A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors
A mechanism for abnormal angiogenesis in human radiation proctitis: analysis of expression profile for angiogenic factors
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DOI：
10.1007/s00535-011-0470-2
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发表时间：
2012-01-01
影响因子：
6.3
通讯作者：
Takayama, Tetsuji
中科院分区：
文献类型：
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作者：
Takeuchi, Hisashi;Kimura, Tetsuo;Takayama, Tetsuji
放射性直肠炎是一个日益普遍的问题，许多患者因盆腔癌接受放射治疗。然而，放射性直肠炎在人类中发展的机制还不清楚。本研究分析了8例放射性直肠炎患者和8例正常人直肠组织中血管生成因子的表达谱，以阐明其在放射性直肠炎病因学中的作用。将组织的蛋白质裂解物应用于血管生成相关因子的抗体阵列。采用Taqman实时荧光定量PCR检测各因子的mRNA水平。免疫组化显示放射性直肠炎组织中血管生成素、成纤维细胞生长因子1（FGF 1）、内皮素、基质金属蛋白酶（MMP）-8、尿激酶型纤溶酶原激活物（uPA）和maspin的表达水平是正常直肠黏膜的2.12 ~ 7.31倍。各因子在放射性直肠炎组织中的mRNA水平均显著高于正常直肠黏膜，提示其转录激活。免疫组织化学染色显示直肠上皮中血管生成素和maspin、浸润淋巴细胞中MMP-8和uPA、成纤维细胞中FGF 1和内皮细胞中endoglin的强表达。提示在放射性直肠炎中，MMP-8和uPA协同降解细胞外基质和基底膜，为血管生成提供空间。同时，血管生成素和FGF 1促进内皮细胞增殖，内皮糖蛋白诱导血管形成，最终导致血管生成。血管生成因子如血管生成素和FGF 1的抑制剂可能对治疗放射性直肠炎有效。
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.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.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.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.