On the origin and development of glioblastoma: multifaceted role of perivascular mesenchymal stromal cells

Abstract

Glioblastoma, IDH wild-type is the most common and aggressive form of glial tumors. The exact mechanisms of glioblastoma oncogenesis, including the identification of the glioma-initiating cell, are yet to be discovered. Recent studies have led to the hypothesis that glioblastoma arises from neural stem cells and glial precursor cells and that cell lineage constitutes a key determinant of the glioblastoma molecular subtype. These findings brought significant advancement to the comprehension of gliomagenesis. However, the cellular origin of glioblastoma with mesenchymal molecular features remains elusive. Mesenchymal stromal cells emerge as potential glioblastoma-initiating cells, especially with regard to the mesenchymal molecular subtype. These fibroblast-like cells, which derive from the neural crest and reside in the perivascular niche, may underlie gliomagenesis and exert pro-tumoral effects within the tumor microenvironment. This review synthesizes the potential roles of mesenchymal stromal cells in the context of glioblastoma and provides novel research avenues to better understand this lethal disease.

Keywords: Glioblastoma; Gliomagenesis; Mesenchymal stromal cells; Microenvironment; Neural crest; Pericytes; Perivascular fibroblasts.

Fig. 1

Signaling pathways involved in GB. Alteration rates are summarized for PI3K/MAPK, p53 and pRb regulatory pathways (created with Biorender.com)

Fig. 2

The origin of glioblastoma. During normal embryonic development and in the adult brain, normal neural stem cells generate glial and neuronal cells. Glioblastoma stem cells may arise from neural stem cells and/or glial precursor cells through the activation of oncogenic pathways. They may also originate from neural crest (NC)-derived, pMSC. During development, the NC arises from the neural tube and its component cells migrate and invade virtually all tissues, giving rise to numerous differentiated cells, such as pMSC, melanocytes, chondrocytes, peripheral neuronal and glial cells, thyroid C cells, and adrenergic cells (created with Biorender.com)

Fig. 3

Glioblastoma tumor micro-environment. GB TME is compartmentalized in perivascular, perinecrotic and peritumoral niches. Tumor-associated macrophages (Bone marrow-derived macrophages and microglia) and mesenchymal stromal cells play key roles in supporting GB proliferation, invasion and angiogenesis (created with Biorender.com)

Fig. 4

Perivascular mesenchymal stromal cells (pMSC) in normal brain and in glioblastoma. In normal brain, pMSC form the neurovascular unit, together with endothelial cells, astrocytes, and neurons. The neurovascular unit supplies nutrients and oxygen through the blood brain barrier. In glioblastoma (GB), resident pMSC and glioma stem cell-differentiated pMSC participate in vascular proliferation. Leaving the vessel, pMSC may give rise to GB stem cells, GB cells, and cancer-associated fibroblasts. (MPZ: Myelin P zero) (created with Biorender.com)

Fig. 5

Origin of mesenchymal glioblastoma subtype (created with Biorender.com)