Grosse-Wilde Anne, Voloshanenko Oksana, Bailey S Lawrence, Longton Gary M, Schaefer Uta, Csernok Andreea I, Schütz Günther, Greiner Erich F, Kemp Christopher J, Walczak Henning
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
J Clin Invest. 2008 Jan;118(1):100-10. doi: 10.1172/JCI33061.
TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种很有前景的抗癌药物，因为它能够选择性地诱导已建立的肿瘤细胞系发生凋亡，而不会诱导未转化细胞凋亡。在此，我们证明了凋亡诱导性TRAIL受体（TRAIL-R）作为一种转移抑制因子的作用。尽管采用肿瘤移植的小鼠模型已表明TRAIL可减少肿瘤生长，但关于TRAIL系统在肿瘤发生过程中的生理作用，原位肿瘤模型产生了相互矛盾的结果。我们使用鳞状细胞癌的多阶段模型来研究TRAIL-R在肿瘤发展的所有阶段中的作用。经二甲基苯并蒽/佛波酯处理的TRAIL-R缺陷小鼠，其良性乳头瘤的数量或生长速率均未增加，向鳞状细胞癌的进展速率也未增加。然而，其向淋巴结的转移显著增强，这表明TRAIL-R在抑制转移中具有特定作用。我们还发现，贴壁的表达TRAIL-R的皮肤癌细胞在体外对TRAIL具有抗性，但在通过ERK信号通路失活而脱离贴壁状态后对TRAIL敏感。由于从原发肿瘤脱离是转移过程中的一个必要步骤，这提供了一种TRAIL-R可能抑制转移的机制。因此，用TRAIL凋亡诱导受体激动剂治疗癌症患者可能有助于降低转移发生率。
