Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor beta 1.
Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor beta 1.
复制标题
DOI：
10.1083/jcb.118.3.715
复制
发表时间：
1992-08
期刊：
影响因子：
--
通讯作者：
Derynck R
中科院分区：
文献类型：
--
作者：
Arrick BA;Lopez AR;Elfman F;Ebner R;Damsky CH;Derynck R
转化生长因子-β（TGF-β）是细胞增殖和细胞外基质形成的有效介质，这取决于细胞类型和生理条件。TGF-β通常以“潜伏”复合物的形式分泌，在发挥作用之前需要激活。一些观察结果将TGF-β 1的表达增加与肿瘤发生相关联。为了评估肿瘤细胞中TGF-β 1合成增加的生理相关性，我们建立了过度表达TGF-β 1的细胞克隆，并观察了体外和体内TGF-β过度产生细胞中产生的生理变化。作为模型系统，我们使用人E1 A转化的293肿瘤细胞，其对TGF-β的直接生长调节作用不敏感。该细胞系的选择允许评估独立于TGF-β诱导的增殖变化的生理变化。使用含有天然或修饰的TGF-β 1前体cDNA的两种TGF-β 1表达载体允许建立单独的293细胞系，其过度表达潜伏或活性TGF-β。比较糖酵解速率、TGF β和整联蛋白和纤溶酶原激活物表达的变化确定，在体外，两种类型的克隆表现相似，表明潜伏TGF-β的表达诱导肿瘤细胞中的自分泌变化，从而表明发生了一定水平的细胞相关活化。TGF-β过度表达导致代谢率增加，这是由于糖酵解增强，这是一种长期与肿瘤细胞相关的特性。这种糖酵解的增加与增殖的改变无关。过表达TGF-β的细胞也显示出增强的纤连蛋白mRNA和纤溶酶原激活物合成，并增加体外增殖。当在没有血清的情况下将它们稀疏地铺在塑料上时，它们显示出增强的存活率，并且更容易附着于层粘连蛋白。此外，几种β 1整联蛋白的合成，特别是α 1/β 1、α 2/β 1和α 3/β 1，所有这些都识别层粘连蛋白，都得到了增强。最后，过度表达活性TGF-β但不表达潜伏性TGF-β的细胞在裸鼠中也显示出致瘤性增加。因此，内源性TGF-β合成的增加赋予了几种增殖非依赖性表型变化，这可能对肿瘤细胞接种物的存活或其随后的生长以及肿瘤形成和发展具有重要意义。在表达活性TGF-β的细胞的情况下，活性TGF-β释放到肿瘤细胞附近也可能导致更适合肿瘤生长的环境。
Transforming growth factor-beta (TGF-beta) is a potent mediator of cell proliferation and extracellular matrix formation, depending on the cell type and the physiological conditions. TGF-beta is usually secreted in a "latent" complex that needs activation before it can exert its effects. Several observations correlate increased expression of TGF- beta 1 with tumorigenesis. To evaluate the physiological relevance of increased TGF-beta 1 synthesis in tumor cells we established cell clones overexpressing TGF-beta 1 and observed the resulting physiological changes in TGF-beta overproducing cells in vitro and in vivo. As a model system we used the human E1A-transformed 293 tumor cells, which are insensitive to the direct growth modulatory effects of TGF-beta. The selection of this cell line allows an assessment of physiological alterations independent of TGF-beta induced proliferative changes. The use of two TGF-beta 1 expression vectors containing either the natural or a modified TGF-beta 1 precursor cDNA permitted the establishment of separate 293 cell lines overexpressing latent or active TGF-beta. Comparison of the resulting changes in glycolytic rate, adhesiveness and integrin and plasminogen activator expression established that, in vitro, both types of clones behaved similarly, indicating that expression of latent TGF-beta induces autocrine changes in the tumor cells and thus suggesting that some level of cell- associated activation occurs. TGF-beta overexpression resulted in an increased metabolic rate due to enhanced glycolysis, a property long associated with tumor cells. This increased glycolysis was not associated with altered proliferation. Cells overexpressing TGF-beta also displayed enhanced fibronectin mRNA and plasminogen activator synthesis and increased adhesiveness in vitro. They showed enhanced survival when plated sparsely on plastic in the absence of serum, and attached more readily to laminin. In addition, synthesis of several beta 1 integrins, in particular the alpha 1/beta 1, alpha 2/beta 1, and alpha 3/beta 1, all of which recognize laminin, were enhanced. Finally, cells overexpressing active TGF-beta, but not latent TGF-beta, also showed increased tumorigenicity in nude mice. Thus, an increase in endogenous TGF-beta synthesis confers several proliferation-independent phenotypic changes which may be of significance for the survival of the tumor cell inoculum or its subsequent growth, and for tumor formation and development. In the case of cells expressing active TGF-beta, the release of active TGF-beta into the vicinity of the tumor cells may also result in a more hospitable environment for tumor growth.