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Mesothelial Signature in Mesenchymal Stem/Stromal cells derived from HighGrade Serous Ovarian Cancer marks their Identity
Bussadori, Giulio
2015-04-28
Abstract
Mesenchymal Stem/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 analyses of molecular and transcriptional data do not provide clear evidence. Moreover a wealth of studies has demonstrated a significant role of the microenvironment and MSCs in tumor growth. In the course of the years MSCs were isolated by different groups from different tissues, both healthy and cancerous. The laboratory in which I conducted my PhD project was able to purify MSCs from different healthy tissues (N-MSCs) and, using an adapted protocol, from High-Grade Serous Ovarian Carcinomas (HG-SOC-MSCs). It was possible to shown that these cells do not possess gross chromosomal aberrations and are not tumorigenic in vivo. To better characterize these cells, an integrative bioinformatics analysis was conducted using the deep-CAGE-derived expression profiles obtained from HG-SOC-MSCs, N-MSCs and the FANTOM5 large comprehensive primary cells and tissues dataset. When compared to the other cells and tissues, HG-SOC-MSCs showed a correlation with mesothelial cells and cells hypothesized to have a mesothelial origin, such as smooth muscle cells and fibroblasts. It is known that mesothelial cells in culture can alternate between epithelioid and fibroblastoid morphologies and express high levels of either keratin or vimentin or both depending on their state of growth and the presence of EGF. When cultivated in the absence of EGF, which is known to induce a morphological switch in mesothelial cells, HG-SOC-MSCs switch from a fibroblast-like to an epithelial-like shape. N-MSCs in the same culture conditions, instead, do not change morphology. Moreover, in absence of EGF, HG-SOC-MSCs but not N-MSCs raise the levels of Keratin 7 both in protein and in mRNA. Starting from the list of up-regulated genes in HG-SOC-MSCs compared to N-MSCs a list of mesothelial-related genes was generated. This mesothelial-related gene list was compared to high-throughput gene expression datasets of MSCs derived from other tissues. Such analysis revealed that the mesothelial-related signature is specific to HG-SOC-MSCs. Moreover, Kaplan-Meier survival analysis conducted on a comprehensive SOC microarray dataset showed that patients with higher levels of the mesothelial-related gene signature displayed shorter progression-free survival time. Such correlation was rather specific for HG-SOC given that its performance was either statistically non-significant in the case of lung cancer or correlated with good prognosis in the case of breast cancer. Altogether, the study allowed us to assign a specific identity for MSCs derived from high-grade serous ovarian cancer. We demonstrated a cell-type specific transcriptional activity associated with HG-SOC-MSCs, which identifies them compared to N-MSCs from other districts and position them close to primary mesothelial and mesothelail-derived cells within the FANTOM5 dataset.
Insegnamento
Publisher
Università degli studi di Trieste
Languages
en
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