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

PLoS One. 2018 Jun 7;13(6):e0198099. doi: 10.1371/journal.pone.0198099. eCollection 2018.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biopsy
  • Capillaries / drug effects
  • Capillaries / metabolism
  • Capillaries / pathology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Dilatation, Pathologic / chemically induced
  • Dilatation, Pathologic / genetics
  • Female
  • Gene Expression Profiling
  • Humans
  • Liver / blood supply
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology*
  • Liver Neoplasms / secondary
  • Macaca fascicularis
  • Male
  • Middle Aged
  • Neovascularization, Pathologic / chemically induced
  • Neovascularization, Pathologic / genetics
  • Oxaliplatin / administration & dosage
  • Oxaliplatin / adverse effects*
  • Transcriptome* / drug effects

Substances

  • Oxaliplatin

Grants and funding

This project was funded by AngioTox [www.angiotox.com], a European Commission funded FP7 Industry Academia Pathways and Partnerships Marie Curie Award (grant agreement number: 251528) to ATB and by Genentech, Inc. The funder provided support in the form of salaries for authors [MAJ], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. ATB is further funded by Science Foundation Ireland (SFI) Career Development Award ‘Coloforetell’ (grant agreement number: 13/CDA/2183) and the European Union's Horizon 2020 Health Research and Innovation award ‘Colossus’ (grant agreement number: 754923). Genentech, Inc. provided support in the form of salaries for authors WRP, JV, RD, GC, RR, JB, DS, PSH, and JMT, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.