Date Published: June 7, 2018
Publisher: Public Library of Science
Author(s): 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, Matias A. Avila.
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.
SD is an expansion of centrilobular hepatic sinusoids that can progress to sinusoidal obstructive syndrome (veno-occlusive disease (SOS/VOD)), a potentially life-threatening complication, which may also include peri-sinusoidal fibrosis and nodular regenerative hyperplasia. Sinusoidal dilation may be clinically silent  with diagnosis requiring at least two symptoms of jaundice, tender hepatomegaly and right-upper quadrant pain, ascites and/or unexplained weight gain . SOS/VOD was responsible for the U.S. market withdrawal of gemtuzumab ozogamicin (Mylotarg®), an antibody-drug-conjugate of anti-CD33 and a calicheamicins cytotoxin for the treatment of patients with acute myeloid leukemia . The presence of SOS/VOD in patients treated by partial hepatectomy for CRLM has been linked to higher risk of morbitidity, including increased peri-operative risk of bleeding, post-hepatectomy liver failure, lower long-term disease specific survival, intra-hepatic tumor recurrence and death due to multi-organ failure . As yet, there are no accurate, non-invasive tests to confirm SOS/VOD diagnosis .
To date, several lines of evidence have implicated NOTCH dysregulation in a variety of pharmacologic, genetic, and toxicologic models of SD [20–22]. In the current study, we investigated transcriptomic changes associated with anti-cancer drug-induced hepatic SD. We reasoned that the development of this uncommon hepatotoxicity following treatment with either oxaliplatin or anti-DLL4 was related to a similar pathological mechanism involving NOTCH signaling. Here, we have employed a NHP model of anti-DLL4 induced SD, which reliably recapitulates the clinical pathology [12, 15]. We have further investigated the molecular pathogenesis oxaliplatin-induced SD in CRLM patient samples. The protective effect of bev against oxaliplatin-induced SD was interrogated by comparing cases from patients who received oxaliplatin treatment with or without anti-VEGF therapy. Using robust targeted transcriptomics analyses we observed important overlap in the genes altered in both the NHP anti-DLL4- and CRLM oxaliplatin-induced SD models. Genes with expression changes common to both anti-DLL4 and oxaliplatin contexts included EFNB2 (downregulated and upregulated respectively) and IL16 (upregulated in both settings) FDR < 0.05), with CCL2, ERG, ICAM1, LFNG and NOTCH4 (upregulated in both settings; FDR<0.05 in NHP and < 0.25 in oxaliplatin-SD). We also observed significantly higher CDH5 and lower HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 in bev-treated patients ((FDR<0.05). Notably, CDH5, IL16, MMP9, NOTCH4 (upregulated) and HEY1 (down-regulated) (FDR<0.25) were also implicated in the anti-DLL4-induced SD NHP model. Collectively, these findings support the hypothesis that NOTCH signaling pathway plays an important role in the maintenance of sinusoidal homeostasis and further implicates NOTCH in the pathogenesis of anti-cancer drug-induced SD. Moreover, IL16 is identified as a putative novel disease marker. Source: http://doi.org/10.1371/journal.pone.0198099