Ye S C, Foster J M, Li W, Liang J, Zborowska E, Venkateswarlu S, Gong J, Brattain M G, Willson J K
Department of Biochemistry and Molecular Biology, Medical College of Ohio at Toledo, 43614-2595, USA.
Cancer Res. 1999 Sep 15;59(18):4725-31.
Transforming growth factor betas (TGF-betas) are a growth factor family with negative autocrine growth functions for most epithelial cells including colon carcinoma cell lines. Both type I (RI) and type II (RII) transmembrane TGF-beta receptors have been shown to be indispensable for TGF-beta-mediated cell growth regulation. Previous studies using different model systems have shown that both overexpression of TGF-beta1 and transfection of antisense TGF-beta1 to reduce TGF-beta1 expression could lead to increased tumorigenicity. These results are seemingly contradictory and suggest that effects of TGF-beta modulation on malignant properties of cancer cells may be contextual. This study addresses this issue using human colon carcinoma cells (CBS and FET) to determine the effects of modulation of the various components of the TGF-beta system on in vitro and in vivo growth properties in two independent isogenic models of colon carcinoma. Cells were stably transfected with a tetracycline-repressible RII expression vector (CBS4-RII), a tetracycline-repressible expression vector containing a truncated RII cDNA lacking the serine/threonine kinase domain (CBS4-deltaRII and FET6-deltaRII), or with a vector containing the TGF-beta1 cDNA (CBS4-beta1S and FET-beta1S). Expression of the truncated RII reduced TGF-beta sensitivity, whereas overexpression of RII increased TGF-beta sensitivity. TGF-beta overexpression did not affect TGF-beta response. In vivo tumorigenicity assays revealed that CBS4-RII cells had lower tumorigenicity than control cells, whereas CBS4-deltaRII and CBS4-beta1S had higher tumorigenicity than controls. The CBS4 cells are poorly tumorigenic in athymic mice, and the wild-type FET6 cells are nontumorigenic. FET6-deltaRII cells formed rapidly growing tumors, and FET-beta1S cells also formed tumors. These data illustrate the paradoxical tumor-promoting and -suppressing effects of TGF-beta signaling activity in two isogenic model systems from human colon carcinomas, thus demonstrating that the effects of modulation of TGF-beta expression or TGF-beta signaling capability affects malignancy in a contextual manner.
转化生长因子β（TGF-β）是一个生长因子家族，对包括结肠癌细胞系在内的大多数上皮细胞具有负性自分泌生长功能。I型（RI）和II型（RII）跨膜TGF-β受体已被证明对于TGF-β介导的细胞生长调节不可或缺。以往使用不同模型系统的研究表明，TGF-β1的过表达和反义TGF-β1转染以降低TGF-β1表达均可导致致瘤性增加。这些结果看似相互矛盾，表明TGF-β调节对癌细胞恶性特性的影响可能因情况而异。本研究使用人结肠癌细胞（CBS和FET）来解决这一问题，以确定在两个独立的同基因结肠癌模型中，TGF-β系统各组分的调节对体外和体内生长特性的影响。用四环素可抑制的RII表达载体（CBS4-RII）、含有缺失丝氨酸/苏氨酸激酶结构域的截短RII cDNA的四环素可抑制表达载体（CBS4-ΔRII和FET6-ΔRII）或含有TGF-β1 cDNA的载体（CBS4-β1S和FET-β1S）对细胞进行稳定转染。截短RII的表达降低了TGF-β敏感性，而RII的过表达增加了TGF-β敏感性。TGF-β的过表达不影响TGF-β反应。体内致瘤性试验显示，CBS4-RII细胞的致瘤性低于对照细胞，而CBS4-ΔRII和CBS4-β1S的致瘤性高于对照细胞。CBS4细胞在无胸腺小鼠中致瘤性较差，野生型FET6细胞无致瘤性。FET6-ΔRII细胞形成快速生长的肿瘤，FET-β1S细胞也形成肿瘤。这些数据说明了在两个人结肠癌同基因模型系统中TGF-β信号活性具有矛盾的促肿瘤和抑肿瘤作用，从而证明TGF-β表达调节或TGF-β信号传导能力调节的影响以上下文相关的方式影响恶性肿瘤。
