Different Effects of Human Umbilical Cord Mesenchymal Stem Cells on Glioblastoma Stem Cells by Direct Cell Interaction or Via Released Soluble Factors

Abstract

Glioblastoma (GBM), the most common primary brain tumor in adults, is an aggressive, fast-growing and highly vascularized tumor, characterized by extensive invasiveness and local recurrence. In GBM and other malignancies, cancer stem cells (CSCs) are believed to drive invasive tumor growth and recurrence, being responsible for radio- and chemo-therapy resistance. Mesenchymal stem cells (MSCs) are multipotent progenitors that exhibit tropism for tumor microenvironment mediated by cytokines, chemokines and growth factors. Initial studies proposed that MSCs might exert inhibitory effects on tumor development, although, to date, contrasting evidence has been provided. Different studies reported either MSC anti-tumor activity or their support to tumor growth. Here, we examined the effects of umbilical cord (UC)-MSCs on in vitro GBM-derived CSC growth, by direct cell-to-cell interaction or indirect modulation, via the release of soluble factors. We demonstrate that UC-MSCs and CSCs exhibit reciprocal tropism when co-cultured as 3D spheroids and their direct cell interaction reduces the proliferation of both cell types. Contrasting effects were obtained by UC-MSC released factors: CSCs, cultured in the presence of conditioned medium (CM) collected from UC-MSCs, increased proliferation rate through transient ERK1/2 and Akt phosphorylation/activation. Analysis of the profile of the cytokines released by UC-MSCs in the CM revealed a strong production of molecules involved in inflammation, angiogenesis, cell migration and proliferation, such as IL-8, GRO, ENA-78 and IL-6. Since CXC chemokine receptor 2 (CXCR2), a receptor shared by several of these ligands, is expressed in GBM CSCs, we evaluated its involvement in CSC proliferation induced by UC-MSC-CM. Using the CXCR2 antagonist SB225002, we observed a partial but statistically significant inhibition of CSC proliferation and migration induced by the UC-MSC-released cytokines. Conversely, CXCR2 blockade did not reduce the reciprocal tropism between CSCs and UC-MSCs grown as spheroids. In conclusion, we show that direct (cell-to-cell contact) or indirect (via the release of soluble factors) interactions between GBM CSCs and UC-MSCs in co-culture produce divergent effects on cell growth, invasion and migration, with the former mainly causing an inhibitory response and the latter a stimulatory one, involving a paracrine activation of CXCR2.

Quantitative Tracking Tumor Suppression Efficiency of Human Umbilical Cord-Derived Mesenchymal Stem Cells by Bioluminescence Imaging in Mice Hepatoma Model

“…UC-MSCs exhibit typically fibroblast-like morphology ( Fig. 1a) and flow cytometry analysis of surface marker expression revealed that these cells express high levels of CD 34, CD44, CD45, CD73, CD90, CD54, CD105, HLA-DR (Table 1), which is consistent with the characteristics of UC-MSCs that have been reported (32). UC-MSC has the potential to differentiate into osteogenic, adipogenic or chondrogenic in vitro under appropriate induction conditions.…”

Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

“…Accumulating evidences indicate that the cross-talk between MSCs and tumor cells results in both pro-tumor and antitumor effects, raising safety concerns for clinical application in oncology (Barkholt et al, 2013) (Figure 3). The discrepancies in the ability of MSCs to promote or suppress tumor development may be attributable to differences in experimental tumor models, MSC tissue source, dose or timing of the MSC treatment, cell delivery method, control group chosen, and other experimental conditions (Bortolotti et al, 2015;Bajetto et al, 2017). In this regard, a study demonstrated that direct (cell-to-cell contact) or indirect (released soluble factors) interaction between umbilical cord MSCs and glioblastoma stem cells produces divergent effects on cell growth, invasion and migration (Bajetto et al, 2017).…”

“…The discrepancies in the ability of MSCs to promote or suppress tumor development may be attributable to differences in experimental tumor models, MSC tissue source, dose or timing of the MSC treatment, cell delivery method, control group chosen, and other experimental conditions (Bortolotti et al, 2015;Bajetto et al, 2017). In this regard, a study demonstrated that direct (cell-to-cell contact) or indirect (released soluble factors) interaction between umbilical cord MSCs and glioblastoma stem cells produces divergent effects on cell growth, invasion and migration (Bajetto et al, 2017). Additionally, the application of MSCs for cancer patients is a more complex situation in which other factors have to be taken into consideration.…”

The impact of Mesenchymal Stem Cells and their secretome as a treatment for gliomas

“…Another interesting finding was the contrasting effect observed by Bajetto et al (2017) regarding direct cell-cell contact and secretome-mediated effects [79]. Human UC-MSCs cultured in direct contact with GBM CSCs inhibited their proliferation, while the factors secreted by UC-MSCs increased CSCs proliferation rate through transient ERK1/2 and Akt phosphorylation/activation.…”

“…Among those factors IL8, CXCL1, CXCL5 and IL6 were present. In addition, activation of the CXC chemokine receptor 2 (expressed in GBM cells) seems to be crucial for the effects observed [79].…”