Abstract 2602: Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling.

Abstract

Abstract Objective: Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumors and drive tumor progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). Design: Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumor xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane NRG1 (tNRG1), HER2 and HER3 expression was analysed in primary CRCs (n = 54), adjacent normal colorectal tissues (n = 4), liver metastases (n = 3) and adjacent normal liver tissues (n = 3) by immunohistochemistry. Results: BM-MSC stimulate invasion, survival and tumorigenesis of CRCs through release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signaling cascade in CRC cells. Tumor-associated mesenchymal cells (T-MC) in CRCs demonstrate high tNRG1 expression. HER2 and HER3 show membrane localization in cancer cells of CRC tissue. High tNRG1 expression in T-MC is significantly associated with advanced UICC stage (P = .005) and invasion depth (P = .04) and decreased 5-year progression-free-survival (PFS) (P = .01). Conclusion: Paracrine NRG1/HER3 signals initiated by BM-MSC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis. Citation Format: Olivier De Wever, Astrid De Boeck, An Hendrix, Hannelore Denys, Geert Braems, Marc Bracke. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2602. doi:10.1158/1538-7445.AM2013-2602