title: Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: Fang-Hsin
authors.initials: FH
authors.lastname: Chen
authors.forename: Chi-Shiun
authors.initials: CS
authors.lastname: Chiang
authors.forename: Chun-Chieh
authors.initials: CC
authors.lastname: Wang
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Tsai
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Jung
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: William H
authors.initials: WH
authors.lastname: McBride
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Hong
mesh_terms: 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
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D012334:RNA, Neoplasm; D012260:Ribonucleases; C067980:CD68 antigen, human; D000097382:CD68 Molecule