AKT in Stromal Fibroblasts Controls Invasion of Epithelial Cells

Ann-Christin Cichon, Adam Pickard, Simon S. McDade, Daniel J. Sharpe, Michael Moran, Jacqueline A. James, Dennis J. McCance*

*Corresponding author for this work

Research output: Contribution to journalArticle

13 Citations (Scopus)
183 Downloads (Pure)

Abstract

The tumour microenvironment has an important role in cancer progression and recent reports have proposed that stromal AKT is activated and regulates tumourigenesis and invasion. We have shown, by immuno-fluorescent analysis of oro-pharyngeal cancer biopsies, an increase in AKT activity in tumour associated stromal fibroblasts compared to normal stromal fibroblasts. Using organotypic raft co-cultures, we show that activation of stromal AKT can induce the invasion of keratinocytes expressing the HPV type 16 E6 and E7 proteins, in a Keratinocyte Growth Factor (KGF) dependent manner. By depleting stromal fibroblasts of each of the three AKT isoforms independently, or through using isoform specific inhibitors, we determined that stromal AKT2 is an essential regulator of invasion and show in oro-pharyngeal cancers that AKT2 specific phosphorylation events are also identified in stromal fibroblasts. Depletion of stromal AKT2 inhibits epithelial invasion through activating a protective pathway counteracting KGF mediated invasions. AKT2 depletion in fibroblasts stimulates the cleavage and release of IL1B from stromal fibroblasts resulting in down-regulation of the KGF receptor (fibroblast growth factor receptor 2B (FGFR2B)) expression in the epithelium. We also show that high IL1B is associated with increased overall survival in a cohort of patients with oro-pharyngeal cancers. Our findings demonstrate the importance of stromal derived growth factors and cytokines in regulating the process of tumour cell invasion.
Original languageEnglish
Pages (from-to)1103-1116
Number of pages14
JournalOncotarget
Volume4
Issue number7
Publication statusPublished - 14 Jul 2013

Keywords

  • stroma
  • invasion
  • AKT
  • Caspase 1
  • HPV
  • mdm2
  • interleukin 1
  • KGF
  • cancer

ASJC Scopus subject areas

  • Oncology

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