Identification of molecular pathways involved in oxaliplatin-associated sinusoidal dilatation.
OBJECTIVE
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.
Paris Descartes University, Paris Sorbonne Cité, INSERM UMR-S775, Paris, France.
Julie
J
Agostini
Stéphane
S
Benoist
Marie
M
Seman
Catherine
C
Julié
Sandrine
S
Imbeaud
Franck
F
Letourneur
Nicolas
N
Cagnard
Philippe
P
Rougier
Antoine
A
Brouquet
Jessica
J
Zucman-Rossi
Pierre
P
Laurent-Puig
D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology; D015179:Colorectal Neoplasms / Q000473:pathology; D004108:Dilatation, Pathologic / Q000503:physiopathology; D005109:Extracellular Matrix / Q000235:genetics / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000098:blood supply*; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000556:secondary; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000503:physiopathology; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D000077150:Oxaliplatin; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014652:Vascular Diseases / Q000139:chemically induced* / Q000503:physiopathology*
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin