Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation
| Autor: | Julie Agostini, Franck Letourneur, Marie Seman, Sandrine Imbeaud, Pierre Laurent-Puig, Jessica Zucman-Rossi, Philippe Rougier, Stéphane Benoist, Antoine Brouquet, Nicolas Cagnard, Catherine Julié |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Pathology Bevacizumab Organoplatinum Compounds Angiogenesis medicine.medical_treatment Population Antineoplastic Agents Gastroenterology Neovascularization Internal medicine medicine Cell Adhesion Humans Vascular Diseases education Retrospective Studies Aspirin Chemotherapy education.field_of_study Hepatology Neovascularization Pathologic business.industry Gene Expression Profiling Liver Neoplasms Middle Aged Pathophysiology Oxaliplatin Extracellular Matrix Liver Case-Control Studies Female medicine.symptom business Colorectal Neoplasms medicine.drug Dilatation Pathologic Signal Transduction |
| Zdroj: | Journal of hepatology. 56(4) |
| ISSN: | 1600-0641 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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