Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma.
Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma.
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DOI：
10.3892/ijo.2012.1624
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发表时间：
2012-11
影响因子：
5.2
通讯作者：
Kuge Y
中科院分区：
文献类型：
--
作者：
Murakami M;Zhao S;Zhao Y;Chowdhury NF;Yu W;Nishijima K;Takiguchi M;Tamaki N;Kuge Y
抗血管生成治疗后“肿瘤饥饿”与“血管正常化”的机械分离是实验研究领域中激烈争论的主题。此外，准确评估抗血管生成治疗后肿瘤微环境的变化对于优化治疗策略至关重要。索拉非尼具有相当大的抗血管生成作用，其导致高度血管化的肾细胞癌（RCC）异种移植物中的肿瘤饥饿并诱导肿瘤缺氧。18F-FMISO（18F-fluoromisonidazole）是一种经证实的缺氧成像探针。因此，为了阐明抗血管生成治疗后肿瘤微环境的早期变化以及18F-FMISO成像是否可以检测到这些变化，我们通过连续组织学分析和18F-FMISO放射自显影（ARG）评估了RCC异种移植物中索拉非尼治疗后肿瘤微环境的早期变化。在裸鼠中建立人RCC异种移植物（A498），用于组织学研究和ARG，并进一步分配至对照组和索拉非尼给药组（80 mg/kg，经口）。在组织学研究中，在索拉非尼处理后的第1、2、3和7天处死小鼠，在ARG中，在索拉非尼处理后的第3和7天处死小鼠。每天测量肿瘤体积。处死前4 h和2 h分别静脉注射18F-FMISO和哌莫硝唑。肿瘤切片用苏木精和伊红染色，用哌莫硝唑和CD 31化学染色。在ARG中定量肿瘤内18F-FMISO分布。肿瘤体积在索拉非尼治疗后第7天没有显著变化。在组织学研究中，索拉非尼治疗后第2天缺氧分数显著增加，第1天平均血管密度显著降低，第2天坏死面积显著增加。肿瘤内18F-FMISO分布在索拉非尼治疗后第3天（10.2倍，p <0.01）和第7天（4.1倍，p <0.01）显著增加。肿瘤微环境的连续组织学评价澄清了用索拉非尼处理的A498异种移植物中的肿瘤饥饿。18F-FMISO乏氧显像证实肿瘤饥饿。18F-FMISO PET可能有助于确定抗血管生成治疗后的最佳治疗方案。
The mechanistic dissociation of ‘tumor starvation’ versus ‘vascular normalization’ following anti-angiogenic therapy is a subject of intense controversy in the field of experimental research. In addition, accurately evaluating changes of the tumor microenvironment after anti-angiogenic therapy is important for optimizing treatment strategy. Sorafenib has considerable anti-angiogenic effects that lead to tumor starvation and induce tumor hypoxia in the highly vascularized renal cell carcinoma (RCC) xenografts. 18F-fluoromisonidazole (18F-FMISO) is a proven hypoxia imaging probe. Thus, to clarify early changes in the tumor microenvironment following anti-angiogenic therapy and whether 18F-FMISO imaging can detect those changes, we evaluated early changes in the tumor microenvironment after sorafenib treatment in an RCC xenograft by sequential histological analysis and 18F-FMISO autoradiography (ARG). A human RCC xenograft (A498) was established in nude mice, for histological studies and ARG, and further assigned to the control and sorafenib-treated groups (80 mg/kg, per os). Mice were sacrificed on Days 1, 2, 3 and 7 in the histological study, and on Days 3 and 7 in ARG after sorafenib treatment. Tumor volume was measured every day. 18F-FMISO and pimonidazole were injected intravenously 4 and 2 h before sacrifice, respectively. Tumor sections were stained with hematoxylin and eosin and immunohistochemically with pimonidazole and CD31. Intratumoral 18F-FMISO distribution was quantified in ARG. Tumor volume did not significantly change on Day 7 after sorafenib treatment. In the histological study, hypoxic fraction significantly increased on Day 2, mean vessel density significantly decreased on Day 1 and necrosis area significantly increased on Day 2 after sorafenib treatment. Intratumoral 18F-FMISO distribution significantly increased on Days 3 (10.2-fold, p<0.01) and 7 (4.1-fold, p<0.01) after sorafenib treatment. The sequential histological evaluation of the tumor microenvironment clarified tumor starvation in A498 xenografts treated with sorafenib. 18F-FMISO hypoxia imaging confirmed the tumor starvation. 18F-FMISO PET may contribute to determine an optimum treatment protocol after anti-angiogenic therapy.
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影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
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