title: Vasculatures in tumors growing from preirradiated tissues: formed by vasculogenesis and resistant to radiation and antiangiogenic therapy.
abstract: OBJECTIVE
  To investigate vasculatures and microenvironment in tumors growing from preirradiated tissues (pre-IR tumors) and study the vascular responses of pre-IR tumors to radiation and antiangiogenic therapy.
  
  
  METHODS
  Transgenic adenocarcinoma of the mouse prostate C1 tumors were implanted into unirradiated or preirradiated tissues and examined for vascularity, hypoxia, and tumor-associated macrophage (TAM) infiltrates by immunohistochemistry. The origin of tumor endothelial cells was studied by green fluorescent protein-tagged bone marrow (GFP-BM) transplantation. The response of tumor endothelial cells to radiation and antiangiogenic agent was evaluated by apoptotic assay.
  
  
  RESULTS
  The pre-IR tumors had obvious tumor bed effects (TBE), with slower growth rate, lower microvascular density (MVD), and more necrotic and hypoxic fraction compared with control tumors. The vessels were dilated, tightly adhered with pericytes, and incorporated with transplanted GFP-BM cells. In addition, hypoxic regions became aggregated with TAM. As pre-IR tumors developed, the TBE was overcome at the tumor edge where the MVD increased, TAM did not aggregate, and the GFP-BM cells did not incorporate into the vessels. The vessels at tumor edge were more sensitive to the following ionizing radiation and antiangiogenic agent than those in the central low MVD regions.
  
  
  CONCLUSIONS
  This study demonstrates that vasculatures in regions with TBE are mainly formed by vasculogenesis and resistant to radiation and antiangiogenic therapy. Tumor bed effects could be overcome at the edge of larger tumors, but where vasculatures are formed by angiogenesis and sensitive to both treatments. Vasculatures formed by vasculogenesis should be the crucial target for the treatment of recurrent tumors after radiotherapy.
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, 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: Sheng-Yung
authors.initials: SY
authors.lastname: Fu
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Tsai
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Jung
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Wen
authors.forename: Chung-Chi
authors.initials: CC
authors.lastname: Lee
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Hong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D016026:Bone Marrow Transplantation; D002449:Cell Aggregation / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004396:Coloring Agents; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D042783:Endothelial Cells / Q000187:drug effects / Q000528:radiation effects; D049452:Green Fluorescent Proteins; D007211:Indoles / Q000627:therapeutic use; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009364:Neoplasm Recurrence, Local / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009381:Neoplasms, Radiation-Induced / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000532:radiotherapy; D009593:Nitroimidazoles; D011471:Prostatic Neoplasms; D011758:Pyrroles / Q000627:therapeutic use; D011829:Radiation Dosage; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents; D016879:Salvage Therapy / Q000379:methods; D000077210:Sunitinib; D047368:Tumor Burden / Q000502:physiology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D020533:Angiogenesis Inhibitors; D004396:Coloring Agents; D007211:Indoles; D009593:Nitroimidazoles; D011758:Pyrroles; D011838:Radiation-Sensitizing Agents; D049452:Green Fluorescent Proteins; C033815:pimonidazole; D000077210:Sunitinib