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

Author

Listed:
  • Monika A Jarzabek
  • William R Proctor
  • Jennifer Vogt
  • Rupal Desai
  • Patrick Dicker
  • Gary Cain
  • Rajiv Raja
  • Jens Brodbeck
  • Dale Stevens
  • Eric P van der Stok
  • John W M Martens
  • Cornelis Verhoef
  • Priti S Hegde
  • Annette T Byrne
  • Jacqueline M Tarrant

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)

Suggested Citation

  • Monika A Jarzabek & William R Proctor & Jennifer Vogt & Rupal Desai & Patrick Dicker & Gary Cain & Rajiv Raja & Jens Brodbeck & Dale Stevens & Eric P van der Stok & John W M Martens & Cornelis Verhoef, 2018. "Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer," PLOS ONE, Public Library of Science, vol. 13(6), pages 1-20, June.
    • Handle: RePEc:plo:pone00:0198099
    DOI: 10.1371/journal.pone.0198099
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    References listed on IDEAS

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    1. Minhong Yan & Christopher A. Callahan & Joseph C. Beyer & Krishna P. Allamneni & Gu Zhang & John Brady Ridgway & Kyle Niessen & Greg D. Plowman, 2010. "Chronic DLL4 blockade induces vascular neoplasms," Nature, Nature, vol. 463(7282), pages 6-7, February.
    2. John Ridgway & Gu Zhang & Yan Wu & Scott Stawicki & Wei-Ching Liang & Yvan Chanthery & Joe Kowalski & Ryan J. Watts & Christopher Callahan & Ian Kasman & Mallika Singh & May Chien & Christine Tan & Jo, 2006. "Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis," Nature, Nature, vol. 444(7122), pages 1083-1087, December.
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