Human Mesenchymal Stem Cells Exploit the Immune Response Mediating Chemokines to Impact the Phenotype of Glioblastoma

Abstract

In contrast to the application of human mesenchymal stem cells (hMSCs) in regenerative medicine, only a limited number of studies are addressing their use in anticancer therapy. As the latter may represent a new hope to improve the survival of patients with glioblastoma multiformae (GBM), the most common and malignant form of the brain tumors, we aimed to investigate the interactions of hMSCs and GBM cells under in vitro conditions. Four hMSC clones and three different GBM cell lines were used to study their mutual paracrine interactions in cocultures compared to their monocultures, where cells were grown under the same experimental conditions. The effects on cell growth, proliferation, and invasion in Matrigel were quantified. Further, bioinformatics tools were used to relate these results to the data obtained from cytokine macroarrays and cDNA microarrays that revealed proteins and genes significantly involved in cellular crosstalk. We showed that hMSCs are responsible for the impairment of GBM cell invasion and growth, possibly via induction of their senescence. On the other hand, GBM cells inversely affected some of these characteristics in hMSCs. We found CCL2/MCP-1 to be the most significantly regulated chemokine during hMSC and U87-MG paracrine signaling in addition to several chemokines that may account for changed cocultured cells' phenotype by affecting genes associated with proliferation (Pmepa-1, NF-κB, invasion (EphB2, Sod2, Pcdh18, Col7A1, Gja1, Mmp1/2), and senescence (Kiaa1199, SerpinB2). As we functionally confirmed the role of CCL2/MCP-1 in GBM cell invasion we thereby propose a novel mechanism of CCL2/ MCP-1 antimigratory effects on GBM cells, distinct from its immunomodulatory role. Significant alterations of GBM phenotype in the presence of hMSCs should encourage the studies on the naive hMSC use for GBM treatment.

Mesenchymal stem cells as therapeutic agents and in gene delivery for the treatment of glioma

“…These also increased the sensitivity of the glioma cell toward temozolomide. This was consistent with the study of Motaln et al (2012) that human BM-MSCs may promote the senescence of the tumor cells by inducing cell morphology and cytokine changes.…”

Glioblastoma‐mesenchymal stem cell communication modulates expression patterns of kinin receptors: Possible involvement of bradykinin in information flow

“…The key finding of our present results is that indirect and direct effects of MSC on GBM U87-MG cells were associated with increased expression levels of both, B1 and B2 receptors, possibly triggering increased invasiveness. By the same token, increased levels of kinin receptor expression would not support previously observed inhibition of invasion of GBM cells in indirect interactions with MSC (9). With respect to the underlying mechanism, Montana and Sontheimer (16) showed that bradykinin via B2R-induced [Ca 21 ] i transients enhanced and directed invasion of glioma cells toward blood vessels.…”

“…The indirect co-cultures were set up in duplicates using six-well Transwell inserts (Corning Costar, Sigma) with 0.4 lm pore size and the corresponding six-well plate, as described previously (9). When indirectly co-cultured, MSC were always plated in the bottom and U87 were always plated in the insert at the density of 1.5 3 10 5 cells in 3 ml final volume of media per well and cultured for 72 h. MSC were left to attach for 4 h before adding the inserts with U87 cells.…”

“…However, reports on MSC effects are contradictory as recently reviewed (7) and possibly depend on the tumor type and stage (8). Indeed, the cross-talk between both cells types in the indirect in vitro co-culture model resulted in alterations of expression of over 500 and 300 genes, respectively, in MSC and GBM (9). These are most likely responsible for the impairment of GBM growth and invasion, due to the enhanced expression of cell adhesion-related genes in the GBM cell line.…”

Development of Anti-Cancer Stem Cells as Theranostic Agents in the Treatment of Different Cancer Types: An Update

“…Unaltered stem cells can have inherent anti-tumor properties to factors that are released by stem cells and physical relationship and connections that are recognized among the stem cells and tumor cells [151][152][153]. Stem cells have been established in many different ways to cover up cancer and several are in detail as given below.…”