Filmus J, Shi W, Spencer T
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Oncogene. 1993 Apr;8(4):1017-22.
Most intestinal tumors express transforming growth factor alpha (TGF-alpha) while normal immature crypt cells, the targets for tumor initiation, do not. We have used a rat intestinal cell line derived from immature epithelial crypt cells (IEC-18) to investigate the role of this growth factor in intestinal tumorigenesis. ras transformation of IEC-18 cells induces expression and secretion of TGF-alpha. By studying several independently derived IEC-ras clones, we have established that the amount of TGF-alpha secreted is proportional to the level of activated ras expressed by each clone. The growth of all ras-transformed IEC clones is significantly inhibited by neutralizing antibodies against TGF-alpha and by an antisense TGF-alpha expression vector, indicating a mitogenic role for this growth factor through an autocrine loop. To determine whether TGF-alpha itself can transform intestinal cells, IEC-18 clones transfected with TGF-alpha expression vectors were isolated and characterized. None of the TGF-alpha-expressing clones show any signs of tumorigenic transformation even when they secrete as much TGF-alpha as the IEC-ras clones. It seems, therefore, that TGF-alpha per se does not have the capacity to transform rat epithelial intestinal cells and that its role is mostly related to autocrine growth stimulation.
大多数肠道肿瘤表达转化生长因子α（TGF-α），而正常的未成熟隐窝细胞（肿瘤起始的靶细胞）则不表达。我们使用了一种源自未成熟上皮隐窝细胞的大鼠肠道细胞系（IEC-18）来研究这种生长因子在肠道肿瘤发生中的作用。IEC-18细胞的ras转化诱导了TGF-α的表达和分泌。通过研究几个独立获得的IEC-ras克隆，我们确定分泌的TGF-α量与每个克隆中表达的活化ras水平成正比。抗TGF-α中和抗体和反义TGF-α表达载体可显著抑制所有ras转化的IEC克隆的生长，这表明该生长因子通过自分泌环发挥促有丝分裂作用。为了确定TGF-α本身是否能转化肠道细胞，我们分离并鉴定了用TGF-α表达载体转染的IEC-18克隆。即使分泌的TGF-α与IEC-ras克隆一样多，表达TGF-α的克隆也没有显示出任何致瘤转化的迹象。因此，似乎TGF-α本身没有能力转化大鼠上皮肠道细胞，其作用主要与自分泌生长刺激有关。
