Villanueva A, García C, Paules A B, Vicente M, Megías M, Reyes G, de Villalonga P, Agell N, Lluís F, Bachs O, Capellá G
Laboratori d'Investigació Gastrointestinal, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Oncogene. 1998 Oct 15;17(15):1969-78. doi: 10.1038/sj.onc.1202118.
Resistance to TGF-beta1 occurred in pancreatic cancer cells suggesting that inactivation of TGF-beta inhibitory signaling pathways may play an important role in human pancreatic cancer. The aim of our study was to determine the presence of alterations in the main putative components of the TGF-beta inhibitory signaling pathways (p15, Smad4, Smad2, TGFbeta-RII, CDC25A). A panel of human carcinomas of the exocrine pancreas orthotopically implanted and perpetuated in nude mice and pancreatic cancer cell lines were studied. p15 gene alterations, mainly homozygous deletions that involved exons 1 and/or 2, were found in the 62.5% (5 of 8) of pancreatic xenografts whereas Smad4 gene aberrations were found in one of eight xenografts and in two of seven cell lines. Additional aberrations in these genes were acquired during in vivo perpetuation and distal dissemination. Paradoxically, TGFbeta-RII overexpression and a decrease in CDC25A protein levels were found in all tumors and cell lines. In one cell line, resistance to TGF-beta1 occurred in the absence of alterations in the genes analysed so far. We conclude that all human pancreatic tumor cells analysed herein have non-functional TGF-beta pathways. The majority of cells harbor alterations in at least one of the putative components of TGF-beta pathways, mainly in p15 and Smad4 genes. These results suggest that inactivation of TGF-beta signaling pathways plays an important role in human pancreatic tumorigenesis.
胰腺癌细胞中出现了对转化生长因子β1（TGF-β1）的抗性，这表明TGF-β抑制信号通路的失活可能在人类胰腺癌中起重要作用。我们研究的目的是确定TGF-β抑制信号通路主要假定成分（p15、Smad4、Smad2、TGFβ-RII、细胞周期蛋白依赖性激酶25A（CDC25A））的改变情况。我们研究了一组原位植入裸鼠并传代的人外分泌性胰腺癌以及胰腺癌细胞系。在62.5%（8个中的5个）的胰腺异种移植瘤中发现了p15基因改变，主要是涉及外显子1和/或2的纯合缺失，而在8个异种移植瘤中的1个以及7个细胞系中的2个中发现了Smad4基因畸变。在体内传代和远处转移过程中，这些基因出现了额外的畸变。矛盾的是，在所有肿瘤和细胞系中均发现了TGFβ-RII的过表达以及CDC25A蛋白水平的降低。在一个细胞系中，在目前分析的基因未发生改变的情况下出现了对TGF-β1的抗性。我们得出结论，本文分析的所有人类胰腺肿瘤细胞的TGF-β信号通路均无功能。大多数细胞至少在TGF-β信号通路的一个假定成分中存在改变，主要是在p15和Smad4基因中。这些结果表明，TGF-β信号通路的失活在人类胰腺癌发生中起重要作用。
