Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinomas

Department of Surgery, Graduate School of Medicine, Kyoto University, and Department of Diagnostic Pathology, Kyoto University Hospital, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan.
Journal of Gastroenterology (Impact Factor: 4.52). 04/2009; 44(7):793-8. DOI: 10.1007/s00535-009-0056-4
Source: PubMed


Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) is an MRI contrast agent with perfusion and hepatoselective properties. The purpose of the study was to examine uptake of Gd-EOB-DTPA in the hepatobiliary phase in hepatocellular carcinoma (HCC).
A retrospective analysis of 22 patients with HCC who underwent preoperative Gd-EOB-DTPA-enhanced MRI was performed. Enhancement ratios (ERs) and expression levels of the organic anion transporter (OATP) 1B3 protein were examined.
Gd-EOB-DTPA accumulated in the hepatobiliary phase in 6 of the 22 cases. All 6 Gd-EOB-DTPA-positive cases were moderately differentiated HCC, but 11 other moderately differentiated HCCs did not show Gd-EOB-DTPA uptake. Histopathologically, 4 Gd-EOB-DTPA-positive HCCs and 5 Gd-EOB-DTPA-negative HCCs produced bile. HCCs with Gd-EOB-DTPA uptake overexpressed OATP1B3 compared with HCCs without Gd-EOB-DTPA uptake, and OATP1B3 levels were significantly correlated with ERs (r=0.91, P<0.0001).
Uptake of Gd-EOB-DTPA in HCC is determined by expression of OATP1B3 rather than by tumor differentiation or bile production.

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Available from: Koji Kitamura, Oct 03, 2015
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    • "It has been suggested that signal-intensity patterns on HP images of hypervascular, progressed HCC depend on the expression of OATP1B3 [28, 29] and may be related to the expression pattern of multidrug resistance protein (MRP) 2 within the nodules [30]. However, it is still unknown whether this theory can be also extended to the evaluation of early HCC, as there has been a lack of data directly comparing the signal intensity on HP images with OATP1B3 expression in early HCC. "
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    ABSTRACT: Objective After much debate, the International Consensus Group for Hepatocellular Neoplasia (ICGHN) has recently arrived at a conclusion regarding the pathological criteria for early hepatocellular carcinoma (HCC). They have stated that stromal invasion should be recognized as the most important pathological finding for precisely diagnosing and differentiating early HCC from dysplastic nodules (DN). Methods We conducted a review of the imaging findings from multi-imaging modalities of early HCC cases diagnosed according to the pathological criteria of the ICGHN. The multi-imaging modalities included gadoxetic acid (Gd-EOB-DTPA) enhanced magnetic resonance imaging (MRI), abbreviated as EOB-MRI, contrast-enhanced CT (CE-CT), CT during arterioportography (CTAP), and CT during hepatic arteriography (CTHA). It has been shown that EOB-MRI is the only imaging modality that has sufficient resolution for the detection and classification of early HCC. Results The most significant imaging feature for diagnosing early HCC was hypointensity on hepatobiliary-phase (HP) images of EOB-MRI; all of the cases of early HCC that were detected on HP images of EOB-MRI showed hypointensity, while all of the images of DN showed isointensity or hyperintensity compared with the liver parenchyma. The results of the diagnostic performance analysis showed that EOB-MRI had excellent sensitivity (97%) for detecting early HCC and outstanding specificity (100%) for distinguishing early HCC from DN. Conclusions Considering the results from imaging-pathologic correlations and follow-up studies indicating that many early-stage hepatocellular nodules showing hypointensity on HP images of EOB-MRI tend to develop hypervascularization during a relatively short follow-up period, it is beginning to be accepted that such nodules may be treated as early HCC. However, hepatologists and radiologists should also recognize that some cases of early HCC may show isointensity or hyperintensity on HP images of EOB-MRI, making it impossible to differentiate early HCC from DN, although the low prevalence of such nodules may be unlikely to affect the generally accepted follow-up protocols for cirrhotic patients. Our results and other recent reports have indicated that signal-intensity patterns on HP images of EOB-MRI for DN and early HCC directly correlate with the degree of expression of the organic anion transporting polypeptide (OATP) 1B3 in the nodules. Thus, the diagnostic performance of pathological analyses for early HCC cases may be dramatically improved, nearly up to that of EOB-MRI, by incorporating an OATP1B3 staining method.
    05/2014; 3(2):97-107. DOI:10.1159/000343865
    • "docetaxel [134] paclitaxel [134] SN-38 [128] liver; basolateral a,b [123] [125] [187] prostate a [147] small intestine a [169] breast cancer b [141] colon polyp (no change) a [62] colon cancer (no change) a [62] colon cancer (increased) a,b [125] colon cancer a,b [123] gastric cancer a,b [123] hepatocellular carcinoma (de- creased) a,b [132] hepatocellular carcinoma b [130] [131] non-small cell lung cancer (in- creased) a [87] pancreatic cancer a,b [123] prostate cancer (no change) a [147] prostate cancer metastasis (in- creased) a [147] OATP1C1 SLCO1C1 brain a [188] eye pars plana ciliary body epithelium; basolateral b [183] lung a [87] testis; Leydig cells a,b [188] brain glioma a [151] non-small cell lung cancer (no change) a [87] OATP2A1 SLCO2A1 brain a [189] breast a [142] colon a [189] eye a [190] heart a [189] kidney a [189] liver a [189] lung a [87] [189] prostate a [147] skeletal muscle a [189] small intestine a [189] testis a [189] breast cancer (no change) a [142] prostate (no change) a [147] prostate cancer metastasis (in- creased) a [147] non-small cell lung cancer (de- creased) a [87] OATP2B1 SLCO2B1 brain capillary endothelium; basolateral (abluminal) b [151] breast lactiferous epithelium a,b [144] [162] [191] colon a [192] [193] eye pars plana ciliary body epithelium; basolateral b [183] heart a [194] kidney a [194] liver; basolateral a,b [194] lung a [87] [194] ovary a [194] prostate a [147] skin a,b [195] small intestine a,b [169] [196] spleen a [194] brain glioma a [151] breast cancer (no change) a [143] breast cancer (decreased) a [142] breast cancer (no change) a,b [144] non-small cell lung cancer (no change) a [87] prostate (no change) a [147] prostate cancer metastasis (in- creased) a [147] "
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    ABSTRACT: The effectiveness of many anticancer agents is dependent on their disposition to the intracellular space of cancerous tissue. Accumulation of anticancer drugs at their sites of action can be altered by both uptake and efflux transport proteins, however the majority of research on the disposition of anticancer drugs has focused on drug efflux transporters and their ability to confer multidrug resistance. Here we review the roles of uptake transporters of the SLC22A and SLCO families in the context of cancer therapy. The many first-line anticancer drugs that are substrates of organic cation transporters (OCTs) organic cation/carnitine transporters (OCTNs) and organic anion- transporting polypeptides (OATPs) are summarized. In addition, where data is available a comparison of the localization of drug uptake transporters in healthy and cancerous tissues is provided. Expression of drug uptake transporters increases the sensitivity of cancer cell lines to anticancer substrates. Furthermore, early observational studies have suggested a causal link between drug uptake transporter expression and positive outcome in some cancers. Quantification of drug transporters by mass spectrometry will provide an essential technique for generation of expression data during future observational clinical studies. Screening of drug uptake transporter expression in primary tumors may help differentiate between susceptible and resistant cancers prior to therapy.
    Current Drug Metabolism 07/2011; 12(8):793-807. DOI:10.2174/138920011798357060 · 2.98 Impact Factor
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    • "Narita et al60 investigated the uptake of gadoxetic acid in the hepatobiliary phase in HCC. Enhancement ratios (ERs) and expression levels of the organic anion transporter (OATP) 1B3 protein were examined. "
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    ABSTRACT: The value of cross-sectional liver imaging is evaluated by the accuracy, sensitivity, and specificity of the specific imaging technique. Magnetic resonance imaging (MRI) has become a key technique for the characterization and detection of focal and diffuse liver disease. More recently, gadoxetic acid, the hepatocyte-specific MR contrast agent, was clinically approved and introduced in many countries. Gadoxetic acid may be considered a "molecular imaging" probe because the compound is actively taken into hepatocytes via the ATP-dependent organic anion transport system in the plasma membrane for the hepatic uptake. The transport of gadoxetic acid from the cytoplasm to the bile is mainly determined by the capacity of the transport protein glutathione-S-transferase. Gadoxetic acid enhances hepatocyte-containing lesions and improves detection of lesions devoid of normal hepatocytes, such as metastases. Innovative rapid MR acquisition techniques with near isotropic 3D pulse sequences with fat saturation parallel the technical progress made by multidetector computed tomography combined with an impressive improvement in tumor-liver contrast when used for gadoxetic acid-enhanced MRI. The purpose of this review is to provide an overview of the development, clinical testing, and applications of this novel MR contrast agent.
    Biologics: Targets & Therapy 08/2010; 4:199-212. DOI:10.2147/BTT.S6479
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