Mesenchymal Stromal Cells (MSCs) are the precursors of various cell types that compose both normal and cancer tissue microenvironments. In order to support the widely diversified parenchymal cells and tissue organization, MSCs are characterized by a large degree of heterogeneity, although available analysis of molecular and transcriptional data do not provide any clear evidence. Moreover, a wealth of study has demonstrated a significant role of the microenvironment and MSCs in tumor growth. In the laboratory in which I carried out my PhD project, MSCs were purified from different healthy tissues (N-MSCs) and from High-Grade Serous Ovarian Carcinomas (HG-SOC-MSCs). In order to study the role of MSCs in High-Grade Serous Ovarian Cancer, two-dimensional (2D) simplified co-culture approaches were established to characterize the interaction between MSCs and an ovarian carcinoma cell line – Skov3 – at short-term (1 hour) and long-term (5 days) settings. It was demonstrated that short-term co-cultures, specifically performed with transient contact between the two cell types, were able to induce a transcriptional remodeling of Skov3 cells as shown by the up-regulation of ALDH1A3, IL1β, PDPN and MT1E transcripts. Moreover, under the same settings, Skov3 cells co-cultured with HG-SOC-MSCs but not N-MSCs nor when cultured in the presence of HG-SOC-MSCs conditioned medium, were reprogrammed as assessed by specific functional assays, highlighting an increased viability, not linked to proliferation, and higher tumorigenicity and motility. Whole genome expression analysis performed on Skov3 cells subjected to long-term co-culture experiments (5 days), allowed us to focus on different up-regulated transcripts, such as IL8, CCL2, CXCL1, CXCL2, TNF (involved in the interleukin-10 signaling pathway), CTGF and CYR61 (members of the CCN family), in addition to FOS, EGR1 and ATF4. Such transcripts are specifically up-regulated in Skov3 cells upon direct co-culture with HG-SOC-MSCs but not N-MSCs or in membrane-separated co-culture experiments. Furthermore, subcutaneous injection of an admix of Skov3 cells and HG-SOC-MSCs in NOD-SCID mice displayed an increased kinetics of the Skov3-derived tumor xenograft, showing that HG-SOC-MSCs are able to shorten the latency period of the tumor formation.
