Possible paracrine mechanism of insulin-like growth factor-2 in the development of liver metastases from colorectal carcinoma

Cancer. 1999 Jan 1;85(1):18-25. doi: 10.1002/(sici)1097-0142(19990101)85:1<18::aid-cncr3>3.0.co;2-4.


Background: Insulin-like growth factor-2 (IGF-2) is considered one of the autocrine growth factors in colorectal carcinoma. In addition, it is well known that IGF-2 is produced in the liver. However, the role of IGF-2 in liver metastasis is not yet understood clearly.

Methods: Immunohistochemical staining of IGF-2 and IGF-1 receptor (IGF-1R) was performed on tissue samples of liver metastases from 30 colorectal carcinoma patients. In situ hybridization of IGF-2 also was conducted on the same tissue samples. Furthermore, proliferating cell nuclear antigen (PCNA) was immunohistochemically stained for use as an indicator of the proliferative activity of cancer cells.

Results: Invasive margins of liver metastases were stained highly by both IGF-2 (70%) and IGF-1R (83%). Overexpression of IGF-2 protein and mRNA was observed in the normal liver adjacent to the tumor. The PCNA labeling indices (LIs) of the IGF-2 positive groups were significantly higher than those of the IGF-2 negative group (P < 0.0001). In addition, the PCNA LIs for the IGF-1R positive groups also were significantly higher than those for the IGF-1R negative group (P=0.0002).

Conclusions: These findings suggest that hepatocyte-derived IGF-2 stimulates tumor cell proliferation by a paracrine mechanism and plays an important role in tumor progression in colorectal carcinoma patients with liver metastases.

MeSH terms

  • Aged
  • Colorectal Neoplasms / chemistry
  • Colorectal Neoplasms / pathology*
  • Disease Progression
  • Female
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Insulin-Like Growth Factor II / analysis
  • Insulin-Like Growth Factor II / physiology*
  • Liver / chemistry
  • Liver Neoplasms / chemistry*
  • Liver Neoplasms / secondary*
  • Male
  • Middle Aged
  • Proliferating Cell Nuclear Antigen / analysis
  • Receptor, IGF Type 1 / analysis


  • Proliferating Cell Nuclear Antigen
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1