实验性肿瘤中18F-FDG分布的瘤内异质性与葡萄糖转运蛋白和己糖激酶-II区域表达的生物学关联

Biologic correlates of intratumoral heterogeneity in 18F-FDG distribution with regional expression of glucose transporters and hexokinase-II in experimental tumor.

作者信息

Zhao Songji, Kuge Yuji, Mochizuki Takafumi, Takahashi Toshiyuki, Nakada Kunihiro, Sato Masayuki, Takei Toshiki, Tamaki Nagara

机构信息

Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

出版信息

J Nucl Med. 2005 Apr;46(4):675-82.

PMID:15809491

Abstract

UNLABELLED

The biologic mechanisms involved in the intratumoral heterogeneous distribution of 18F-FDG have not been fully investigated. To clarify factors inducing heterogeneous 18F-FDG distribution, we determined the intratumoral distribution of 18F-FDG by autoradiography (ARG) and compared it with the regional expression levels of glucose transporters Glut-1 and Glut-3 and hexokinase-II (HK-II) in a rat model of malignant tumor.

METHODS

Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle (n = 7). Tumor tissues were excised 1 h after the intravenous injection of 18F-FDG and sectioned to obtain 2 adjacent slices for ARG and histochemical studies. The regions of interest (ROIs) were placed on ARG images to cover mainly the central (CT) and peripheral (PT) regions of viable tumor tissues and necrotic/apoptotic (NA) regions. The radioactivity in each ROI was analyzed quantitatively using a computerized imaging analysis system. The expression levels of Glut-1, Glut-3, and HK-II were determined by immunostaining and semiquantitative evaluation. The hypoxia-inducible factor 1 (HIF-1) was also immunostained.

RESULTS

ARG images showed that intratumoral 18F-FDG distribution was heterogeneous. The accumulation of 18F-FDG in the CT region was the highest, which was 1.6 and 2.3 times higher than those in the PT and NA regions, respectively (P < 0.001). The expression levels of Glut-1, Glut-3, and HK-II were markedly higher in the CT region (P < 0.001) compared with those in the PT region. The intratumoral distribution of 18F-FDG significantly correlated with the expression levels of Glut-1, Glut-3, and HK-II (r = 0.923, P < 0.001 for Glut-1; r = 0.829, P < 0.001 for Glut-3; and r = 0.764, P < 0.01 for HK-II). The positive staining of HIF-1 was observed in the CT region.

CONCLUSION

These results demonstrate that intratumoral 18F-FDG distribution corresponds well to the expression levels of Glut-1, Glut-3, and HK-II. The elevated expression levels of Glut-1, Glut-3, and HK-II, induced by hypoxia (HIF-1), may be contributing factors to the higher 18F-FDG accumulation in the CT region.

摘要

未标记

18F-FDG在肿瘤内异质性分布所涉及的生物学机制尚未得到充分研究。为了阐明导致18F-FDG分布异质性的因素，我们通过放射自显影（ARG）测定了18F-FDG在肿瘤内的分布，并将其与恶性肿瘤大鼠模型中葡萄糖转运蛋白Glut-1、Glut-3和己糖激酶-II（HK-II）的区域表达水平进行了比较。

方法

将同种异体肝癌细胞（KDH-8）接种到大鼠左小腿肌肉中（n = 7）。静脉注射18F-FDG后1小时切除肿瘤组织，切片以获得相邻的两片用于ARG和组织化学研究。在ARG图像上放置感兴趣区域（ROI），主要覆盖存活肿瘤组织的中央（CT）和周边（PT）区域以及坏死/凋亡（NA）区域。使用计算机成像分析系统对每个ROI中的放射性进行定量分析。通过免疫染色和半定量评估确定Glut-1、Glut-3和HK-II的表达水平。还对缺氧诱导因子1（HIF-1）进行了免疫染色。

结果

ARG图像显示肿瘤内18F-FDG分布是异质性的。18F-FDG在CT区域的积聚最高，分别比PT区域和NA区域高1.6倍和2.3倍（P < 0.001）。与PT区域相比，CT区域中Glut-1、Glut-3和HK-II的表达水平明显更高（P < 0.001）。18F-FDG在肿瘤内的分布与Glut-1、Glut-3和HK-II的表达水平显著相关（Glut-1：r = 0.923，P < 0.001；Glut-3：r = 0.829，P < 0.001；HK-II：r = 0.764，P < 0.01）。在CT区域观察到HIF-1的阳性染色。