Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells
Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells
复制标题
成纤维细胞激活蛋白调节肿瘤相关成纤维细胞和上皮性卵巢癌细胞
DOI：
10.3892/ijo.2012.1475
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发表时间：
2012-08-01
影响因子：
5.2
通讯作者：
Wang, Fangyuan
中科院分区：
文献类型：
--
作者：
Lai, Dongmei;Ma, Li;Wang, Fangyuan
成纤维细胞活化蛋白（FAP）是一种细胞表面丝氨酸蛋白酶，已成为肿瘤相关成纤维细胞（TAF）的特异性标志物。已显示FAP具有体外二肽基肽酶和胶原酶活性。然而，FAP在肿瘤微环境中的生物学功能在很大程度上是未知的。在这项研究中，我们首先证明从卵巢癌样本中分离的TAFs具有干细胞的特征。为了探索FA P的功能作用，通过siRNA慢病毒载体转染沉默该蛋白。FAP基因沉默抑制TAFs的生长，并使TAFs的细胞周期阻滞在G2和S期。FAP沉默也降低了TAFs中干细胞标志物基因的表达。SKOV3细胞不表达FAP。尽管FAP沉默的SKOV3细胞诱导卵巢肿瘤，但肿瘤生长速率显著降低，如异种移植小鼠模型中所示。通过免疫组织化学进一步测定异种移植肿瘤组织中的TAF表型。FAP基因沉默的SKOV3细胞诱导的肿瘤间质中TAF标志物的表达减少，包括成纤维细胞特异性蛋白、FAP、平滑肌肌动蛋白、结蛋白、血管内皮生长因子和成纤维细胞生长因子。总之，FA P是肿瘤形成中微环境的重要调节剂，靶向FAP是对抗卵巢癌的潜在治疗策略。
The fibroblast activation protein (FAP) is a cell surface serine protease which has emerged as a specific marker of tumor-associated fibroblasts (TAFs). FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity. However, the biological function of FAP in the tumor microenvironment is largely unknown. In this study, we first show that TAFs isolated from ovarian cancer samples have the characteristics of stem cells. To explore the functional role of FA P, the protein was silenced by siRNA lentiviral vector transfection. FAP silencing inhibited the growth of TAFs in vitro, accompanied with cell cycle arrest at the G2 and S phase in TAFs. FAP silencing also reduced the stem cell marker gene expression in TAFs. SKOV3 cells do not express FA P. Although FAP-silenced SKOV3 cells induced ovarian tumors, the rate of tumor growth was significantly decreased, as shown in the xenograft mouse model. TAF phenotypes in the xenograft tumor tissues were further assayed by immunohistochemistry. The expression of TAF markers, including fibroblast-specific protein, FAP, smooth muscle actin, desmin, vascular endothelial growth factor and fibroblast growth factor was decreased in the tumor stroma induced by FAP-silenced SKOV3 cells. In conclusion, FA P is an important regulator of the microenvironment in tumor formation and targeting FAP is a potential therapeutic strategy to combat ovarian cancer.