Tumor Microenvironment-Dependent 18F-FDG, 18F-Fluorothymidine, and 18F-Misonidazole Uptake: A Pilot Study in Mouse Models of Human Non-Small Cell Lung Cancer
Tumor Microenvironment-Dependent 18F-FDG, 18F-Fluorothymidine, and 18F-Misonidazole Uptake: A Pilot Study in Mouse Models of Human Non-Small Cell Lung Cancer
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DOI：
10.2967/jnumed.111.098087
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发表时间：
2012-08-01
影响因子：
9.3
通讯作者：
Li, Xiao-Feng
中科院分区：
文献类型：
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作者：
Huang, Tao;Civelek, A. Cahid;Li, Xiao-Feng
F-18-FDG、F-18-fluorothymidine和F-18-misonidazole PET扫描已成为治疗癌症的重要临床工具;然而，它们中没有一种显示出决定性的优越性。本研究的目的是比较F-18-FDG、F-18-氟胸苷和F-18-米索咪唑的肿瘤内蓄积，并将其与人非小细胞肺癌（NSCLC）小鼠模型中肿瘤微环境的特定组分相关联。方法：我们使用NSCLC A549和HTB 177细胞在裸鼠皮下和腹腔建立异种移植瘤。在动物安乐死前1小时，对动物静脉内共注射PET放射性示踪剂、哌莫硝唑（缺氧标记物）和溴脱氧尿苷（增殖标记物）。通过在处死前1分钟给予Hoechst 33342注射来评估肿瘤灌注。PET放射性示踪剂的肿瘤内分布通过数字放射自显影可视化，并与增殖、缺氧、灌注、间质和坏死的显微镜可视化相关。结果：非小细胞肺癌异种移植瘤具有复杂的结构，混合区域的活癌细胞，间质和坏死。癌细胞要么氧合良好（pimonidazole染色阴性）和高度增殖（染色阳性溴脱氧尿苷）或缺氧（pimonidazole阳性）和非循环（很少溴脱氧尿苷）。低增殖率的低分化癌细胞具有高的（18）F-FDG和F-18-misonidazole摄取，但低的F-18-fluorothymidine积累。具有高增殖率的氧合良好的癌细胞积累高水平的F-18-氟胸苷，但低F-18-FDG和F-18-米索咪唑。肿瘤间质和坏死区总是与低F-18-FDG、F-18-misonidazole和F-18-fluorothymidine活性相关。结论：在NSCLC A549和HTB 177皮下或腹膜内生长的异种移植物中，F-18-氟胸苷在氧合良好和增殖的癌细胞中蓄积，而F-18-米索硝唑和F-18-FDG主要在增殖不良和缺氧的癌细胞中蓄积。F-18-FDG和F-18-misonidazole显示出相似的肿瘤内分布模式，并且两者相互排斥F-18-氟胸苷。
F-18-FDG, F-18-fluorothymidine, and F-18-misonidazole PET scans have emerged as important clinical tools in the management of cancer; however, none of them have demonstrated conclusive superiority. The aim of this study was to compare the intratumoral accumulation of F-18-FDG, F-18-fluorothymidine, and F-18-misonidazole and relate this to specific components of the tumor microenvironment in mouse models of human non-small cell lung cancer (NSCLC). Methods: We used NSCLC A549 and HTB177 cells to generate subcutaneous and peritoneal xenografts in nude mice. Animals were coinjected with a PET radiotracer, pimonidazole (hypoxia marker), and bromodeoxyuridine (proliferation marker) intravenously 1 h before animal euthanasia. Tumor perfusion was assessed by Hoechst 33342 injection, given 1 min before sacrifice. The intratumoral distribution of PET radiotracers was visualized by digital autoradiography and related to microscopic visualization of proliferation, hypoxia, perfusion, stroma, and necrosis. Results: NSCLC xenografts had complex structures with intermingled regions of viable cancer cells, stroma, and necrosis. Cancer cells were either well oxygenated (staining negatively for pimonidazole) and highly proliferative (staining positively for bromodeoxyuridine) or hypoxic (pimonidazole-positive) and noncycling (little bromodeoxyuridine). Hypoxic cancer cells with a low proliferation rate had high(18)F-FDG and F-18-misonidazole uptake but low F-18-fluorothymidine accumulation. Well-oxygenated cancer cells with a high proliferation rate accumulated a high level of F-18-fluorothymidine but low F-18-FDG and F-18-misonidazole. Tumor stroma and necrotic zones were always associated with low F-18-FDG, F-18-misonidazole, and F-18-fluorothymidine activity. Conclusion: In NSCLC A549 and HTB177 subcutaneously or intraperitoneally growing xenografts, F-18-fluorothymidine accumulates in well-oxygenated and proliferative cancer cells, whereas F-18-misonidazole and F-18-FDG accumulate mostly in poorly proliferative and hypoxic cancer cells. F-18-FDG and F-18-misonidazole display similar intratumoral distribution patterns, and both mutually exclude F-18-fluorothymidine.