Mesenchymal stem cells differentially affect the invasion of distinct glioblastoma cell lines

Abstract

Glioblastoma multiforme are an aggressive form of brain tumors that are characterized by distinct invasion of single glioblastoma cells, which infiltrate the brain parenchyma. This appears to be stimulated by the communication between cancer and stromal cells. Mesenchymal stem cells (MSCs) are part of the glioblastoma microenvironment, and their ‘cross-talk’ with glioblastoma cells is still poorly understood. Here, we examined the effects of bone marrow-derived MSCs on two different established glioblastoma cell lines U87 and U373. We focused on mutual effects of direct MSC/glioblastoma contact on cellular invasion in three-dimensional invasion assays in vitro and in a zebrafish embryo model in vivo. This is the first demonstration of glioblastoma cell-type-specific responses to MSCs in direct glioblastoma co-cultures, where MSCs inhibited the invasion of U87 cells and enhanced the invasion of U373. Inversely, direct cross-talk between MSCs and both of glioblastoma cell lines enhanced MSC motility. MSC-enhanced invasion of U373 cells was assisted by overexpression of proteases cathepsin B, calpain1, uPA/uPAR, MMP-2, -9 and -14, and increased activities of some of these proteases, as determined by the effects of their selective inhibitors on invasion. In contrast, these proteases had no effect on U87 cell invasion under MSC co-culturing. Finally, we identified differentially expressed genes, in U87 and U373 cells that could explain different response of these cell lines to MSCs. In conclusion, we demonstrated that MSC/glioblastoma cross-talk is different in the two glioblastoma cell phenotypes, which contributes to tumor heterogeneity.

Mesenchymal Stem Cells Relevance in Multicellular Bioengineered 3D In Vitro Tumor Models

“…Thus underlining the importance of accounting for the heterogeneity and phenotypic variations present in actively proliferating tumors. [92] These results emphasize the necessity of considering the use of MSCs from several tissue origins, as well as different types of malignant cells to account for intrinsic in vivo tumor cellular heterogeneity.…”

“…Tumor heterogeneity may also play a role in cancer‐MSCs interactions and hence influence the conclusions extrapolated from in vitro models. A recent study by Breznik and co‐workers, 2017, demonstrated how phenotypically different cell lines used as models for glyoblastoma can lead to different MSC‐cancer cells interactions and outcomes, with U87 cells showing decreased invasive potential, and U373 cells displaying the opposite, both in vivo and in vitro . The researchers attributed this difference to alternatively favored metabolic pathways resulting from TGF‐β release by MSCs.…”

“…Human multiple myeloma (MM) aspirates Scaffold Hydrogel composed by 0.5% PuraMatrix IMiDs, bortezomib, carfilzomib, doxorubicin, dexamethasone, melphalan [82] BM-MSC Human glioma À U87 À U373 Spheroids embedded into a scaffold Spheroids embedded in collagen I, laminin, or matrigel None [92] www.advancedsciencenews.com www.biotechnology-journal.com increasing EMT and ERK1/2 activity. These researchers used a lower ratio of MSCs to cancer cells (1:500 and 1:1000) when compared to other studies performed by Mcandrews and coworkers (MSCs:Cancer cells, 1:1 ratio [27] ), or Zhu and co-workers (MSCs:Cancer cells, 1:2 and 1:5 ratio [78] ), in which different ratios were employed to establish the co-culture of MSCs and breast cancer cells in hydrogel-based scaffolds.…”

“…A recent study by Breznik and co-workers, 2017, demonstrated how phenotypically different cell lines used as models for glyoblastoma can lead to different MSC-cancer cells interactions and outcomes, with U87 cells showing decreased invasive potential, and U373 cells displaying the opposite, both in vivo and in vitro. [92] The researchers attributed this difference to alternatively favored metabolic pathways resulting from TGF-b release by MSCs. Thus underlining the importance of accounting for the heterogeneity and phenotypic variations present in actively proliferating tumors.…”

New Proposal to Define the Fascial System

“…The embryonic mesenchyme, or embryonic connective tissue or undifferentiated mesenchyme, is made up of star-shaped branched cells with a high mitotic rate (high reproductive capacity); they are considered as pluripotent cells because they can differentiate into several different tissues [28,29,30]. …”