Transgenic overexpression of IGF-II induces spontaneous lung tumors: a model for human lung adenocarcinoma

Oncogene. 2003 Feb 13;22(6):853-7. doi: 10.1038/sj.onc.1206188.


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.

MeSH terms

  • Adenocarcinoma, Bronchiolo-Alveolar
  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Disease Models, Animal*
  • Humans
  • Immunohistochemistry
  • Insulin-Like Growth Factor II / biosynthesis
  • Insulin-Like Growth Factor II / genetics*
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / genetics
  • Mice
  • Mice, Transgenic
  • Signal Transduction / physiology


  • Cyclic AMP Response Element-Binding Protein
  • Insulin-Like Growth Factor II