Cross talk between mesenchymal and glioblastoma stem cells: Communication beyond controversies

Abstract

Mesenchymal stem cells (MSCs) can be isolated from bone marrow or other adult tissues (adipose tissue, dental pulp, amniotic fluid, and umbilical cord). In vitro, MSCs grow as adherent cells, display fibroblast-like morphology, and self-renew, undergoing specific mesodermal differentiation. High heterogeneity of MSCs from different origin, and differences in preparation techniques, make difficult to uniform their functional properties for therapeutic purposes. Immunomodulatory, migratory, and differentiation ability, fueled clinical MSC application in regenerative medicine, whereas beneficial effects are currently mainly ascribed to their secretome and extracellular vesicles. MSC translational potential in cancer therapy exploits putative anti-tumor activity and inherent tropism toward tumor sites to deliver cytotoxic drugs. However, controversial results emerged evaluating either the therapeutic potential or homing efficiency of MSCs, as both antitumor and protumor effects were reported. Glioblastoma (GBM) is the most malignant brain tumor and its development and aggressive nature is sustained by cancer stem cells (CSCs) and the identification of effective therapeutic is required. MSC dualistic action, tumor-promoting or tumor-targeting, is dependent on secreted factors and extracellular vesicles driving a complex cross talk between MSCs and GBM CSCs. Tumor-tropic ability of MSCs, besides providing an alternative therapeutic approach, could represent a tool to understand the biology of GBM CSCs and related paracrine mechanisms, underpinning MSC-GBM interactions. In this review, recent findings on the complex nature of MSCs will be highlighted, focusing on their elusive impact on GBM progression and aggressiveness by direct cell-cell interaction and via secretome, also facing the perspectives and challenges in treatment strategies.

High Adenosine Extracellular Levels Induce Glioblastoma Aggressive Traits Modulating the Mesenchymal Stromal Cell Secretome

“…Within the TME, the interactions between MSCs and tumor cells involve several MSC-secreted signaling molecules, such as cytokines and growth factors that stimulate signaling pathways involved in tumor cell survival, growth, motility, and immune escape [ 53 ]. Among these, a pivotal role is played by IL-6 and TGF-β as inducers of GMT and cancer growth, IL-10 as a modulator of immune response and the chemoattractant IL-8 as a promoter of GBM motility [ 53 ]. The ability of BM-MSCs to release these cytokines in response to extracellular stimuli has been reported previously [ 54 ].…”

“…The CM of MSCs derived from adipose tissue induces the transition to a more invasive GBM cell phenotype modulating the EMT [ 57 ]. However, it is well known that the secretome of MSCs derived from diverse sources differently affected the GBM properties [ 53 ]. Herein, we first evaluated the effects of BM-MSCs derived CM on the regulation of GMT transcription factors ( Figure 5 B) and GMT markers ( Figure 5 C) in U343MG.…”

“…Although the mechanisms governing the glioma pathogenesis and development have been extensively studied, recently the role of TME has emerged as a pivotal player in modulating GBM aggressiveness and invasiveness [ 66 ]. The TME affects glioma cells by the interactions with other types of cells such as MSCs [ 53 , 67 ] or soluble factors released by cancer cells as well as other types of cells in the TME. In this context, a crucial role has been proposed for ADO and the entire purinome [ 30 ].…”

“…There is increasing evidence of the presence of MSCs in GBM recruited from local sites or from BM [ 89 ]. The MSC role in glioma progression is still debated considering that both anti-tumor and pro-tumor effects have been reported based on the source of MSCs, the cellular model used and the type of MSC-GBM interaction [ 53 ]. However, the puzzle is complicated by the presence of soluble factors in TME that could affect each single cell type but also the cross-talk between different cells in TME.…”

“…The communication in a cell system is bidirectional, and the effects evoked by the MSC-CM could not fully reflect the interplay between the MSCs and glioma cells [ 53 ]. Accordingly, different effects of the direct or soluble factor-mediated interaction of GBM stem cells with the human umbilical cord-derived MSCs have been reported [ 56 ].…”