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Global proteome changes in liver tissue 6 weeks after FOLFOX treatment of colorectal cancer liver metastases
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Pfizer Inc, Pharmacokinet Dynam & Metab, Pfizer Global Res & Dev, Groton, CT 06340 USA.
Max Planck Inst Biochem, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
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2016 (English)In: PROTEOMES, ISSN 2227-7382, Vol. 4, no 4, 30Article in journal (Refereed) Published
Abstract [en]

(1) Oxaliplatin-based chemotherapy for colorectal cancer liver metastasis is associated with sinusoidal injury of liver parenchyma. The effects of oxaliplatin-induced liver injury on the protein level remain unknown. (2) Protein expression in liver tissue was analyzed-from eight patients treated with FOLFOX (combination of fluorouracil, leucovorin, and oxaliplatin) and seven controls-by label-free liquid chromatography mass spectrometry. Recursive feature elimination-support vector machine and Welch t-test were used to identify classifying and relevantly changed proteins, respectively. Resulting proteins were analyzed for associations with gene ontology categories and pathways. (3) A total of 5891 proteins were detected. A set of 184 (3.1%) proteins classified the groups with a 20% error rate, but relevant change was observed only in 55 (0.9%) proteins. The classifying proteins were associated with changes in DNA replication (p < 0.05) through upregulation of the minichromosome maintenance complex and with the innate immune response (p < 0.05). The importance of DNA replication changes was supported by the results of Welch t-test (p < 0.05). (4) Six weeks after FOLFOX treatment, less than 1% of identified proteins showed changes in expression associated with DNA replication, cell cycle entry, and innate immune response. We hypothesize that the changes remain after recovery from FOLFOX treatment injury.

Place, publisher, year, edition, pages
2016. Vol. 4, no 4, 30
Keyword [en]
oxaliplatin-based chemotherapy, protein expression, label-free liquid chromatography mass spectrometry, DNA replication, minichromosome maintenance complex, innate immune response, recovery of liver injury
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-233788DOI: 10.3390/proteomes4040030ISI: 000388105200002OAI: oai:DiVA.org:uu-233788DiVA: diva2:754314
Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2016-12-20Bibliographically approved
In thesis
1. Colorectal Cancer Liver Metastases: Effects of Chemotherapy on Liver Parenchyma and Resections
Open this publication in new window or tab >>Colorectal Cancer Liver Metastases: Effects of Chemotherapy on Liver Parenchyma and Resections
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Current multimodal treatment of colorectal cancer liver metastasis often combines liver resections with preoperative chemotherapy with a 5-year survival of 40-50%. Preoperative chemotherapy includes conversion of initially non-resectable situation and control of micrometastatic disease. Despite its potential advantages also problems with associated steatosis, steatohepatitis and sinusoidal injury has been discussed. Paper I focused on prospective steatosis evaluation prior to resections using proton MR spectroscopy, most sensitive non-invasive method. Proton MR spectroscopy showed high concordance with digital quantification of steatosis and was also able to predict steatohepatitis with 100% sensitivity and 89% specificity without knowing lobular inflammation or hepatocyte ballooning. Paper II focused on portal vein hemodynamics changes in patients treated with oxaliplatin-based treatment and with sinusoidal injury. Magnetic resonance imaging flowmetry demonstrated portal vein dilatation associated with oxaliplatin treatment. Patients with SI showed a tendency towards decreased mean portal flow velocity. Portal vein flow was not changed. This may indicate that SI is associated with an increased resistance to blood flow in the liver parenchyma and stasis in splanchnic system. Paper III attempted to enlighten the effects of FOLFOX treatment on human liver tissue 6 weeks after treatment cessation by quantification of protein expression changes using label-free global proteome analysis. Deep proteome analysis identified 5891 proteins, where machine learning algorithm identified 3% of classifying proteins, associated with changes in DNA replication through upregulation of the minichromosome maintenance complex and with the innate immune response. Significant changes were observed in 1% of proteins, associated with DNA replication and cell cycle entry. Results support the hypothesis that liver has already regenerated from the FOLFOX treatment injury after 6 weeks. Paper IV aimed to identify possible patient, disease and chemotherapy characteristics associated with liver specific and severe general complications in a retrospective single centre cohort composed of 516 consecutive resections. Chemotherapy with more than 4 cycles of oxaliplatin was associated with post-hepatectomy hemorrhage. Underlying liver disease and diabetes mellitus were associated with 90-day mortality. Size of resection, intraoperative blood loss and transfusions were verified as independent predictors of liver specific complications to resections.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 53 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1041
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-233790 (URN)978-91-554-9066-9 (ISBN)
Public defence
2014-11-22, Museum Gustavianum, Auditorium Minus, Akademigatan 3, Uppsala, 09:00 (English)
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Supervisors
Available from: 2014-10-30 Created: 2014-10-10 Last updated: 2015-01-23

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Urdzik, JozefVildhede, AnnaDuraj, FransHaglund, UlfArtursson, PerNorén, Agneta

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