Role of transforming growth factor alpha (TGF-alpha) in the transformation of ras-transfected rat intestinal epithelial cells.
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.
Filmus
J
J
Division of Cancer Research, Sunnybrook Health Science Centre, Toronto, Ontario, Canada.
Shi
W
W
Spencer
T
T
D000818:Animals; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D011905:Genes, ras; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014162:Transfection; D016211:Transforming Growth Factor alpha / Q000502:physiology*
D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors