Aberrant TGF-beta production and regulation in metastatic malignancy.
Aberrant TGF-beta production and regulation in metastatic malignancy.
复制标题
转移性恶性肿瘤中异常的 TGF-β 产生和调节。
作者：
L. C. Schwarz;J. Wright;M. Gingras;P. Kondaiah;D. Danielpour;M. Pimentel;M. Sporn;A. Greenberg
我们通过分析转化生长因子β 1和β 2的产生和激活以及癌基因转化的转移性纤维肉瘤中TGF-β反应基因的调节，研究了转化生长因子β（TGF-β）在转移性恶性肿瘤中的可能作用。所有来自10 T1/2或NIH 3 T3的转化株系通过编码H-ras或蛋白激酶的癌基因产生比亲本细胞更多的TGF-β。然而，只有高转移性纤维肉瘤分泌活化TGF-β的速率大于亲本成纤维细胞。TGF-β 1的免疫组化染色显示在转移性肺结节和邻近组织中广泛的细胞内和细胞外分布。从成功转移到肺的肿瘤中分离的细胞的TGF-β 1 mRNA水平比体外对照增加了19倍。尽管活化的TGF-β的分泌速率大大提高，但转移性细胞表现出TGF-β 1和TGF-β 2的显著改变的反应，不能增加胶原蛋白分泌或提高胶原蛋白α 2（1）或TGF-β 1 mRNA水平。这种反应的缺乏不是由于TGF-β受体亲和力或数量的改变。因此，转移进展与活化的TGF-β 1分泌增加和TGF-β反应基因失调的能力丧失有关。
We have examined the possible role of transforming growth factor-beta (TGF-beta) in metastatic malignancy by analyzing the production and activation of TGF-beta 1 and -beta 2 and the regulation of TGF-beta-responsive genes in oncogene-transformed metastatic fibrosarcomas. All transformed lines derived from either 10T1/2 or NIH 3T3 by either H-ras or protein-kinase encoding oncogenes produced more TGF-beta than parental cells. However, only highly metastatic fibrosarcomas secreted activated TGF-beta at rates that were greater than parental fibroblasts. Immunohistochemical staining for TGF-beta 1 showed widespread intra- and extracellular distribution in metastatic lung nodules and adjacent tissue. Cells isolated from tumors successfully metastasizing to the lung had TGF-beta 1 mRNA levels which were increased 19-fold over in vitro controls. Despite the greatly enhanced rate of secretion of activated TGF-beta, metastatic cells exhibited markedly altered responses of TGF-beta 1 and TGF-beta 2, being unable to either increase collagen secretion or enhance collagen alpha 2(1) or TGF-beta 1 mRNA levels. This lack of response was not due to either altered TGF-beta receptor affinity or numbers. Metastatic progression was, therefore, associated with an increase in the secretion of activated TGF-beta 1 and a loss of the ability to deregulate TGF-beta-responsive genes.