Frzb, a secreted wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of met signalling
Frzb, a secreted wnt antagonist, decreases growth and invasiveness of fibrosarcoma cells associated with inhibition of met signalling
复制标题
DOI：
10.1158/0008-5472.can-07-3220
复制
发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Hoang, Bang H.
中科院分区：
文献类型：
--
作者：
Guo, Yi;Me, Jun;Hoang, Bang H.
软组织肉瘤（STS）具有侵袭性生长和转移的强烈倾向。我们发现分泌的Wnt拮抗剂Frzb对前列腺癌（一种上皮型恶性肿瘤）表现出有效的抗肿瘤活性。在这项研究中，我们进一步显示了Frzb在STS（一种间充质组癌症）中的抗肿瘤疗效。Frzb转染HT 1080（纤维肉瘤）和SW 872（脂肪肉瘤）细胞系和它们的条件培养基导致在软琼脂中的细胞侵袭，运动性和集落形成与载体对照转染的细胞相比显着减少。在异种移植小鼠模型中，Frzb显著抑制了裸鼠中HT 1080细胞的肿瘤生长。在尾静脉注射转移模型中，Frzb转染的HT 1080细胞形成的肺结节比载体对照细胞少且小。此外，我们确定了新的机制Frzb抗肿瘤活性。Frzb降低c-Met表达并抑制Met介导的信号传导，与上皮标志物的上调相关（即，角蛋白8和18）和间充质标志物的下调（即，波形蛋白、N-钙粘蛋白、纤连蛋白、Slug和Twist）。与Frzb类似，通过短发夹RNA或使用显性负性LRP 5受体沉默c-Met也抑制Met信号传导，导致细胞运动性、侵袭和体内肿瘤生长降低。鉴于最近的研究表明c-Met在肉瘤发展和进展中的重要作用，我们的数据显示，Frzb表达与STS细胞系和组织中的Met表达显著负相关。这些结果表明Frzb在调节Met信号传导中作为STS的新治疗策略的有用性。
Soft tissue sarcomas (STS) have a strong propensity for aggressive growth and metastasis. We showed that the secreted Wnt antagonist Frzb exhibited potent antitumor activity against prostate cancer, an epithelial type of malignancy. In this study, we further showed the antitumor efficacy of Frzb in STS, a mesenchymal group of cancer. Frzb transfection of HT1080 (fibrosarcoma) and SW872 (liposarcoma) cell lines and their conditioned media resulted in a significant reduction in cellular invasion, motility, and colony formation in soft agar compared with vector control-transfected cells. In a xenograft mouse model, Frzb dramatically suppressed tumor growth of HT1080 cells in nude mice. In a tail-vein injection metastatic model, Frzb-transfected HT1080 cells formed fewer and smaller lung nodules than vector control cells. In addition, we identified new mechanisms for Frzb antitumor activities. Frzb reduced c-Met expression and inhibited Met-mediated signaling, associated with up-regulation of epithelial markers (i.e., keratins 8 and 18) and down-regulation of mesenchymal markers (i.e., vimentin, N-cadherin, fibronectin, Slug, and Twist). Similar to Frzb, silencing of c-Met by short hairpin RNA or using a dominant-negative LRP5 receptor also suppressed Met signaling, leading to reduced cellular motility, invasion, and in vivo tumor growth,. Given recent studies indicating an important role of c-Met in sarcoma development and progression, our data showed that Frzb expression was significantly inversely correlated with Met expression in both STS cell lines and tissues. These results suggested the usefulness of Frzb in modulating Met signaling as a new treatment strategy for STS.