic; Retrospective Studies; Signal Transduction

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.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).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.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.