Skip to main content
Top
Published in: European Radiology 10/2011

01-10-2011 | Gastrointestinal

The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging

Authors: Azusa Kitao, Osamu Matsui, Norihide Yoneda, Kazuto Kozaka, Rieko Shinmura, Wataru Koda, Satoshi Kobayashi, Toshifumi Gabata, Yoh Zen, Tatsuya Yamashita, Shuichi Kaneko, Yasuni Nakanuma

Published in: European Radiology | Issue 10/2011

Login to get access

Abstract

Objectives

To clarify the changes in organic anion-transporting polypeptide 8 (OATP8) expression and enhancement ratio on gadoxetic acid-enhanced MR imaging in hepatocellular nodules during multistep hepatocarcinogenesis.

Methods

In imaging analysis, we focused on 71 surgically resected hepatocellular carcinomas (well, moderately and poorly differentiated HCCs) and 1 dysplastic nodule (DN). We examined the enhancement ratio in the hepatobiliary phase of gadoxetic acid enhanced MR imaging [(1/postcontrast T1 value−1/precontrast T1 value)/(1/precontrast T1 value)], then analysed the correlation among the enhancement ratio, tumour differentiation grade and intensity of immunohistochemical OATP8 expression. In pathological analysis, we focused on surgically resected 190 hepatocellular nodules: low-grade DNs, high-grade DNs, early HCCs, well-differentiated, moderately differentiated and poorly differentiated HCCs, including cases without gadoxetic acid-enhanced MR imaging. We evaluated the correlation between the immunohistochemical OATP8 expression and the tumour differentiation grade.

Results

The enhancement ratio of HCCs decreased in accordance with the decline in tumour differentiation (P < 0.0001, R = 0.28) and with the decline of OATP8 expression (P < 0.0001, R = 0.81). The immunohistochemical OATP8 expression decreased from low-grade DNs to poorly differentiated HCCs (P < 0.0001, R = 0.15).

Conclusions

The immunohistochemical expression of OATP8 significantly decreases during multistep hepatocarcinogenesis, which may explain the decrease in enhancement ratio on gadoxetic acid-enhanced MR imaging.
Literature
1.
go back to reference Caldwell S, Park SH (2009) The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol 44(Suppl 19):96–101PubMedCrossRef Caldwell S, Park SH (2009) The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol 44(Suppl 19):96–101PubMedCrossRef
2.
go back to reference Takayama T, Makuuchi M, Hirohashi S et al (1990) Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 336:1150–1153PubMedCrossRef Takayama T, Makuuchi M, Hirohashi S et al (1990) Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 336:1150–1153PubMedCrossRef
3.
go back to reference Sakamoto M, Hirohashi S, Shimosato Y (1991) Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 22:172–178PubMedCrossRef Sakamoto M, Hirohashi S, Shimosato Y (1991) Early stages of multistep hepatocarcinogenesis: adenomatous hyperplasia and early hepatocellular carcinoma. Hum Pathol 22:172–178PubMedCrossRef
4.
go back to reference Matsui O, Kadoya M, Kameyama T et al (1991) Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 178:493–497PubMed Matsui O, Kadoya M, Kameyama T et al (1991) Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 178:493–497PubMed
5.
go back to reference Hayashi M, Matsui O, Ueda K et al (1999) Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. Am J Roentgenol 172:969–976 Hayashi M, Matsui O, Ueda K et al (1999) Correlation between the blood supply and grade of malignancy of hepatocellular nodules associated with liver cirrhosis: evaluation by CT during intraarterial injection of contrast medium. Am J Roentgenol 172:969–976
6.
go back to reference Lencioni R, Piscaglia F, Bolondi L (2008) Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma. J Hepatol 48:848–857PubMedCrossRef Lencioni R, Piscaglia F, Bolondi L (2008) Contrast-enhanced ultrasound in the diagnosis of hepatocellular carcinoma. J Hepatol 48:848–857PubMedCrossRef
7.
go back to reference Ohashi I, Hanafusa K, Yoshida T (1993) Small hepatocellular carcinomas: two-phase dynamic incremental CT in detection and evaluation. Radiology 189:851–855PubMed Ohashi I, Hanafusa K, Yoshida T (1993) Small hepatocellular carcinomas: two-phase dynamic incremental CT in detection and evaluation. Radiology 189:851–855PubMed
8.
go back to reference Hecht EM, Holland AE, Israel GM et al (2006) Hepatocellular carcinoma in the cirrhotic liver: gadolinium-enhanced 3D T1-weighted MR imaging as a stand-alone sequence for diagnosis. Radiology 239:438–447PubMedCrossRef Hecht EM, Holland AE, Israel GM et al (2006) Hepatocellular carcinoma in the cirrhotic liver: gadolinium-enhanced 3D T1-weighted MR imaging as a stand-alone sequence for diagnosis. Radiology 239:438–447PubMedCrossRef
9.
go back to reference Vogl TJ, Kümmel S, Hammerstingl R et al (1996) Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology 200:59–67PubMed Vogl TJ, Kümmel S, Hammerstingl R et al (1996) Liver tumors: comparison of MR imaging with Gd-EOB-DTPA and Gd-DTPA. Radiology 200:59–67PubMed
10.
go back to reference Huppertz A, Balzer T, Blakeborough A et al (2004) European EOB Study Group. Improved detection of focal liver lesions at MR imaging: multicenter comparison of gadoxetic acid-enhanced MR images with intraoperative findings. Radiology 230:266–275PubMedCrossRef Huppertz A, Balzer T, Blakeborough A et al (2004) European EOB Study Group. Improved detection of focal liver lesions at MR imaging: multicenter comparison of gadoxetic acid-enhanced MR images with intraoperative findings. Radiology 230:266–275PubMedCrossRef
11.
go back to reference Schuhmann-Giampieri G, Schmitt-Willich H, Press WR, Negishi C, Weinmann HJ, Speck U (1992) Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology 183:59–64PubMed Schuhmann-Giampieri G, Schmitt-Willich H, Press WR, Negishi C, Weinmann HJ, Speck U (1992) Preclinical evaluation of Gd-EOB-DTPA as a contrast agent in MR imaging of the hepatobiliary system. Radiology 183:59–64PubMed
12.
go back to reference Bartolozzi C, Crocetti L, Lencioni R, Cioni D, Della Pina C, Campani D (2007) Biliary and reticuloendothelial impairment in hepatocarcinogenesis: the diagnostic role of tissue-specific MR contrast media. Eur Radiol 17:2519–2530PubMedCrossRef Bartolozzi C, Crocetti L, Lencioni R, Cioni D, Della Pina C, Campani D (2007) Biliary and reticuloendothelial impairment in hepatocarcinogenesis: the diagnostic role of tissue-specific MR contrast media. Eur Radiol 17:2519–2530PubMedCrossRef
13.
go back to reference Huppertz A, Haraida S, Kraus A et al (2005) Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: correlation with histopathologic findings and spiral CT—initial observations. Radiology 234:468–478PubMedCrossRef Huppertz A, Haraida S, Kraus A et al (2005) Enhancement of focal liver lesions at gadoxetic acid-enhanced MR imaging: correlation with histopathologic findings and spiral CT—initial observations. Radiology 234:468–478PubMedCrossRef
14.
go back to reference Reimer P, Schneider G, Schima W (2004) Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications. Eur Radiol 14:559–578PubMedCrossRef Reimer P, Schneider G, Schima W (2004) Hepatobiliary contrast agents for contrast-enhanced MRI of the liver: properties, clinical development and applications. Eur Radiol 14:559–578PubMedCrossRef
15.
go back to reference Saito K, Kotake F, Ito N et al (2005) Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci 4:1–9PubMedCrossRef Saito K, Kotake F, Ito N et al (2005) Gd-EOB-DTPA enhanced MRI for hepatocellular carcinoma: quantitative evaluation of tumor enhancement in hepatobiliary phase. Magn Reson Med Sci 4:1–9PubMedCrossRef
16.
go back to reference Kogita S, Imai Y, Okada M et al (2010) Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow. Eur Radiol 20:2405–2413PubMedCrossRef Kogita S, Imai Y, Okada M et al (2010) Gd-EOB-DTPA-enhanced magnetic resonance images of hepatocellular carcinoma: correlation with histological grading and portal blood flow. Eur Radiol 20:2405–2413PubMedCrossRef
17.
go back to reference Kitao A, Zen Y, Matsui O et al (2010) Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imaging—correlation with molecular transporters and histopathologic features. Radiology 256:817–826PubMedCrossRef Kitao A, Zen Y, Matsui O et al (2010) Hepatocellular carcinoma: signal intensity at gadoxetic acid-enhanced MR imaging—correlation with molecular transporters and histopathologic features. Radiology 256:817–826PubMedCrossRef
18.
go back to reference Narita M, Hatano E, Arizono S et al (2009) Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 44:793–798PubMedCrossRef Narita M, Hatano E, Arizono S et al (2009) Expression of OATP1B3 determines uptake of Gd-EOB-DTPA in hepatocellular carcinoma. J Gastroenterol 44:793–798PubMedCrossRef
19.
go back to reference Leonhardt M, Keiser M, Oswald S et al (2010) Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos 38:1024–1028PubMedCrossRef Leonhardt M, Keiser M, Oswald S et al (2010) Hepatic uptake of the magnetic resonance imaging contrast agent Gd-EOB-DTPA: role of human organic anion transporters. Drug Metab Dispos 38:1024–1028PubMedCrossRef
20.
go back to reference Ishimori Y, Kimura H, Uematsu H, Matsuda T, Itoh H (2003) Dynamic T1 estimation of brain tumors using double-echo dynamic MR imaging. J Magn Reson Imaging 18:113–120PubMedCrossRef Ishimori Y, Kimura H, Uematsu H, Matsuda T, Itoh H (2003) Dynamic T1 estimation of brain tumors using double-echo dynamic MR imaging. J Magn Reson Imaging 18:113–120PubMedCrossRef
21.
go back to reference Hayashi N, Miyati T, Koda W et al (2010) Quantitative evaluation of Gd-EOB-DTPA uptake in phantom study for liver MRI. Jpn J Radiol Technol 66:502–508, Japanese Hayashi N, Miyati T, Koda W et al (2010) Quantitative evaluation of Gd-EOB-DTPA uptake in phantom study for liver MRI. Jpn J Radiol Technol 66:502–508, Japanese
22.
go back to reference Hirohashi S, Ishak KG, Kojiro M et al (2000) Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics of tumours of the digestive system. IARC Press, Lyon, pp 157–172 Hirohashi S, Ishak KG, Kojiro M et al (2000) Hepatocellular carcinoma. In: Hamilton SR, Aaltonen LA (eds) Pathology and genetics of tumours of the digestive system. IARC Press, Lyon, pp 157–172
23.
go back to reference International Consensus Group for Hepatocellular Neoplasia (2009) Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49:658–664CrossRef International Consensus Group for Hepatocellular Neoplasia (2009) Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49:658–664CrossRef
24.
go back to reference Takano M, Otani Y, Tanda M, Kawami M, Nagai J, Yumoto R (2009) Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. Drug Metab Pharmacokinet 24:418–427PubMedCrossRef Takano M, Otani Y, Tanda M, Kawami M, Nagai J, Yumoto R (2009) Paclitaxel-resistance conferred by altered expression of efflux and influx transporters for paclitaxel in the human hepatoma cell line, HepG2. Drug Metab Pharmacokinet 24:418–427PubMedCrossRef
25.
go back to reference Vavricka SR, Jung D, Fried M, Grützner U, Meier PJ, Kullak-Ublick GA (2004) The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. J Hepatol 40:212–218PubMedCrossRef Vavricka SR, Jung D, Fried M, Grützner U, Meier PJ, Kullak-Ublick GA (2004) The human organic anion transporting polypeptide 8 (SLCO1B3) gene is transcriptionally repressed by hepatocyte nuclear factor 3beta in hepatocellular carcinoma. J Hepatol 40:212–218PubMedCrossRef
26.
go back to reference Cui Y, König J, Nies AT et al (2003) Detection of the human organic anion transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in liver and hepatocellular carcinoma. Lab Invest 83:527–538PubMed Cui Y, König J, Nies AT et al (2003) Detection of the human organic anion transporters SLC21A6 (OATP2) and SLC21A8 (OATP8) in liver and hepatocellular carcinoma. Lab Invest 83:527–538PubMed
27.
go back to reference Hayashi Y, Wang W, Ninomiya T, Nagano H, Ohta K, Itoh H (1999) Liver enriched transcription factors and differentiation of hepatocellular carcinoma. Mol Pathol 52:19–24PubMedCrossRef Hayashi Y, Wang W, Ninomiya T, Nagano H, Ohta K, Itoh H (1999) Liver enriched transcription factors and differentiation of hepatocellular carcinoma. Mol Pathol 52:19–24PubMedCrossRef
28.
go back to reference Pascolo L, Petrovic S, Cupelli F et al (2001) Abc protein transport of MRI contrast agents in canalicular rat liver plasma vesicles and yeast vacuoles. Biochem Biophys Res Commun 282:60–66PubMedCrossRef Pascolo L, Petrovic S, Cupelli F et al (2001) Abc protein transport of MRI contrast agents in canalicular rat liver plasma vesicles and yeast vacuoles. Biochem Biophys Res Commun 282:60–66PubMedCrossRef
29.
go back to reference Asayama Y, Tajima T, Nishie A et al (2010) Uptake of Gd-EOB-DTPA by hepatocellular carcinoma: radiologic-pathologic correlation with special reference to bile production. Eur J Radiol. doi:10.1016/j.ejrad.2010.10.032 Asayama Y, Tajima T, Nishie A et al (2010) Uptake of Gd-EOB-DTPA by hepatocellular carcinoma: radiologic-pathologic correlation with special reference to bile production. Eur J Radiol. doi:10.​1016/​j.​ejrad.​2010.​10.​032
Metadata
Title
The uptake transporter OATP8 expression decreases during multistep hepatocarcinogenesis: correlation with gadoxetic acid enhanced MR imaging
Authors
Azusa Kitao
Osamu Matsui
Norihide Yoneda
Kazuto Kozaka
Rieko Shinmura
Wataru Koda
Satoshi Kobayashi
Toshifumi Gabata
Yoh Zen
Tatsuya Yamashita
Shuichi Kaneko
Yasuni Nakanuma
Publication date
01-10-2011
Publisher
Springer-Verlag
Published in
European Radiology / Issue 10/2011
Print ISSN: 0938-7994
Electronic ISSN: 1432-1084
DOI
https://doi.org/10.1007/s00330-011-2165-8

Other articles of this Issue 10/2011

European Radiology 10/2011 Go to the issue