A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors.

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.