Pericytes in Glioblastomas: Multifaceted Role Within Tumor Microenvironments and Potential for Therapeutic Interventions

Abstract

Glioblastoma (GBM) is an aggressive and lethal disease that often results in a poor prognosis. Unlike most solid tumors, GBM is characterized by diffuse infiltrating margins, extensive angiogenesis, hypoxia, necrosis, and clonal heterogeneity. Recurrent disease is an unavoidable consequence for many patients as standard treatment options such as surgery, radiotherapy, and chemotherapy have proven to be insufficient in causing long-term survival benefits. Systemic delivery of promising drugs is hindered due to the blood-brain barrier and non-uniform perfusion within GBM tissue. In recent years, many investigations have highlighted the role of GBM stem cells (GSCs) and their microenvironment in the initiation and maintenance of tumor tissue. Preclinical and early clinical studies to target GSCs and microenvironmental components are currently underway. Of these strategies, immunotherapy using checkpoint inhibitors and redirected cytotoxic T cells have shown promising results in early investigations. But, GBM microenvironment is heterogenous and recent investigations have shown cell populations within this microenvironment to be plastic. These studies underline the importance of identifying the role of and targeting multiple cell populations within the GBM microenvironment which could have a synergistic effect when combined with novel therapies. Pericytes are multipotent perivascular cells that play a vital role within the GBM microenvironment by assisting in tumor initiation, survival, and progression. Due to their role in regulating the blood-brain barrier permeability, promoting angiogenesis, tumor growth, clearing extracellular matrix for infiltrating GBM cells and in helping GBM cells evade immune surveillance, pericytes could be ideal therapeutic targets for stymieing or exploiting their role within the GBM microenvironment. This chapter will introduce hallmarks of GBM and elaborate on the contributions of pericytes to these hallmarks by examining recent findings. In addition, the chapter also highlights the therapeutic value of targeting pericytes, while discussing conventional and novel GBM therapies and obstacles to their efficacy.

Disproportion in Pericyte/Endothelial Cell Proliferation and Mechanisms of Intussusceptive Angiogenesis Participate in Bizarre Vessel Formation in Glioblastoma

“…The marked hyperplasia and hypertrophy of pericytes, which occupied the entire EC abluminal surface of the frequently folded bizarre vessels, suggest that their contractile force can be an important factor in vessel folding and contraction (e.g., capillaries with tortuous and narrow lumen in glomeruloid bodies). Likewise, the great proliferation of pericytes in the BM has morphogenic and clinical interest since pericytes facilitate (a) GBM growth through immunosuppression (reduction in T-cell activation) and anti-inflammatory response, and (b) GBM cell resistance to temozolomide or chemotherapeutic efficacy by targeting glioma stem cell-derived pericytes, which disrupt the blood-tumor barrier [40][41][42][43][44][45]. Likewise, the inhibition of NG2 proteoglycan, which promotes tumor vascularization [46] and is expressed by pericytes, induces a decrease in GBM microvessels [47,48].…”

MRI radiomics to differentiate between low grade glioma and glioblastoma peritumoral region

“…The PTR of GBM has been described as the area around contrast enhancement identi ed as hyperintense on T2 weighted and T2-FLAIR MRI sequences [16]. The complex microenvironment in the PTR region contains edema, vascular alterations, neoplastic cells, astrocytes, oligodendrocytes, in ammatory cells, microglia, stromal cells, pericytes [17], as well as GBM stem cells [18]. As approximately 90 percent of recurrences are witnessed in the PTR region [19], understanding tumor cell heterogeneity and microinvasion of cells in this region have the potential to impact treatment.…”

Pericytes: Intrinsic Transportation Engineers of the CNS Microcirculation

“…Stable microvasculature was shown to constitute a “dormant niche,” whereas neoangiogenic sprouts initiate metastatic outgrowth ( Ghajar et al, 2013 ; Weis and Cheresh, 2013 ). A multifaceted role of pericytes in various critical events of Glioblastoma Multiforme (GBM) initiation, establishment, maintenance, and progression has been proposed ( Sattiraju and Mintz, 2019 ). Strikingly, GBM-activated pericytes were shown to support tumor growth via immunosuppression ( Valdor et al, 2017 ; Sena et al, 2018 ).…”