Z Gastroenterol 2016; 54(12): 1343-1404
DOI: 10.1055/s-0036-1597496
4. Tumors/Liver Surgery
Georg Thieme Verlag KG Stuttgart · New York

The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma

A Geier
1   University Hospital Würzburg, Würzburg, Division of Hepatology, Department of Medicine II, Würzburg, Germany
,
RIR Macias
2   University of Salamanca, Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, Salamanca, Spain
,
D Bettinger
3   University Hospital Freiburg, Clinic for Internal Medicine II, Department of Medicine, Freiburg, Germany
,
J Weiss
1   University Hospital Würzburg, Würzburg, Division of Hepatology, Department of Medicine II, Würzburg, Germany
,
H Bantel
4   Hannover Medical School, Department of Gastroenterology, Hepatology and Endocrinology, Hannover, Germany
,
D Jahn
1   University Hospital Würzburg, Würzburg, Division of Hepatology, Department of Medicine II, Würzburg, Germany
,
JJ Marin
2   University of Salamanca, Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, Salamanca, Spain
› Author Affiliations
Further Information
Geier, Andreas

Publication History

Publication Date:
19 December 2016 (online)

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    Background: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC), however its beneficial effect is limited by the effectiveness of mechanisms of chemoresistance present in tumor cells, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. Since the organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and OCT1 expression is decreased in HCC, which has been associated with poorer response to sorafenib, here we have elucidated whether the presence of the protein at the plasma membrane rather than the mRNA/protein levels of the transporter was related to the outcome of the pharmacological treatment.

    Methods: The multicenter retrospective study involved liver tumor biopsy in 39 patients with sorafenib therapy for advanced HCC with known outcome (survival, radiological response) of a minimum duration of 4 weeks, collected at three German hospitals (TRANSFER study). Endpoint was the relationship between clinicopathological features and the result of immunohistological examination. Immunostaining was performed on whole sections from paraffin-embedded material using primary anti-OCT1 antibody. Slides were reviewed independently by two observers blinded to clinical data. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, and taking into account the localization of the staining at the plasma membrane as positive or negative.

    Results: The results confirmed OCT1 downregulation in approximately half of the cases investigated (10.3% absent, 38.4% weak). However, only one third of the tumors expressing OCT1 displayed plasma membrane location of the protein (15.4% vs. 35.9% cytosolic expression). When comparing HCC with and without OCT1 expression, no different response to sorafenib was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found in these cases (Log Rank p < 0.001). No association between OCT1 expression at the plasma membrane with the stage of the tumor, the previous treatment with TACE or the radiological response was seen.

    In conclusion, these results indicate that the presence at the plasma membrane, rather than the overall OCT1 expression, is related with better outcome of HCC patients treated with sorafenib. A prospective study is warranted to investigate the use of OCT1 immunostaining for the guidance of systemic HCC treatment.


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    No conflict of interest has been declared by the author(s).

    Geier, Andreas