Abstract
IntroductionTumor microenvironment conferred by stromal (mesenchymal) stem cells (MSCs) plays a key role in tumor development, progression, and response to therapy. Defining the role of MSCs in tumorigenesis is crucial for their safe utilization in regenerative medicine. Herein, we conducted comprehensive investigation of the cross-talk between human MSCs (hMSCs) and 12 cancer cell lines derived from breast, prostate, colon, head/neck and skin.MethodsHuman bone marrow-derived MSC line expressing green fluorescence protein (GFP) (hMSC-GFP) were co-cultured with the following cancer cell lines: (MCF7, BT-20, BT-474, MDA-MB-468, T-47D, SK-BR-3, MDA-MB-231, PC-3, HT-29, MDA-MB-435s, and FaDu) and changes in their morphology were assessed using fluorescent microscopy. For cellular tracking, cells were labeled with Vybrant DiO, DiL, and DiD lipophilic dyes. Time-lapse microscopy was conducted using Nikon BioStation IM-Q. Stable expression of mCherry, and luciferase genes was achieved using lentiviral technology. IL1-Beta neutralizing experiments were conducted using soluble recombinant IL-1R (srIL-1R). Changes in gene expression in sorted hMSCs were assessed using Agilent microarray platform while data normalization and bioinformatics were conducted using GeneSpring software.ResultsWe observed a dynamic interaction between cancer cells and hMSCs. High CDH1 (E-cadherin) and low IL1-Beta expression by cancer cells promoted reorganization of hMSCs into a niche-like formation, which was dependent on direct cell-cell contact. Our data also revealed transfer of cellular components between cancer cells and hMSCs as one possible mechanism for intercellular communication. Global gene expression analysis of sorted hMSCs following co-culturing with MCF7 and BT-20 cells revealed enrichment in signaling pathways related to bone formation, FAK and MAPKK signaling. Co-culturing hMSCs with MCF7 cells increased their growth evidenced by increase in Ki67 and PCNA staining in tumor cells in direct contact with hMSCs niche. On the other hand, co-culturing hMSCs with FaDu, HT-29 or MDA-MB-231 cells led remarkable decline in their cell growth.ConclusionsDynamic interaction exists between hMSCs and cancer cells. CDH1 and IL1-Beta expression by cancer cells mediates the crosstalk between hMSCs and cancer cells. We propose a model where hMSCs act as the first line of defense against cancer cell growth and spread.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0123-0) contains supplementary material, which is available to authorized users.
Highlights
Tumor microenvironment conferred by stromal stem cells (MSCs) plays a key role in tumor development, progression, and response to therapy
Changes in Human bone marrow-derived mesenchymal stem cell (hMSC) morphology when co-cultured with cancer cell lines We have previously reported significant changes in hMSC morphology when exposed to tumor-derived conditioned media, which was dependent on the nature of tumor cells [20]
Our data revealed dynamic bidirectional interaction between hMSCs and tumor cells. Data show that this interaction is dependent on the nature rather than the type of tumor cells and that cadherin type 1 (CDH1) and IL-1β expression by tumor cells are key factors in determining the outcome of hMSC–tumor cross-talk
Summary
Tumor microenvironment conferred by stromal (mesenchymal) stem cells (MSCs) plays a key role in tumor development, progression, and response to therapy. Liu et al [5] reported that MSCs promoted breast cancer stem cell expansion via interleukin (IL)-6 and chemokine (C–X–C motif) ligand 7 signaling. Huang et al [6] demonstrated that activation of caspase 3 by tumor or stroma cells triggers tumor repopulation during radiation therapy While these reports suggest a pro-tumorigenic role for MSCs, a number of other studies revealed an antitumor effect of MSCs. For example, Cooke et al [7] have shown that targeted depletion of pericytes (which are part of the MSC lineage) in vivo promoted tumor metastasis, which was mediated via hypoxia-induced epithelial to mesenchymal transition. The precise role of MSCs in tumorigenicity and the conditions under which MSCs exert pro-tumor or antitumor effects need to be determined
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