Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.
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 pa...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2018-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5991753?pdf=render |
| _version_ | 1819240269763051520 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Monika A Jarzabek |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T14:05:20Z |
| format | Article |
| id | doaj.art-fe0051c7ad654064b4d0da667c7b0515 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T14:05:20Z |
| publishDate | 2018-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-fe0051c7ad654064b4d0da667c7b05152022-12-21T17:44:12ZengPublic Library of Science (PLoS)PLoS ONE1932-62032018-01-01136e019809910.1371/journal.pone.0198099Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.Monika A JarzabekWilliam R ProctorJennifer VogtRupal DesaiPatrick DickerGary CainRajiv RajaJens BrodbeckDale StevensEric P van der StokJohn W M MartensCornelis VerhoefPriti S HegdeAnnette T ByrneJacqueline M TarrantDrug-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.http://europepmc.org/articles/PMC5991753?pdf=render |
| spellingShingle | 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 Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. PLoS ONE |
| title | Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. |
| title_full | Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. |
| title_fullStr | Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. |
| title_full_unstemmed | Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. |
| title_short | Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer. |
| title_sort | interrogation of transcriptomic changes associated with drug induced hepatic sinusoidal dilatation in colorectal cancer |
| url | http://europepmc.org/articles/PMC5991753?pdf=render |
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