Role of the EGFR ligand/receptor system in the secretion of angiogenic factors in mesenchymal stem cells

Abstract

Increasing evidence suggests that bone marrow-derived mesenchymal stem cells (MSCs) are recruited into the stroma of developing tumors where they contribute to cancer progression. MSCs produce different growth factors that sustain tumor-associated neo-angiogenesis. Since the majority of carcinomas secrete ligands of the epidermal growth factor receptor (EGFR), we assessed the role of EGFR signaling in regulating the release of angiogenic factors in MSCs. Treatment of human primary MSCs and of the human osteoblastic cell line hFOB with transforming growth factor α (TGF-α), one of the main ligands of the EGFR, significantly induced activation of this receptor and of different intracellular signaling proteins, including the PI3K/AKT and the MEK/MAPK pathways. TGF-α induced a significant increase in the levels of secretion of vascular endothelial growth factor in both MSCs and hFOB. Conditioned medium from TGF-α treated MSCs showed an higher in vivo angiogenic effect as compared with medium from untreated cells. Treatment of MSCs with TGF-α also produced a significant increase in the secretion of other angiogenic growth factors such as angiopoietin-2, granulocyte-colony stimulating factor, hepatocyte growth factor, interleukin (IL)-6, IL-8, and platelet-derived growth factor-BB. Using selective MEK and PI3K inhibitors, we found that both MEK/MAPK and the PI3K/AKT signaling pathways mediate the ability of TGF-α to induce secretion of angiogenic factors in MSCs. Finally, stimulation with TGF-α increased the ability of MSCs to induce migration of MCF-7 breast cancer cells. These data suggest that EGFR signaling regulates the ability of MSCs to sustain cancer progression through the release of growth factors that promote neo-angiogenesis and tumor cell migration.

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

“…The presence of breast cancer cells upsets this balance, leading to a net increase in bone destruction via os- 3). There is now a growing appreciation that bone-marrow-derived mesenchymal stem cells (MSC) are recruited to the stroma of developing tumours and also contribute to formation of the tumour cell-derived TGF simulated release of angiogenic factors and induced breast carcinoma cell migration; another example of mutual Erb-mediated tumour-host interactions involved in tumour progression (De Luca et al, 2011).…”

NELL-1-dependent mineralisation of Saos-2 human osteosarcoma cells is mediated via c-Jun N-terminal kinase pathway activation

“…Other signalling cascades such as fibroblast growth factor (FGF) [14,15] and TGF-α signalling [16] are also known to influence osteogenic differentiation via MAPK signalling modulation.…”

Involvement of Mesenchymal Stem Cells in Breast Cancer Progression

“…MSCs or similarly IL-6 induced the phosphorylation of STAT3 (signal transducer and activator of transcription 3) on tyrosine-705 in MCF-7 cells (Sasser et al, 2007b). Incubation of MSCs with TGF, a ligand of the EGFR (epidermal growth factor receptor), further stimulated the secretion of IL-6 and other factors (De Luca et al, 2010). This suggests that TGF-primed MSCs would even be more effective in promoting proliferation of MCF-7 cells.…”

“…E.g., IL-6 induces the expression of CXCL7, which further enhances the expression levels of IL-6, IL-8, CXCL5 and CXCL6 (Liu et al, 2011). TGF (transforming growth factor ) was found to stimulate MSCs to secrete more IL-6, IL-8, angiopoietin-2, G-CSF, HGF, VEGF and PDGF-BB (De Luca et al, 2010). TNF forced MSCs to increase their expression of CXCL9, CXCL10 and CXCL11 (Shin et al, 2010).…”