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01.01.2012 | Original Article—Alimentary Tract | Ausgabe 1/2012

Journal of Gastroenterology 1/2012

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

Zeitschrift:
Journal of Gastroenterology > Ausgabe 1/2012
Autoren:
Hisashi Takeuchi, Tetsuo Kimura, Koichi Okamoto, Eriko Aoyagi, Hiroshi Miyamoto, Masako Kaji, Hidetaka Takenaka, Seisuke Okamura, Yasushi Sato, Junji Kato, Toshiya Okahisa, Tetsuji Takayama
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00535-011-0470-2) contains supplementary material, which is available to authorized users.

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.

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Zusatzmaterial
Supplemental Fig. 2Double immunofluorescence for MMP-8 and lymphoid surface markers. Double immunofluorescence for MMP-8 and CD20 (ac) or CD3 (df) was performed by our previously reported method [ 14]. A rabbit anti-human MMP-8 polyclonal antibody, mouse anti-human CD20, and CD3 antibodies were used as primary antibodies. Rhodamine-conjugated anti-rabbit immunoglobulin G and fluorescein isothiocyanate conjugated anti-mouse immunoglobulin G were used as secondary antibodies. a CD20, b MMP-8, c merged image, d CD3, e MMP-8, f merged image. MMP-8 was positive in CD20 (+) cells but was negative in CD3 (+) cells. (TIFF 809 kb)
Supplemental Table 1 (DOC 34 kb)
535_2011_470_MOESM3_ESM.doc
Literatur
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