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

Monika A Jarzabek,Rajiv Raja,Cornelis Verhoef,John W M Martens,Eric P Van Der Stok,William R Proctor,Priti S Hegde,Dale Stevens,Patrick Dicker,Jennifer Vogt,Annette T Byrne,Jens Brodbeck,Jacqueline M Tarrant,Rupal Desai,Gary Cain,Matias A Avila

doi:10.1371/journal.pone.0198099

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.

Highlights

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 include peri-sinusoidal fibrosis and nodular regenerative hyperplasia
SOS/VOD is associated with exposure to pyrrolizidine alkaloid-containing herbal remedies [5], chemotherapy prior to hematopoietic stem cell transplantation [2] and oxaliplatin-based adjuvant or neo-adjuvant chemotherapy for CRLM [6, 7], DLL4 represents an attractive target in cancer therapy due to its role in tumor angiogenesis and its contribution to the maintenance and proliferation of cancer stem cells [8] with several anti-DLL4 antibodies having been developed and tested both in pre-clinical and clinical settings [9,10,11]
principal component analysis (PCA) on the identified gene-set (FDR

Summary

Introduction

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 include peri-sinusoidal fibrosis and nodular regenerative hyperplasia. 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 [4]. SOS/VOD is associated with exposure to pyrrolizidine alkaloid-containing herbal remedies [5], chemotherapy prior to hematopoietic stem cell transplantation [2] and oxaliplatin-based adjuvant or neo-adjuvant chemotherapy for CRLM [6, 7], DLL4 (an endothelium-specific NOTCH ligand) represents an attractive target in cancer therapy due to its role in tumor angiogenesis and its contribution to the maintenance and proliferation of cancer stem cells [8] with several anti-DLL4 antibodies having been developed and tested both in pre-clinical and clinical settings [9,10,11]. Pre-clinical studies in mice, rats and NHP have reported anti-DLL4-associated hepatotoxicity characterized by SD and induction of vascular neoplasms in the liver [11, 12]

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Results

Conclusion