A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer

J Clin Endocrinol Metab. 2002 Jan;87(1):245-54. doi: 10.1210/jcem.87.1.8142.


The insulin receptor (IR) occurs in two isoforms (IR-A and IR-B) resulting from alternative splicing of exon 11 of the gene. The IR-A isoform is predominantly expressed in fetal tissues and malignant cells and binds IGF-II with high affinity. We previously observed that IRs are overexpressed in thyroid cancer cells; now we evaluated whether these cells preferentially express IR-A and produce IGF-II, which would activate a growth-promoting autocrine loop. The IR content ranged 6.0-52.6 ng/100 microg cell membrane protein in thyroid cancer primary cultures (n = 8) and permanent cell lines (n = 6) vs. 1.2-1.7 in normal thyroid cells (n = 11 primary cultures; P < 0.0001). IR-A isoform relative abundance ranged from 36-79% in cancer cells (with the highest values in undifferentiated cancers) vs. 27-39% in normal cells. Similar results were obtained in normal vs. cancer thyroid tissue specimens. IGF-II caused IR autophosphorylation with an ED(50) of 1.5-40.0 nM in cancer cells vs. more than 100 nM in normal cells; IGF-II affinity correlated with the relative abundance of IR-A (r = 0.628; P < 0.0001). IGF-II was expressed in all cancer cells, highly expressed in anaplastic cells, and less expressed in normal cells. In conclusion, malignant thyrocytes, especially when poorly differentiated, produce IGF-II and overexpress IR, predominantly as IGF-II-sensitive isoform A. A growth-promoting autocrine loop is activated, therefore, and may affect thyroid cancer biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Autocrine Communication
  • Cell Differentiation
  • Cell Division
  • Humans
  • Insulin-Like Growth Factor II / metabolism*
  • Phosphorylation
  • Protein Binding
  • Receptor, Insulin / analysis
  • Receptor, Insulin / metabolism*
  • Thyroid Neoplasms / metabolism*
  • Thyroid Neoplasms / pathology
  • Tumor Cells, Cultured


  • Antigens, CD
  • Insulin-Like Growth Factor II
  • INSR protein, human
  • Receptor, Insulin