Wharton's Jelly-Derived Mesenchymal Stromal Cells and Fibroblast-Derived Extracellular Matrix Synergistically Activate Apoptosis in a p21-Dependent Mechanism in WHCO1 and MDA MB 231 Cancer Cells In Vitro.

Kevin Dzobo,M Iqbal Parker,Michael S Pepper,Nicholas E Thomford,Matjaz Vogelsang,Collet Dandara,Karlien Kallmeyer

doi:10.1155/2016/4842134

Kevin Dzobo, M Iqbal Parker + Show 5 more

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https://doi.org/10.1155/2016/4842134

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Abstract

The tumour microenvironment plays a crucial role in tumour progression and comprises tumour stroma which is made up of different cell types and the extracellular matrix (ECM). Mesenchymal stromal cells (MSCs) are part of the tumour stroma and may have conflicting effects on tumour growth. In this study we investigated the effect of Wharton's Jelly-derived MSCs (WJ-MSCs) and a fibroblast-derived ECM (fd-ECM) on esophageal (WHCO1) and breast (MDA MB 231) cancer cells in vitro. Both WJ-MSCs and the fd-ECM, alone or in combination, downregulate PCNA, cyclin D1, Bcl-2, Bcl-xL, and MMPs and upregulate p53 and p21. p21 induction resulted in G2 phase cell cycle arrest and induced apoptosis in vitro. Our data suggest that p21 induction is via p53-dependent and p53-independent mechanisms in WHCO1 and MDA MB 231 cells, respectively. Vascular endothelial growth factor, Akt, and Nodal pathways were downregulated in cancer cells cocultured with WJ-MSCs. We also demonstrate that WJ-MSCs effects on cancer cells appear to be short-lived whilst the fd-ECM effect is long-lived. This study shows the influence of tumour microenvironment on cancer cell behaviour and provides alternative therapeutic targets for potential regulation of tumour cells.

Highlights

Mesenchymal stromal cells (MSCs) are a heterogeneous population of stromal derived cells that contain a subpopulation of multipotent progenitor cells defined according to their ability to self-renew and differentiate into tissues of mesodermal and nonmesodermal lineages [1,2,3]
We show in this study that both Wharton’s Jelly-derived MSCs (WJ-MSCs) and the fdECM inhibit the proliferation of WHCO1 and MDA MB 231 cancer cells and induced G2 phase cell cycle arrest leading to apoptosis
We have previously shown that the fd-extracellular matrix (ECM) directs embryonic stem cell differentiation via the endodermal lineage [34] and we explored the possibility that this in vitro 3D ECM synthesised by fibroblasts, alone or in combination with Wharton’s Jelly (WJ)-MSCs, could reprogram the tumour cell phenotype

Summary

Introduction

Mesenchymal stromal cells (MSCs) are a heterogeneous population of stromal derived cells that contain a subpopulation of multipotent progenitor cells defined according to their ability to self-renew and differentiate into tissues of mesodermal and nonmesodermal lineages [1,2,3]. MSCs have the ability to influence the growth of other cells through the release of growth factors, cytokines, and antifibrotic mediators. MSCs have the ability to repair and regenerate various types of damaged tissues, their use in cell therapy and tissue regeneration [8, 9]. MSCs have received attention for their role in tumour growth and metastasis [10,11,12,13]. Several studies have shown contradictory results regarding the role of MSCs during tumour growth and metastasis [14,15,16]. This is mainly due to the involvement of many factors in determining whether MSCs promote or inhibit

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