Abstract 51: Stromal AKT2 controls epithelial invasions

Abstract

Abstract The tumor microenvironment is gaining importance in the regulation of tumorigenesis, invasion and metastasis. Loss of PTEN, a negative regulator of AKT, in stromal fibroblasts results in an increased tumor occurrence in ErbB2 expressing murine mammary tumors. Furthermore, we have shown that activation of AKT in stromal fibroblasts, following loss of the Retinoblastoma Protein (Rb), induces epithelial invasions in organotypic raft cultures, via an increase in Keratinocyte Growth Factor (KGF) expression. In addition, we have shown that loss of the PTEN tumor suppressor in stromal fibroblasts and subsequent activation of AKT, increases invasive potential of Human Papilloma Virus Type 16 E6 and E7 expressing keratinocytes. This is mediated by an increase in KGF expression. There are three isoforms of AKT expressed in human fibroblasts, AKT1, AKT2 and AKT3. By depleting each individual AKT isoform in stromal fibroblasts we have been able to establish that AKT2 is essential in regulating the cross talk between epithelium and stroma, and depletion of stromal AKT2 inhibits invasions. However, loss of stromal AKT2 does not function exclusively through regulation of KGF levels as it activates a second, protective pathway, which is able to counteract the effects of KGF. This protective pathway is mediated by increased Interleukin1 beta levels produced by the fibroblasts. Preliminary data from head and neck cancer specimens show that AKT is activated in stroma of cells associated with tumor but not normal tissue. Future work will determine the AKT dependent pathways that lead to increased KGF and Interleukin1 beta expression as well as how these factors mediate invasions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 51. doi:1538-7445.AM2012-51