Regulation of pro-angiogenic and pro-inflammatory cytokines during epithelial-to-mesenchymal transition associated to the metastatic progression of breast and lung tumor cells.

Even though epithelial-to-mesenchymal transition (EMT) existence in cancer epithelial cells has been a topic of debate for a long time, it is now widely accepted that cancer cells undergo EMT-like changes, which are tightly regulated in time and space and endow cells with intrinsically enhanced invasive and survival capacities that might favor metastatic dissemination. Clinical observations showing that presence of EMT markers relates to a high histological grade, presence of lymph node metastasis and chemoresistance are corroborated by animal models and in vitro data demonstrating a role for EMT in invasion and intravasation. Nevertheless, although signaling cascades triggering EMT have been extensively studied, the impact of EMT on the crosstalk between tumor cells and the tumor microenvironment remains elusive. Metastatic dissemination indeed largely relies on tumor-stroma interactions. Tumor cells can secrete numerous soluble factors such as cytokines, chemokines and growth factors, some of which have been described as upregulated in cancer progression, even though the mechanisms of such an overexpression remain unclear. During this thesis, we aimed at characterizing the impact of EMT on the tumor-stroma crosstalk. Using in vitro models of cell lines inducible for EMT, we identified five EMT-induced soluble factors: Interleukin 8 (IL-8), Interleukin-6 (IL-6), soluble form of InterCellular Adhesion Molecule-1 (sICAM-1), Plasminogen Activator Inhibitor-1 (PAI-1) and Granulocyte Monocyte-Colony Stimulating Factor (GM-CSF). These factors are partially regulated by Snail even though other transcription factors are most likely involved. We further demonstrated that EMT-derived soluble factors are pro-angiogenic. Finally, our preliminary data suggest that conditioned medium from EMT-positive cells stimulates the recruitment of myeloid-derived suppressor cells (MDSC). Taken together, our results show that EMT programs trigger the expression of soluble mediators in breast and lung cancer cells that stimulate angiogenesis and recruit MDSCs, which might in turn favor metastatic dissemination.