Netrin-1 in Glioblastoma Neovascularization: The New Partner in Crime?

Abstract

Glioblastoma (GBM) is the most aggressive and common primary tumor of the central nervous system. It is characterized by having an infiltrating growth and by the presence of an excessive and aberrant vasculature. Some of the mechanisms that promote this neovascularization are angiogenesis and the transdifferentiation of tumor cells into endothelial cells or pericytes. In all these processes, the release of extracellular microvesicles by tumor cells plays an important role. Tumor cell-derived extracellular microvesicles contain pro-angiogenic molecules such as VEGF, which promote the formation of blood vessels and the recruitment of pericytes that reinforce these structures. The present study summarizes and discusses recent data from different investigations suggesting that Netrin-1, a highly versatile protein recently postulated as a non-canonical angiogenic ligand, could participate in the promotion of neovascularization processes in GBM. The relevance of determining the angiogenic signaling pathways associated with the interaction of Netrin-1 with its receptors is posed. Furthermore, we speculate that this molecule could form part of the microvesicles that favor abnormal tumor vasculature. Based on the studies presented, this review proposes Netrin-1 as a novel biomarker for GBM progression and vascularization.

Netrin-1: A Serum Marker Predicting Cognitive Impairment after Spinal Cord Injury

“…Evidence suggests that Netrin-1 may be a promising drug candidate for reducing stroke severity and improving prognosis, and its neuroprotective mechanisms may be achieved through regulation of angiogenesis, autophagy, apoptosis, and neuroinflammation [ 29 ]. Glioblastoma is one of the most common tumors in neurosurgery, and evidence in recent years suggests that Netrin-1, as an atypical angiogenic ligand, may be involved in the promotion of neovascularization in glioblastoma [ 30 ]. Evidence that Netrin-1 is involved in the pathogenesis of Alzheimer's disease has been found in cells, animals, and clinical experiments, indicating that Netrin-1 may be involved in the regulation of neuroplasticity [ 31 – 33 ].…”

Shaping the brain vasculature in development and disease in the single-cell era

“…Many of the discussed classic axon guidance cues of the NVL are reactivated in glial brain tumours in a general way. Besides possible involvement of netrin 1 and semaphorins in glioblastoma vascularization 252 , the role of additional classic and non-classic axon guidance cues and CNS-specific cues in this process remains to be explored.…”

Glioblastoma-Specific Strategies of Vascularization: Implications in Anti-Angiogenic Therapy Resistance

“…Two distinct vascular phenotypes associated with different statuses of the EGFR gene have been described, characterized by GSC-derived pericytes closely related to ECs or delocalized with the disruption of the BBB [ 123 , 124 ]. Interestingly, an emerging regulatory mechanism of this transdifferentiation process involves netrin-1, a protein recently postulated as a non-canonical angiogenic ligand [ 125 ]. In particular, it has been hypothesized that the netrin-1 contained in exosomes secreted in the microenvironment could interact with the receptor UNC5, trigger the activation of NF-kB, and regulate the transdifferentiation to pericyte [ 125 ].…”

“…Interestingly, an emerging regulatory mechanism of this transdifferentiation process involves netrin-1, a protein recently postulated as a non-canonical angiogenic ligand [ 125 ]. In particular, it has been hypothesized that the netrin-1 contained in exosomes secreted in the microenvironment could interact with the receptor UNC5, trigger the activation of NF-kB, and regulate the transdifferentiation to pericyte [ 125 ].…”