Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma

Murakami,Masahiro; Zhao,Songji; Zhao,Yan; Chowdhury,Nusrat  Fatema; Yu,Wenwen; Nishijima,Ken-Ichi; Takiguchi,Mitsuyoshi; Tamaki,Nagara; Kuge,Yuji

doi:10.3892/ijo.2012.1624

Evaluation of changes in the tumor microenvironment after sorafenib therapy by sequential histology and 18F-fluoromisonidazole hypoxia imaging in renal cell carcinoma

Authors:
- Masahiro Murakami
- Songji Zhao
- Yan Zhao
- Nusrat Fatema Chowdhury
- Wenwen Yu
- Ken-Ichi Nishijima
- Mitsuyoshi Takiguchi
- Nagara Tamaki
- Yuji Kuge
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Affiliations: Laboratory of Veterinary Internal Medicine, Graduate School of Veterinary Medicine, Hokkaido University, Kita-ku, Sapporo 060-0818, Japan, Department of Nuclear Medicine, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan, Department of Tracer Kinetics and Bioanalysis, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan, Central Institute of Isotope Science, Hokkaido University, Kita-ku, Sapporo 060-0815, Japan
Published online on: September 10, 2012 https://doi.org/10.3892/ijo.2012.1624
Pages: 1593-1600
Copyright: © Murakami et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

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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