title: A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors.
abstract: BACKGROUND
  Radiation proctitis is an increasingly prevalent problem, with many patients being treated with radiotherapy for pelvic cancers. However, the mechanisms by which radiation proctitis develops in humans are not well understood. In this study, the expression profiles of angiogenic factors were analyzed to clarify their role in the etiology of radiation proctitis.
  
  
  METHODS
  Rectal biopsies were taken from 8 patients with radiation proctitis and 8 normal subjects. Protein lysates of the tissues were applied to an antibody array for angiogenesis-related factors. The mRNA level of each factor was evaluated by Taqman real-time PCR. Immunohistochemistry was performed using the labeled streptavidin biotin method.
  
  
  RESULTS
  Antibody array analysis revealed 2.12- to 7.31-fold higher expression levels of angiogenin, fibroblast growth factor 1 (FGF1), endoglin, matrix metalloproteinase (MMP)-8, urokinase-type plasminogen activator (uPA) and maspin in radiation proctitis tissues compared with normal rectal mucosa. The mRNA level of each factor in radiation proctitis tissue was significantly higher than in normal rectal mucosa, suggesting their transcriptional activation. Immunohistochemical staining showed strong expression of angiogenin and maspin in rectal epithelia, MMP-8 and uPA in infiltrating lymphocytes, FGF1 in fibroblasts and endoglin in endothelial cells. The expression of VEGF was not evident.
  
  
  CONCLUSIONS
  Our results suggest that in radiation proctitis, MMP-8 and uPA cooperatively degrade the extracellular matrix and basement membrane to provide space for angiogenesis. Simultaneously, angiogenin and FGF1 promote endothelial cell proliferation, and endoglin induces vessel formation, culminating in angiogenesis. Inhibitors of angiogenic factors such as angiogenin and FGF1 may be effective for treating radiation proctitis.
authors.affiliation: Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kimura
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Eriko
authors.initials: E
authors.lastname: Aoyagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyamoto
authors.forename: Masako
authors.initials: M
authors.lastname: Kaji
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Takenaka
authors.forename: Seisuke
authors.initials: S
authors.lastname: Okamura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sato
authors.forename: Junji
authors.initials: J
authors.lastname: Kato
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okahisa
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Takayama
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005109:Extracellular Matrix / Q000473:pathology; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000209:etiology* / Q000235:genetics; D010386:Pelvic Neoplasms / Q000532:radiotherapy*; D016133:Polymerase Chain Reaction; D011349:Proctitis / Q000209:etiology*; D012333:RNA, Messenger; D011832:Radiation Injuries / Q000473:pathology*; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D016220:Fibroblast Growth Factor 1; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D014568:Urokinase-Type Plasminogen Activator; D020784:Matrix Metalloproteinase 8
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