Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model.
Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model.
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发表时间：
2002-08
期刊：
影响因子：
11.2
通讯作者：
Jonathan D. Cheng;Roland L. Dunbrack;Matthildi Valianou;A. Rogatko;R. Alpaugh;L. Weiner
中科院分区：
文献类型：
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作者：
Jonathan D. Cheng;Roland L. Dunbrack;Matthildi Valianou;A. Rogatko;R. Alpaugh;L. Weiner
成纤维细胞活化蛋白（FAP）是一种II型膜糖蛋白，属于丝氨酸蛋白酶家族。人FAP选择性地由上皮癌中的肿瘤基质成纤维细胞表达，但不由上皮癌细胞、正常成纤维细胞或其他正常组织表达。FAP已被证明具有体外二肽基肽酶和胶原酶活性，但其在肿瘤微环境中的生物学功能尚不清楚。小鼠FAP的模型结构由短的胞质尾区、单个疏水跨膜区和大的胞外结构域组成。一个七叶β-螺旋桨结构域位于催化三联体的顶部，可以作为一个“门”，选择性地过滤蛋白质进入催化位点。当异种移植到scid小鼠中时，转染以组成型表达鼠FAP的HEK 293细胞发生s.c.与模拟转染的HEK 293细胞相比，肿瘤生长增强了10-40倍。用重组鼠FAP免疫家兔，产生了多克隆抗FAP抗体，其在体外显著抑制鼠FAP二肽基肽酶活性。与用免疫前兔抗血清处理的肿瘤相比，用这些抑制性抗FAP抗血清处理的HT-29异种移植物表现出减弱的生长。这些数据证明了FAP在动物模型中增强肿瘤生长的能力。此外，抑制FAP蛋白水解活性的抗体可减弱肿瘤生长。这些发现表明FAP活性的功能抑制可能具有治疗作用。
Fibroblast activation protein (FAP) is a type II integral membrane glycoprotein belonging to the serine protease family. Human FAP is selectively expressed by tumor stromal fibroblasts in epithelial carcinomas, but not by epithelial carcinoma cells, normal fibroblasts, or other normal tissues. FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity, but its biological function in the tumor microenvironment is unknown. The modeled structure of murine FAP consists of a short cytoplasmic tail, a single hydrophobic transmembrane region, and a large extracellular domain. A seven-bladed beta-propeller domain is situated on top of the catalytic triad and may serve as a "gate" to selectively filter protein access to the catalytic site. HEK293 cells transfected to constitutively express murine FAP, when xenografted into scid mice, were 2-4 times more likely to develop s.c. tumors and showed a 10-40-fold enhancement of tumor growth compared with mock-transfected HEK293 cells. Rabbits immunized with recombinant murine FAP developed polyclonal anti-FAP antibodies that significantly inhibited murine FAP dipeptidyl peptidase activity in vitro. HT-29 xenografts treated with these inhibitory anti-FAP antisera exhibited attenuated growth compared with tumors treated with preimmunization rabbit antisera. These data demonstrate the ability of FAP to potentiate tumor growth in an animal model. Moreover, tumor growth is attenuated by antibodies that inhibit the proteolytic activity of FAP. These findings suggest a possible therapeutic role for functional inhibition of FAP activity.