Pericyte–Glioblastoma Cell Interaction: A Key Target to Prevent Glioblastoma Progression

Abstract

Multiple biological processes rely on direct intercellular interactions to regulate cell proliferation and migration in embryonic development and cancer processes. Tumor development and growth depends on close interactions between cancer cells and cells in the tumor microenvironment. During embryonic development, morphogenetic signals and direct cell contacts control cell proliferation, polarity, and morphogenesis. Cancer cells communicate with cells in the tumor niche through molecular signals and intercellular contacts, thereby modifying the vascular architecture and antitumor surveillance processes and consequently enabling tumor growth and survival. While looking for cell-to-cell signaling mechanisms that are common to both brain development and cancer progression, we have studied the infiltration process in glioblastoma multiforme (GBM), which is the most malignant primary brain tumor and with the worst prognosis. Cell-to-cell contacts, by means of filopodia-like structures, between GBM cells and brain pericytes (PCs) are necessary for adequate cell signaling during cancer infiltration; similarly, contacts between embryonic regions, via cytonemes, are required for embryo regionalization and development. This GBM–PC interaction provokes two important changes in the physiological function of these perivascular cells, namely, (i) vascular co-option with changes in cell contractility and vascular malformation, and (ii) changes in the PC transcriptome, modifying the microvesicles and protein secretome, which leads to the development of an immunosuppressive phenotype that promotes tumor immune tolerance. Moreover, the GTPase Cdc42 regulates cell polarity across organisms, from yeast to humans, playing a central role in GBM cell–PC interaction and maintaining vascular co-option. As such, a review of the molecular and cellular mechanisms underlying the development and maintenance of the physical interactions between cancer cells and PCs is of particular interest.

Pericytes Are Immunoregulatory Cells in Glioma Genesis and Progression

“…We have demonstrated that the principal target cell of GBM during vascular co-option is the pericyte [7,11], which constitutes the primary cell type in the normal brain perivascular space. Then, cell-to-cell contact between GBMcs and PCs, along with the subsequent activation of pro-tumoral cellular and molecular processes in PCs, is essential for GBM growth and progression (Figure 2) ( [7,11,12] and reviewed in [13]). Additionally, following primary vascular co-option after GBM initial singularity, the GBM is generated and will invade the surrounding parenchyma, with the subsequent alteration of the brain-blood barrier (BBB), allowing other cells such as tumor-associated macrophages (TAMs) to infiltrate perivascular spaces, as well as the activation of microglia in the tumor microenvironment (TME) [14,15].…”

“…Glioblastoma cells create an immunosuppressive TME at the edges of the tumor, where they encounter normal brain parenchyma cells, protecting GBMcs from detection and elimination by the immune system. They can release immunoregulative factors and establish cellular interactions that suppress immune responses, allowing the tumor to evade detection and destruction by immune cells [11][12][13][14]. Communication between GBMcs and TME cells is achieved through exosome interchange, soluble factors such as cytokines, chemokines, matrix-remodeling enzymes, and growth factors.…”

“…Communication between GBMcs and TME cells is achieved through exosome interchange, soluble factors such as cytokines, chemokines, matrix-remodeling enzymes, and growth factors. Additionally, it has been demonstrated that GBMcs employ cell-to-cell contact-dependent signals, including filopodia, intercellular gap junctions, and tunneling nanotubes (reviewed in [13,15]). Therefore, it is fundamental to understand the processes activated by the communication between GBMcs and normal cells in the TME for GBM initiation and progression, as well as for better targeting GBM therapeutically (reviewed in [16]).…”

“…Given that the immunotolerance of cancer may be initiated by interactions between GBMcs and PCs [11][12][13], which commence during the early stages of tumor development subsequent to the initial singularity of GBM in the hypervascularized SVZ, the conditioning of PCs by GBMcs in the process of vascular co-option, conferring an immunosuppressive state in the TME, may strongly diminish or impede the efficiency of immunological stimulation-dependent therapies. Therefore, these immunotherapies, which are specifically targeted at cancer or other cells within the TME, have little chance to have success without previously suppress PCs' immunoregulatory activity.…”

“…This molecular heterogeneity observed in immunocompetent cells within the TME may represent distinct reactive states resulting from the interaction between GBMcs and TME cells. Given the absence of definitive and reliable markers for specific immunocompetent cells within the TME, it is plausible to consider that conditioned PCs could potentially be identified as TAMs or reactive microglia, particularly during the early stages of GBM initiation and at the infiltration edges where vascular co-option predominates and where both PC proliferation and migration have been observed [11][12][13].…”