Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation

详细信息	查看全文 | 推荐本文 |

• 作者：Julie Agostini¹ ; Sté ; phane Benoist¹ ; ² ; Marie Seman¹ ; Catherine Julié ; ³ ; Sandrine Imbeaud⁴ ; Franck Letourneur⁵ ; Nicolas Cagnard⁵ ; Philippe Rougier¹ ; Antoine Brouquet² ; Jessica Zucman-Rossi⁴ ; Pierre Laurent-Puig¹ ; ^{pierre.laurent-puig@parisdescartes.fr}
• 关键词：Sinusoidal dilatation ; Oxaliplatin ; Colorectal liver metastases ; Molecular pathways
• 刊名：Journal of Hepatology
• 出版年：2012
• 期刊代码：162_01688278
• 类别：med
• 出版时间：April, 2012
• 卷：56
• 期：4
• 页码：869-876
• 文件大小：1098 K

摘要

| Figures/TablesFigures/Tables | ReferencesReferences

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.