Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors.
OBJECTIVE
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.


METHODS
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.


CONCLUSIONS
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.
Chen
Fang-Hsin
FH
Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
Chiang
Chi-Shiun
CS
Wang
Chun-Chieh
CC
Tsai
Chien-Sheng
CS
Jung
Shih-Ming
SM
Lee
Chung-Chi
CC
McBride
William H
WH
Hong
Ji-Hong
JH
D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D015687:Cell Hypoxia / Q000528:radiation effects*; D004195:Disease Models, Animal; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000473:pathology / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000532:radiotherapy*; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011829:Radiation Dosage; D012260:Ribonucleases / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D012334:RNA, Neoplasm; D012260:Ribonucleases; C067980:CD68 antigen, human; D000097382:CD68 Molecule