See the article by Lim et al in this issue, pp. 1452–1462.
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is one of the most lethal cancers overall, with very high rates of recurrence and resistance to treatment. Current standard therapy for GBM mainly focuses on targeting cancer cells directly and uniformly. This approach is rarely curative, because GBM is heterogeneous at the cellular level and manipulates its microenvironment to evade therapy. The tumor microenvironment contains a large number of cells recruited from the surrounding stroma, including mesenchymal stemlike cells (MSLCs). These are cells of heterogeneous origins, which have the capacity to self-renew and undergo specific mesodermal differentiation.1 MSLCs seem to be attracted to glioma tumors, especially as a result of ionizing radiation.
In this issue of Neuro-Oncology, Lim et al show that signals from tumor-associated MSLCs can drive phenotypic changes in GBM cells, leading to greater tumor infiltration.2 Specifically, they found that MSLCs residing in GBMs secreted complement component 5a, which activated p38 mitogen-activated protein kinase in GBM cells. This, in turn, increased the expression of ZEB1 (zinc finger E-box-binding homeobox 1), boosting GBM cell infiltration. In their cohort, patients whose GBMs had greater numbers of MSLCs had worse clinical outcomes than patients whose tumors had fewer MSLCs. Tumor cells from the MSLC-high group produced more YKL40 (chitinase 3-like protein 1) and cluster of differentiation 44, suggesting a role for C5a-expressing MSLCs in the mesenchymal transition of GBM cells.
This study is in line with other recent reports on the direct and indirect interactions between MSLCs and GBM cells. An earlier study by this same research group demonstrated that MSLCs facilitate GBM cell migration by remodeling the extracellular matrix.3 In an in vitro study, Oliveira et al found that MSLCs could stimulate kinin-B1 receptors on certain GBM cells to promote infiltration.4 Sun et al found that in vivo combinations of human GBM cells SU3 with mouse bone marrow–derived MSLCs produced fusion cells that were more angiogenic than the parental cells.5 (It is, however, unclear if this observed phenomenon is relevant in the human tumor microenvironment.) Huang et al reported that tumor-associated endothelial cells (ECs) might also acquire an MSLC phenotype, driving tumor resistance. Glioma conditions induced stemlike activation and mesenchymal transition in ECs via the axis of hepatocyte growth factor/Wnt-β catenin/multidrug-resistance related protein 1. Wnt signaling in ECs was shown to be critical for EC chemoresistance, which modulates the sensitivity of GBMs to temozolomide.6
It is necessary to keep in mind that the crosstalk between MSLCs and GBM cells is very complex due to the heterogeneous nature of the mesenchymal cells, which can originate from many different tissues, including bone marrow, adipose tissue, and umbilical cord.1 In animal models of GBM, umbilical cord–derived MSLCs promoted apoptosis, whereas MSLCs from adipose tissue suppressed apoptosis and elevated angiogenesis.7 The effects of MSLCs may also vary by the mode of interactions, whether directly cell-to-cell or indirectly via chemokines, extracellular vesicles, and miRNAs.1
In sum, MSLCs are emerging as potential targets to limit GBM aggressiveness. Further understanding of exactly how they enhance GBM malignancy should provide better insights as to the best ways of blocking their effects.
Funding
N.T was supported by American Brain Tumor Association Basic Research Fellowship in Honor of Ned Smith and Team Smith Strong (BRF1900021). C.H. was supported by R01 NS102669 and R01 NS117104, in part by Northwestern University’s P50 CA221747 SPORE in Brain Tumor Research, as well as by the Lou and Jean Malnati Brain Tumor Institute.
Conflict of interest statement. The authors declare no conflicts of interest.
Authorship statement. ANT prepared the manuscript; CH revised the manuscript critically for important intellectual content.
References
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