Interaction between IGF2-PI3K axis and cancer-associated-fibroblasts promotes anal squamous carcinogenesis

Int J Cancer. 2019 Oct 1;145(7):1852-1859. doi: 10.1002/ijc.32178. Epub 2019 Feb 18.

Abstract

Anal squamous cell carcinoma (ASCC) is a rare tumour, but its incidence is increasing. Standard chemoradiotherapy fails to cure 20% of patients and no targeted therapy is currently approved for recurrent ASCC. The PI3K/Akt/mTOR pathway is frequently altered in this poorly characterised carcinoma. IGF2 was identified here as a key factor in ASCC oncogenesis, as IGF2 was shown to play a crucial role in the PI3K pathway with frequent (~60%) and mutually exclusive genomic alterations in IGF2, IGF1R, PTEN and PIK3CA genes. We also demonstrated that IGF2 expression is mainly due to cancer-associated fibroblasts and that IGF2 secreted by cancer-associated fibroblasts from ASCC samples promotes proliferation of a human ASCC cell line via IGF2 paracrine signalling. Altogether, these results highlight the key role of the IGF2/PI3K axis, and the major role of cancer-associated fibroblasts in tumour growth via IGF2 secretion, suggesting a major role of IGF2/IGF1R inhibitors in ASCC therapies.

Keywords: IGF2; PDGFRB; PI3K; anal cancer; cancer-associated fibroblast.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anus Neoplasms / genetics
  • Anus Neoplasms / metabolism*
  • Cancer-Associated Fibroblasts / metabolism*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Insulin-Like Growth Factor II / genetics*
  • Insulin-Like Growth Factor II / metabolism*
  • Male
  • Mice
  • Mutation
  • Neoplasm Transplantation
  • Paracrine Communication
  • Phosphatidylinositol 3-Kinases / metabolism
  • Signal Transduction

Substances

  • IGF2 protein, human
  • Insulin-Like Growth Factor II