Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer

Abstract

Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab’)2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

Molecular Biomarkers in Drug-Induced Liver Injury: Challenges and Future Perspectives

“…CDH5 can be found in most tissues, save for bone marrow, with placenta, lung, and adipose tissues being the highest ranked. Further, its increased concentration was reported in APAP-induced liver injury and oxaliplatin-induced sinusoidal dilatation (Mikus et al, 2017;Jarzabek et al, 2018). Currently, few studies have reported on the role of CDH5 in DILI; therefore, this should serve as an important focus for future investigations ( Table 3).…”

“…• At present, there are a few reports about the role of CDH5 in DILI, so it needs further study and confirmation. Mikus et al, 2017;Jarzabek et al, 2018 HMGB1, high mobility group box-1 protein; FABP1, fatty acid binding protein 1; CDH5, cadherin 5.…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…162 However, although general toxicity is reduced, the liver toxicity of anti-DLL4 F(ab') 2 at the genetic level is unavoidable. 162,163 The anti-DLL4 nanobody 3Nb3, has a smaller size (15 KD) and higher affinity and specificity to the DLL4 antigen on the surface of tumor cells and ECs. 164,165 As nanobodies generally have a reduced half-life and higher clearance compared to antibodies, they are speculated to reduce DLL4 blockadeassociated toxicity, although this has not been confirmed experimentally.…”

Effect of lipid metabolism disorder on liver function in patients with malignant tumors after chemotherapy: a case-control study

“…Chemotherapeutic drugs have been shown to induce liver damage [12, 14, 15]. Almost all chemotherapeutic drugs are metabolized by the liver, the metabolic center of the body, and thus easily lead to drug-induced liver damage.…”