A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis

Nature. 1994 Jun 2;369(6479):414-8. doi: 10.1038/369414a0.


Transgenic mice expressing the simian virus-40 large T-antigen (Tag) under the control of the insulin gene regulatory region offer a useful model for tumorigenesis. All the islets of Langerhans express Tag, although there is at first no aberrant proliferation. Over half of the islets become hyperplastic, however, and neovascularization of a further subset (about 10%)3 leads eventually to formation of highly vascularized solid tumours in 1-2% of islets by about 14 weeks of age. Here we show that the initial proliferative switch is correlated with focal activation of insulin-like growth factor II (IGF-II). Transfection with an antisense oligonucleotide to the IGF-II messenger RNA interferes with tumour cell proliferation in vitro, and transgenic mice homozygous for a disruption of the IGF-II gene develop tumours with reduced malignancy and a higher incidence of apoptosis. Several signals, in this case including an oncoprotein and a growth/survival factor, thus appear to be needed to elicit hyperproliferation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antigens, Polyomavirus Transforming / genetics
  • Apoptosis
  • Base Sequence
  • Cell Division
  • Cell Transformation, Neoplastic / metabolism*
  • In Situ Hybridization
  • Insulin / genetics
  • Insulin-Like Growth Factor II / genetics
  • Insulin-Like Growth Factor II / metabolism*
  • Insulinoma / genetics
  • Insulinoma / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Nuclear Proteins / metabolism
  • Oligodeoxyribonucleotides
  • Oncogenes*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Proliferating Cell Nuclear Antigen
  • RNA, Antisense / pharmacology
  • Regulatory Sequences, Nucleic Acid
  • Signal Transduction*
  • Tumor Cells, Cultured


  • Antigens, Polyomavirus Transforming
  • Insulin
  • Nuclear Proteins
  • Oligodeoxyribonucleotides
  • Proliferating Cell Nuclear Antigen
  • RNA, Antisense
  • Insulin-Like Growth Factor II