Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) contribute to breast cancer progression by releasing soluble factors that sustain tumor progression. MSCs express functional epidermal growth factor receptor (EGFR) and breast cancer cells secrete EGFR-ligands including transforming growth factor-α (TGFα). Using RNA-sequencing, we analysed the whole transcriptome of MSCs stimulated with TGFα. We identified 1,640 highly differentially regulated genes: 967 genes up-regulated with Fold Induction (FI) ≥ 1.50 and 673 genes down-regulated with FI ≤ 0.50. When highly regulated genes were categorized according to GO molecular function classification and KEGG pathways analysis, a large number of genes coding for potentially secreted proteins or surface receptors resulted enriched following TGFα treatment, including VEGFA, IL6, EREG, HB-EGF, LIF, NGF, NRG1, CCL19, CCL2, CCL25 and CXCL3. Secretion of corresponding proteins was confirmed for selected factors. Finally, we identified 4,377 and 4,262 alternatively spliced genes in untreated and TGFα-treated MSCs, respectively. Among these, an unannotated splice variant of VEGFA coding for a secreted VEGF protein of 172 amino acids (VEGFA(172)), was found only in MSCs stimulated with TGFα. These findings suggest that EGFR activation in MSCs leads to a significant change in the expression of a wide array of genes coding for secreted proteins that can significantly enhance tumor progression.
Highlights
Several studies demonstrated that bone marrowderived mesenchymal stem cells (MSCs) contribute to breast cancer progression [1]
We identified a panel of growth factors, cytokines and chemokines potentially involved in the epidermal growth factor receptor (EGFR)-mediated cross-talk between MSCs and breast cancer cells
In order to characterize the whole transcriptome of MSCs following EGFR activation, we stimulated serum-starved MSCs with recombinant transforming growth factor-α (TGFα) (10 ng/ ml) for 1 hour and purified poly(A) RNA fractions from not stimulated (MSC) or TGFα-stimulated (MSC+TGFα) MSCs
Summary
Several studies demonstrated that bone marrowderived mesenchymal stem cells (MSCs) contribute to breast cancer progression [1]. MSCs secrete a number of growth factors, chemokines and cytokines that sustain breast cancer cell proliferation, survival and invasion and that are able to modulate functions of the tumor microenvironment essential for tumor growth including angiogenesis. In this respect, the chemokine (C-C motif) ligand 5 (CCL5/RANTES), the monocyte chemotactic protein-1 (MCP-1/CCL2), interleukin 17B (IL17B) and the chemokine (C-X-C motif) ligand 10 (CXCL10) are known to be involved in the cross-talk between MSCs and breast cancer cells and to favour the development of metastases [2,3,4,5]. The ErbB receptors form homo- or heterodimers with subsequent phosphorylation of the tyrosine kinase domain and activation of different signalling pathways, including the RAS/MEK/ERK and the PI3K/
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