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.
Highlights
Tumor heterogeneity is recognized as one of the key reasons for ineffective radiotherapy, chemotherapy and recurrence in many cancers, as occurs in the most aggressive glioma stage WHO IV, glioblastoma multiforme (GBM)
Glioblastoma (GBM) cell heterogeneity is a consequence of the presence of different tumor and infiltrating stromal cells, among which the mesenchymal stem cells (MSCs) have not been studied to a great extent, compared to various types of immune cells
The present study clearly demonstrates the intertwined relations of both kinds of heterogeneity in vitro and in vivo, showing opposite effects on invasiveness of two types of GBM cells by co-culturing them with bone marrow-derived MSCs
Summary
Tumor heterogeneity is recognized as one of the key reasons for ineffective radiotherapy, chemotherapy and recurrence in many cancers, as occurs in the most aggressive glioma stage WHO IV, glioblastoma multiforme (GBM). Clonal evolution via GBM stem-like cells gives rise to heterogeneous populations of differentiated, invasive GBM cells [3]. We demonstrated that the generally used GBM cell lines, U87 and U373, show distinct phenotypes and they differ in expression of genes associated with extracellular matrix (ECM) organization, developmental processes and cell differentiation [4]. Upon the in vitro co-culturing of U87 and U373 cells, we identified different clusters of de-regulated genes in these two GBM cell lines. The molecular ‘cross-talk’ between U87 and U373 cells strikingly increased the invasiveness of both cells types [4], reflecting the mutually induced phenotypic changes, as may occur in tumors in vivo, and as has been suggested recently by Ricklefs et al [5]
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