Radiotherapy Decreases Vascular Density and Causes Hypoxia with Macrophage Aggregation in TRAMP-C1 Prostate Tumors

被引:112
作者
Chen, Fang-Hsin [1 ,5 ]
Chiang, Chi-Shiun [1 ]
Wang, Chun-Chieh [3 ,5 ]
Tsai, Chien-Sheng [3 ,5 ]
Jung, Shih-Ming [2 ]
Lee, Chung-Chi [3 ]
McBride, William H. [4 ]
Hong, Ji-Hong [3 ,5 ]
机构
[1] Natl Tsing Hua Univ, Dept Biomed Engn & Environm Sci, Hsinchu, Taiwan
[2] Chang Gung Mem Hosp Linkou, Dept Pathol, Tao Yuan, Taiwan
[3] Chang Gung Univ, Dept Med Imaging & Radiol Sci, Tao Yuan, Taiwan
[4] Univ Calif Los Angeles, Dept Radiat Oncol, Roy E Coats Res Labs, Los Angeles, CA 90024 USA
[5] Chang Gung Mem Hosp Linkou, Dept Radiat Oncol, Tao Yuan, Taiwan
关键词
GENE-EXPRESSION; BREAST-CANCER; NITRIC-OXIDE; STEM-CELLS; ANGIOGENESIS; MECHANISMS; APOPTOSIS; THERAPY; GROWTH; HIF-1;
D O I
10.1158/1078-0432.CCR-08-1471
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Purpose: To investigate how single or fractionated doses of radiation change the microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors with respect to vascularity, hypoxia, and macrophage infiltrates. Experimental Design: Murine prostate TRAMP-C1 tumors were grown in C57BL/6J mice to 4 mm tumor diameter and were irradiated with either 25 Gy in a single dose or 60 Gy in 15 fractions. Changes in vascularity, hypoxia, and macrophage infiltrates were assessed by immunohistochemistry and molecular assays. Results: Tumor growth was delayed for 1 week after both radiation schedules. Tumor microvascular density (MVD) progressively decreased over a 3-week period to nadirs of 25% and 40% of unirradiated tumors for single or fractionated treatment, respectively. In accord with the decrease in MVDs, mRNA levels of endothelial markers, such as CD31, endoglin, and TIE, decreased over the same time period after irradiation. Central dilated vessels developed surrounded by avascularized hypoxic regions that became infiltrated with aggregates of CD68+ tumor-associated macrophages, reaching a maximum at 3 weeks after irradiation. Necrotic regions decreased and were more dispersed. Conclusion: Irradiation of TRAMP-Cl tumors with either single or fractionated doses decreases MVD, leading to the development of disperse chronic hypoxic regions, which are infiltrated with CD68+ tumor-associated macrophages. Approaches to interfere in the development of these effects are promising strategies to enhance the efficacy of cancer radiotherapy.
引用
收藏
页码:1721 / 1729
页数:9
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