Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma.
Elevated levels of insulin-like growth factor (IGF)-II are associated with a poor prognosis in human pulmonary adenocarcinoma; however, a causal role for IGF-II in pulmonary adenocarcinoma has not been demonstrated. Here, we show that transgenic overexpression of IGF-II in lung epithelium induces lung tumors in 69% of mice older than 18 months of age. These tumors displayed morphological characteristics of human pulmonary adenocarcinoma such as their epithelial origin, tubulo-acinar architecture and expression of TTF-1, SP-B and proSP-C. Examination of signaling molecules downstream of the IGF-IR showed the activation of either the Erk1/Erk2 or p38 MAPK pathways, but not both, within the lung tumors. Notably, all lung tumors contained high levels of phosphorylated CREB, suggesting that both the Erk1/Erk2 and p38 MAPK pathways converged on this transcription factor. Moreover, IGF-II induced proliferation and CREB phosphorylation in human lung cancer cell lines, suggesting that IGF-II and CREB also contribute to the growth of human lung tumors. Thus, IGF-II is an important genetic factor in the development of lung tumorigenesis, in which activation of CREB is a ubiquitous event. The MMTV-IGF-II transgenic mice provide a critical model for elucidating the role of IGF-II in this fatal human disease.
Moorehead
Roger A
RA
Ontario Cancer Institute, University of Toronto, Canada.
Sanchez
Otto H
OH
Baldwin
R Mitchell
RM
Khokha
Rama
R
D002282:Adenocarcinoma, Bronchiolo-Alveolar; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics*; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D007335:Insulin-Like Growth Factor II