The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome

Abstract

Background: Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury.

Methods: We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI.

Results: In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury.

Conclusion: It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.

Figure 1

MCA38 cells were treated in vitro with FOLFOX. Cell death in response to FOLFOX after 48 h treatment was confirmed by propidium iodide staining (A). MCA38 cells treated with FOLFOX for 24 h show increased expression of the chemokines CXCL1, CXCL5, CCL2 and CCL5 (B). The increased expression of CXCL1 transcript was confirmed by ELISA (C). (*=P<0.05, **=P<0.01, ***=P<0.001).

Figure 2

C57Bl/6 mice underwent either laparotomy alone (shams) or laparotomy with implantation of MCA38 cells beneath the liver capsule. After 5 days tumour was detectable with IVIS imaging (A). Three weekly doses of i.p. FOLFOX resulted in a reduced tumour mass as demonstrated by tumour volume (B) and tumour/body weight ratio (C). The tumour/liver interface is shown in (D) and typical gross appearances of the tumours in (E). FOLFOX-treated animals demonstrated significant weight loss as compared with controls (F). H&E stained sections (G) did not demonstrate histological changes of SOS. (*=P<0.05).

Figure 3

Tumour-bearing mice treated with FOLFOX have increased expression of the fibrogenic genes αSMA and pro-collagen I as compared with sham-operated vehicle controls (A). In addition, there were more αSMA positive cells detected by immunohistochemistry (B). Increased expression of αSMA was also demonstrated in patients with Oxalipaltin-induced vascular injury (C). In keeping with a pro-fibrogenic environment, there is increased hepatic expression of TIMP-1 transcript in tumour-bearing FOLFOX-treated mice (D). It is likely that these changes are, in part, driven by increased expression of the master regulator TGFβ-1 (E). Injury to the hepatic sinusoid in SOS is driven by gelatinases and in keeping with this there is increased expression of MMP-2 transcript in FOLFOX-treated tumour-bearing mice (F). In keeping with an angiogenic process, there is up-regulation of VEGF-C transcript in FOLFOX-treated tumour-bearing mice (G) and in patients with Oxaliplatin-induced liver injury (H). (*=P<0.05, **=P<0.01).

Figure 4

Oxaliplatin-induced liver injury has also been associated with a pro-thrombotic tendency in the hepatic sinusoid and in accordance with this we demonstrated increased hepatic expression of both PAI-1 (A) and vWF (B) in tumour-bearing FOLFOX-treated animals. In addition, there is a trend to increased vWF expression in patients with Oxaliplatin-induced vascular injury (C). Furthermore, there was an accumulation of megakaryocytes within the spleen (D and E) of these animals as determined by P-Selectin immunohistochemistry. (*=P<0.05, **=P<0.01).