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Published on: February 6, 2019
Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors
Fang-Hsin Chen1, Chi-Shiun Chiang, Chun-Chieh Wang
1Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
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-C1 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.
Insights
Radiation therapy decreases tumor vascularity, causing hypoxia and attracting macrophages. Targeting these changes may improve cancer treatment efficacy.
Area of Science:
- Oncology
- Radiation Oncology
- Tumor Microenvironment Research
Background:
- The tumor microenvironment significantly influences radiotherapy response.
- Understanding radiation-induced changes in tumor vascularity, hypoxia, and immune cell infiltration is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the effects of single versus fractionated radiation doses on the tumor microenvironment in transgenic adenocarcinoma of the mouse prostate (TRAMP)-C1 tumors.
- To assess changes in vascularity, hypoxia, and macrophage infiltrates following irradiation.
Main Methods:
- TRAMP-C1 murine prostate tumors were irradiated with either a single 25 Gy dose or 60 Gy in 15 fractions.
- Immunohistochemistry and molecular assays were employed to evaluate vascularity, hypoxia, and macrophage infiltration.
Main Results:
- Both radiation schedules delayed tumor growth. Tumor microvascular density (MVD) decreased significantly over 3 weeks post-irradiation.
- Irradiation led to the development of hypoxic regions infiltrated by CD68+ tumor-associated macrophages.
- Endothelial marker mRNA levels decreased, correlating with reduced MVD.
Conclusions:
- Single or fractionated radiation doses reduce MVD, inducing chronic hypoxic regions infiltrated by macrophages.
- Targeting these radiation-induced microenvironmental changes presents a promising strategy to enhance radiotherapy efficacy.
