The Roles of miRNA in Glioblastoma Tumor Cell Communication: Diplomatic and Aggressive Negotiations

Abstract

Glioblastoma (GBM) consists of a heterogeneous collection of competing cellular clones which communicate with each other and with the tumor microenvironment (TME). MicroRNAs (miRNAs) present various exchange mechanisms: free miRNA, extracellular vesicles (EVs), or gap junctions (GJs). GBM cells transfer miR-4519 and miR-5096 to astrocytes through GJs. Oligodendrocytes located in the invasion front present high levels of miR-219-5p, miR-219-2-3p, and miR-338-3p, all related to their differentiation. There is a reciprocal exchange between GBM cells and endothelial cells (ECs) as miR-5096 promotes angiogenesis after being transferred into ECs, whereas miR-145-5p acts as a tumor suppressor. In glioma stem cells (GSCs), miR-1587 and miR-3620-5p increase the proliferation and miR-1587 inhibits the hormone receptor co-repressor-1 (NCOR1) after EVs transfers. GBM-derived EVs carry miR-21 and miR-451 that are up-taken by microglia and monocytes/macrophages, promoting their proliferation. Macrophages release EVs enriched in miR-21 that are transferred to glioma cells. This bidirectional miR-21 exchange increases STAT3 activity in GBM cells and macrophages, promoting invasion, proliferation, angiogenesis, and resistance to treatment. miR-1238 is upregulated in resistant GBM clones and their EVs, conferring resistance to adjacent cells via the CAV1/EGFR signaling pathway. Decrypting these mechanisms could lead to a better patient stratification and the development of novel target therapies.

Keywords: glioblastoma; intercellular communication; miRNA; tumor microenvironment.

Figure 1

miRNA biogenesis. The red strand represents the guide strand and the black strand represents the passenger strand. Abbreviations: Pol II = polymerase II, pri-miRNA = primary miRNA, pre-miRNA = precursor miRNA, DGCR8 = DiGeorge syndrome critical region in gene 8, RISC = RNA-induced silencing complex.

Figure 2

The mechanisms of intercellular communication via miRNA. miRNA can be released as Ago2-bound miRNA or packaged in membrane structures (exosomes and extracellular vesicles). Exosomes and extracellular vesicles (EVs) are englobed by recipient cells through endocytosis or pinocytosis, and miRNAs exert their effects at this level. Cell-cell contact can be mediated by gap junctions (GJs) which directly transfer miRNA between adjacent cells. A similar mechanism is realized by nanotubes which permit direct contact at a distance. Connexins from GJs may also form hemichannels (HCs) and ensure communication with the extracellular environment.

Figure 3

Glioblastoma cell—astrocyte—endothelial cell exchanging miRNAs via gap junctions (GJs): miR-5096 and miR-4519 are transferred from glioblastoma (GBM) cells to astrocytes and favors astrocyte recruitment to support tumor formation. The same miR-5096 is exchanged with miR-145-5p from the endothelial cell, promoting angiogenesis.

Figure 4

(A) Microglia recruitment and M2 polarization under the influence of soluble factors and miRNAs from GBM cells. (B) miR-21, miR-451, and miR-146-5p roles in the activation of microglia (arrows—activation; dotted T-bars—inhibitory effect).

Figure 5

Vascular cell adhesion molecule 1 (VCAM-1)-mediated monocyte adhesion and differentiation towards the M2-macrophage (arrows—activation; dotted T-bars—inhibitory effect).

Figure 6

M2-macrophage maintenance by miRNA dysregulations in GBM. Hypoxic-derived exosomes contain miR-1246, which modulate STAT3 activity, alongside miR-21 EVs released from both GBM cells and M2-macrophages in order to support each other by STAT3 activation. miR-340-5p downregulation is a key mechanism of communication, since its downstream targets contribute both to M2 polarization and the maintenance of miR-340-5p underexpression; (arrows—activation; dotted T-bars inhibitory effect).

Figure 7

Natural killer T cells (NKT) differentiation and roles of the immunotolerant NKT in glioblastoma maintenance and immune evasion (arrows—activation; dotted T-bars—inhibitory effect).