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Table of Contents
REVIEW
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 35-42

Molecular mechanisms involved in angiogenesis and potential target of antiangiogenesis in human glioblastomas


Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China

Date of Web Publication30-Apr-2018

Correspondence Address:
Dr. Bao-Hui Liu
Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_10_17

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  Abstract 

Glioblastoma multiforme (GBM) is the most devastating and common primary malignant brain tumor in adults. Angiogenesis as a hallmark in glioblastoma has attracted more and more attention of the research community. Over the past years, several systematic studies have provided vital results in this field discovering alterations in unanticipated number of genes and other regulatory factors and the associated signaling pathways. Recent discoveries about such genes and signaling pathway associated with angiogenesis in GBM provide a picture of the genomic routes in angiogenesis and antiangiogenesis pathways and may lay the foundation for improved antiangiogenesis therapy and clinical care. In this review, we discuss several such recent progresses in the genes associated with GBM angiogenesis/antiangiogenesis pathways and explore the potential new targets for GBM treatment.

Keywords: Angiogenesis, antiangiogenic therapy, genes, glioblastoma, resistance, signaling pathway


How to cite this article:
Xu Y, Yuan FE, Chen QX, Liu BH. Molecular mechanisms involved in angiogenesis and potential target of antiangiogenesis in human glioblastomas. Glioma 2018;1:35-42

How to cite this URL:
Xu Y, Yuan FE, Chen QX, Liu BH. Molecular mechanisms involved in angiogenesis and potential target of antiangiogenesis in human glioblastomas. Glioma [serial online] 2018 [cited 2020 Aug 15];1:35-42. Available from: http://www.jglioma.com/text.asp?2018/1/2/35/231495


  Introduction Top


Glioblastoma multiforme (GBM), WHO grade IV astrocytoma, is one of the most common primary malignant tumors of the central nervous system in adults.[1],[2] Despite the multimodal therapeutic strategies, including surgery, radiation, and chemotherapy with temozolomide (TMZ), the median overall survival of GBM patients remains as low as a little over 1 year, with the overall 5-year survival rate of <5%.[3],[4]

It is well known that the angiogenesis is a hallmark of cancers.[5] "Angiogenic switch" is a process through which tumor cells develop an angiogenic phenotype, thus initiating angiogenesis.[6] The "angiogenic switch" can promote tumorigenesis and invasion through activating oncogenes and/or downregulating tumor-suppressor genes while upregulating the expression/signaling of angiogenic pathways.[7],[8],[9] Thus, angiogenesis is termed an important influencing factor in tumor growth, and now, increasing number of studies have investigated the potential of antiangiogenic treatment strategy against GBM.[10],[11]

In this review, we discuss several recent progresses in the genes associated with GBM angiogenesis/antiangiogenesis pathways and explore potential new targets in this regard.


  Genes Potentially Related to Glioblastoma Angiogenesis Top


There are a number of genes related to the development and progression of glioblastoma angiogenesis. Here, we focus on several advanced genes.

YKL-40 (chitinase 3 like 1, CHI3L1) is a highly conserved 40-kDa chitin or heparin-binding glycoprotein, which places it into the family of chitinase-like proteins. The gene expression profiling has identified YKL-40 as a cancer-promoter gene in GBM.[12],[13] YKL-40 activates downstream signals focal adhesion kinase (FAK) 397 and extracellular-regulated kinase (ERK) 1/2 through stimulating coordination of Syndecan-1 (Syn-1) and integrin αvβ5 and elevates the expression of vascular endothelial growth factor (VEGF) in glioblastoma cells.[14] Consistently, all these findings established YKL-40 as a proangiogenic factor promoting angiogenesis in GBM through activating coordination of Syn-1, integrin αvβ5, and vascular endothelial cadherin (VE-cad), which stimulates intracellular signaling via FAK861 and ERK 1/2[15] and VEGF receptor 2 (VEGFR2, Flk-1) expression to enhance the endothelial cell (EC)-mediated angiogenesis.[16]

Cluster of differentiation 147 (CD147), a highly glycosylated transmembrane glycoprotein with two Ig-like extracellular domains that belong to the immunoglobulin superfamily, plays a crucial role in GBM angiogenesis.[17] CD147 was recently reported to function via a new mechanism that induces the effective formation of angiogenic niches through the positive feedback with insulin-like growth factor-1 (IGF-1).[18] It is known that VEGF, IGF-1, and hypoxia-inducible factor-1 alpha (HIF-1α) influence angiogenesis of GBM, and CD147 has been reported to induce angiogenesis via HIF-1α-VEGF signaling pathway.[19]

Leucine rich repeat containing 4/Netrin-G ligand-2 (LRRC4/NGL-2), a gene expressed in brain specifically, is a member of the LRRC4/NGL family and is a part of the leucine-rich repeat superfamily.[20] It has been reported that LRRC4/NGL-2 might inhibit cell invasion through regulating the expression of C-X-C chemokine receptor type 4 (CXCR4) and Stromal cell-derived factor 1α (SDF-1α)/CXCR4 axis in vitro.[21] LRRC4 expression might eliminate VEGF-mediated neovascularization, which was demonstrated by Wu et al.[22] where VEGF induced tube-like structure formation in the human umbilical vein endothelial cell was lost in LRRC4β cells. Conceivably, these results portray LRRC4/NGL-2 as a candidate for tumor-suppressor gene, acting against the angiogenesis in GBM. However, further studies are essential to explore detailed mechanisms.

In brief, YKL-40 and CD147 are identified as promoters of tumor through stimulating FAK397 and ERK1/2 pathways and HIF-1α-VEGF signaling pathway, respectively. Conversely, LRRC4/NGL-2 may suppress GBM by eliminating VEGF-mediated angiogenesis.


  Micro-Rnas Potentially Related to Glioblastoma Angiogenesis Top


In recent years, more and more studies have shown microRNAs (miRNAs), as a novel class of noncoding tumor-suppressor or oncogenes, might play key roles in the process of tumorigenesis. In GBM, a group of miRNAs, termed as angiomiRs or anti-angiomiRs, that can contribute toward tumor vascularization was recently identified.[23] Here, we discuss a few of such angiomiRs and anti-angiomiRs.

Hypoxia can augment angiogenesis by influencing miRNA expression in GBM cells. Overexpression of miR-210-3p can increase angiogenesis by inducing HIF, VEGF, and carbonic anhydrase IX (CA9) transcriptional activity. Under hypoxic condition, inhibiting the expression of miR-210-3p impedes HIF-mediated induction of VEGF and CA9 activity, resulting in decreased tumor growth and reduced vascular density, in vivo.[24] Similarly, the expression of miR-21 is usually high in glioblastoma, and HIF-1α is the center for miR-21-induced upregulation of VEGF. This significant correlation of miR-21 with HIF-1α and VEGF implied a link between miR-21 and glioblastoma angiogenesis.[25] miR-296 is another angiomiR, and it has been found that, in GBM, the angiogenic growth factors such as VEGF can elevate miR-296 expression in endothelial cells. Furthermore, downregulation of miR-296 might inhibit human endothelial cells from expressing morphologic characteristics associated with angiogenesis, while upregulation of miR-296 might result in the induction of the same.[26]

miR-15b is an anti-angiomiR which decreases angiogenesis, largely suppressing capillary-like tube formation, via Neuropilin 2 (NRP-2) downregulation.[27] miR-299, located at chromosome 14q32.31, is characterized as a candidate that could suppress GBM. Overexpression or knockdown of miR-299 apparently resulted in suppressing or promoting tumor-induced angiogenesis, respectively, under in vitro assessments. Furthermore, miR-299 overexpression not only suppressed tumor growth but also reduced tumor microvascular density (MVD), inhibiting the tube formation of vascular endothelial cells, in xenograft glioblastoma models.[28]

As we have discussed above, miRNAs play a complex role in the process of GBM angiogenesis. miR-210-3p, miR-21, and miR-296 promote angiogenesis, while miR-15b and miR-299 are potential targets to antiangiogenesis. However, the specific mechanisms of these miRNAs regulating angiogenesis in GBM are still unclear.


  Receptors and Signaling Pathways Potentially Involved in Glioblastoma Multiforme Angiogenesis Top


In GBM, several genetic and molecular alterations modify major signaling pathways that result in brain tumor angiogenesis. Although the involvement of several well-known angiogenic pathways is indubitable, the yet to be understood underlying complex interactions among them, and with few additional unknown players, potentially contribute to the angiogenesis of GBM. Here, we discuss several receptors and signaling pathways potentially involved in GBM angiogenesis.

Three VEGFRs have been reported: VEGFR1, VEGFR2, and VEGFR3, all of which are related to angiogenesis. phosphatidylinositol 3-kinase (PI3K) family members are lipid kinases and play a part in various cellular processes, such as proliferation, migration, and metabolism.[29] The serine/threonine kinase sites (Thr308 and Ser473) on these P13K family members will recruit the downstream AKT to inner membranes and phosphorylate it. It has been found that mTOR pathway regulates many physiological and pathological processes in angiogenesis of tumor cells. In this signaling pathway, mTOR acts not only as an upstream regulator but also as a downstream effector.[30] Furthermore, inhibiting the PI3K pathway not only limits tumor cell growth but also blocks tumor angiogenesis. Interestingly, the PI3K pathway plays a key role in regulating VEGF and VEGFR.[31] In addition, mice treated with FK228 (a histone deacetylase inhibitor) in combination with TMZ significantly decreased the expression of the key members in PI3K/AKT/mTOR signal pathway and significantly enhanced the antitumor efficacy.[32] The phosphorylation of Akt/PKB may inhibit apoptosis and mTOR activation. Endothelial nitric oxide synthase (eNOS) is also involved in angiogenesis through Akt/PKB pathway.[33] Interestingly, overexpression of VEGFR2 is associated with proliferation of tumor cells in GBM. However, the process may be independent of VEGF.[34],[35] The platelet-derived growth factor (PDGF) family has a PDGF/VEGF homology domain which is a common domain to growth factors. Two PDGF receptors (PDGFRs) have been reported, PDGFRα and PDGFRβ.[36],[37] PDGFRβ contributes to tumor expansion by activating genetic alterations associating with DNA karyokinesis and synthesis, through RAS/RAF/ERK/MAPK signaling pathway. Furthermore, signal transduction and transcription activator (STAT) pathway is also involved by both PDGFRα and PDGFRβ, through various phosphorylated tyrosine residues produced by autophosphorylation of PDGFR.[38],[39],[40]

The epidermal growth factor receptor (EGFR) is associated with tumor growth and angiogenesis and is found activated in nearly 50% of primary glioblastomas (GBM).[41] It is structurally related to four human receptors including Her1, Her2, Her3, and Her4, all of which belong to ErbB family. Activation of EGFR can activate a variety of molecules such as SH1, SH2, and STAT, through ligand binging. EGFR is reportedly involved in several signal pathways, including PI3K/AKT/mTOR and RAS/RAF/ERK/MAPK, WNT/β-catenin, and transforming growth factor (TGF)-β signaling.[42],[43] EGFR can modulate both TGF-β pathway, which is involved in invasion and migration of glioblastoma, and Notch1 pathway, which is fundamental to normal development. What's more, downregulation of EGFR may induce tumor cell proliferation, tumor angiogenesis in glioblastoma, and apoptosis in breast cancer.[44],[45],[46] In addition, RAS/MAPK and PI3K/AKT/mTOR signaling pathway regulates cell proliferation, differentiation, tumor angiogenesis, and survival in glioblastoma.[39],[47]

Fibroblast growth factor receptor (FGFR) modulates a series of processes in tumor cells, including FGF-mediated migration and proliferation. FGFR plays a key role in survival and angiogenesis of glioblastoma cell through PI3K/AKT/mTOR signaling pathway. FGF1-FGFR also activates Jnk-p38-MAPK and STAT3-NF-κB pathways, which are crucially associated with tumorigenesis, cell proliferation, and so on.[48] Furthermore, FGF2 has been reported as a prognostic biomarker in glioblastoma [Figure 1] and [Table 1].[49]
Figure 1: Associated receptors and their signaling pathways involved in angiogenesis. RAS/RAF/ERK/MAPK and PI3K/Akt signaling pathways activation can produce a variety of processes involved in angiogenesis such as cell proliferation, migration, and survival

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Table 1: Major angiogenic receptors in GBM

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The Notch signaling pathway is an intercellular signaling pathway which can affect various cellular processes during embryonic and postnatal development of cells.[50] The Notch1 is naturally expressed in developing vasculature and in extravascular tissues. However, Dll4 and Notch4 expression is specified to vascular endothelial cells.[51] El Hindy et al.[52] demonstrated that the coactions between tumor cells, endothelial cells, and microglia/macrophages may regulate the Dll4-Notch signaling determining typical or atypical vascular patterns in glioblastoma. Furthermore, inhibiting Dll4-Notch signaling pathway can block the formation of functional vessels, but interestingly, it can promote the formation of nonfunctional vessels.[53],[54]

Briefly, VEGFR, EGFR, and FGFR promote angiogenesis via various signaling pathways including Notch signaling pathway, which is a key signaling pathway.


  Potential Mechanisms of Resistance to Antiangiogenic Therapy Top


A formidable challenge to antiangiogenic therapy is the development of resistance to the therapy. Here, we discuss several related potential molecular mechanisms.

Although bevacizumab has been approved for the treatment of GBM patients and most patients are benefited from the treatment initially, these effects are usually limited in confronting tumor regrowth.[55],[56] It has been reported that Dll4-Notch signaling pathway was activated and regulated in the growth of GBM.[57] Interestingly, Dll4 and Jag1 have opposing effects on angiogenesis in GBM.[58] Consistently, it has been reported that when Dll4 is expressed, and Jag1 is not in GBM, then the tumor can develop resistance to bevacizumab mediated antiangiogenesis therapy.[59] The β1 integrins are found to be involved in a series of physiological and pathophysiological processes, including tumorigenesis, proliferation, invasion, and migration of tumor cells, and also have recently been reported to influence the therapeutic resistance in multiple solid cancer models.[60] Recent research demonstrated that blocking β1 integrin in GBM could suppress the associated angiogenesis and tumor growth. Furthermore, the study also showed that suppressing β1 integrin may reverse the resistance to bevacizumab in GBM.[61]

Hypoxia-inducible gene 2 (HIG2) is a marker of hypoxia and is found elevated in several cancer conditions.[62] HIG2 can serve as a diagnostic marker for several cancers and as a potential target for antiangiogenesis therapy.[63] A recent study showed a positive correlation of HIG2 with VEGFA and HIF-1α expression, which ultimately results in resistance against bevacizumab.[64] What's more, HIG2 upregulation may contribute to bevacizumab resistance through other cellular processes such as inhibiting apoptosis, promoting lipid biosynthesis, and activation of WNT signaling pathway.[63],[65],[66]

STAT3 is a receptor that is activated by ligand interaction and can be overexpressed and constitutively activated in tumors.[67],[68] A recent study has found that AZD1480 (a STAT3 inhibitor) combined with cediranib markedly reduced the volume and microvessel density (MVD) of GBM, implying that the STAT3 pathway may mediate resistance to antiangiogenic therapy and the regulation of which might be of use in treating the condition.[69]

Cylindromatosis (CYLD), described as a mutant tumor suppressor gene in familial CYLD,[70] can regulate diverse processes of tumor cell's biology including proliferation, migration, inflammation, and survival.[71] Recently, a reduction in the CYLD expression is noted in gliomas, establishing an inverse relation with the tumor grade and patient prognosis.[72] A recent study found CYLD was downregulated in human GBM tissues under hypoxic condition and acted as an important regulator of hypoxia-induced angiogenesis in GBM.[73] Thus, it may contribute to the antiangiogenesis resistance, and may affect the long-term efficacy of anti-VEGF therapy. On inhibiting VEGF signaling, the tumor and its microenvironment release alternative proangiogenic growth factors to promote VEGF-independent angiogenesis.[74],[75]

Phosphatase and tensin homolog (PTEN), a tumor-suppressor gene, is often inactivated in cancer.[76] Specifically, in GBM, loss of the PTEN leads to VEGFR-2 expression in tumor cells, which may contribute to resistance against antiangiogenic treatments. Furthermore, a recent study showed that overexpression of VEGFR2 in tumor cells could develop early resistance to chemotherapy with TMZ and antiangiogenesis therapy with bevacizumab, in GBM.[77]

The resistance to antiangiogenesis is an emerging severe problem of antiangiogenesis therapy. Expression of Dll4-Notch, HIG2, and CYLD and loss of PTEN are described as potential mechanisms which lead to the resistance.


  New Regulated Factors and Target for Antiangiogenesis Top


As mentioned before, angiogenesis is one of the most obvious hallmarks of glioblastoma, which contrasts glioblastoma from normal tissues.[5],[11] Thus, antiangiogenesis therapy has become a worthy strategy to consider in glioblastoma patients. VEGF has been found to play an important role in the angiogenesis of GBM,[78] and inhibiting the expression of VEGF always seems like to be the most effective therapeutic strategy to inhibit GBM growth.[79] However, this strategy did not meet the expectations in human patients, as shown by studies over the past few years. Here, we discuss several new targets for antiangiogenesis.

Vasculogenic mimicry (VM) [Figure 2] is a newly discovered vascular-like network structure. Maniotis et al.[80] defined and described this structure for malignant melanoma for the first time in 1999. VM is EC-independent, consisting of tumor cells and matrix, and is associated with poor prognosis in GBM patients.[81],[82],[83] More and more emerging studies have confirmed that the involvement of a series of genes and several molecular pathways in VM. Thus, these molecular mechanisms of VM may provide potential targets for antiangiogenic therapy. SU1498 and AZD2171, the inhibitors of VEGFR-2 kinase, have been reported to reduce VM formation in GBM cell lines accompanied by reduced proliferation and tumor growth, both in vivo and in vitro.[84]
Figure 2: Tumor blood supply pattern based on VM. The possible connection between VM channels and the endothelium-dependent vessels: a continuous process of vessels development: (A) VM channels, (B) mosaic vessels, and (C) the endothelium-dependent vessels. (D) Tumor proliferation which leads to hypoxia acts as a trigger to stimulate tumor blood supply cycle. VM: Vasculogenic mimicry

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It has been reported that downregulating HIF-1α and mTOR signaling pathway through rapamycin and mTOR siRNA, respectively, may inhibit VM formation.[85] This study not only provided the evidence for a more integrated signaling cascade for VM formation but also demonstrated mTOR as a potential therapeutic target in glioblastoma. Similarly, the TGF inhibitor isoxanthohumol [86] impairs VM formation and the matrix metalloproteinase (MMP) inhibitor chemically modified tetracycline [87] and downregulates VE-cad and MMPs in cancer cells. Francescone et al.[88] showed that targeting VEGFR-2 using Flk-1 shRNA in GBM derived cell lines, limited VM formation, and subsequently inhibited the development of tumors. The results of this study show a key role of VEGFR2 in the formation of VM in GBM and provide a possible therapeutic target, clarifying a molecular mechanism mediating tumor aggressiveness. Chromodomain helicase DNA-binding protein 5 (CHD5) is a novel candidate as a suppressor gene, which is deleted from 1p36 in glioblastomas.[89] A recent study showed that expressing CDH5 in glioblastoma stem cells (GSCs) could benefit GSC-derived neovasculogenesis in GBM, especially under hypoxia.[90] This study also revealed the novel angiogenesis mechanisms contributed by GSCs. These studies on VM is hoped to contribute to the development of antiangiogenesis and antitumor treatments in future.

As mentioned above, hypoxia is one of the most important features of GBM. This condition promotes the expression of HIF-1α, which plays a key role in regulating the biological behaviors of tumor under hypoxic microenvironment. Recent studies demonstrate that vincristine promotes an antiangiogenic effect through the inhibition of HIF-1α in glioblastomas under hypoxia.[91],[92] A recent study has established a positive correlation between the expression of CD31 and HIF-1α in human GBM specimens [93] and characterized N-cadherin and ADAM-10 as biomarkers of aggressiveness in the same specimens.[94] This result may provide a new target for antiangiogenesis therapy. In addition, HIF-1α also induces the overexpression of anterior gradient protein 2 (AGR2), which is important in promoting angiogenesis not only at the level of RNA but also at the level of protein in GBM. Consistently, inhibition of AGR2 may reduce proangiogenesis in GBM cell lines.[95],[96],[97] Thus, this mechanism may provide a potential target to enhance antiangiogenic strategies.

In addition, emerging studies have identified miRNAs as the inhibitors of tumor angiogenesis. A recent study showed that miRNA-7 could effectively suppress angiogenesis by targeting O-GlcNAc transferase (OGT) gene; thus, tube formation and sprouting were suppressed in GBM xenograft in mice.[98] The increased expression of miRNA-16 in GBM cells has a critical effect on repressing endothelial function and angiogenesis by targeting Bmi-1.[99] miR-137 inhibits angiogenesis and proliferation in human glioblastoma by targeting EZH2, and the overexpression of EZH2 can reverse the effect,[100] revealing miRNA-137 as a new target for GBM treatments.

Besides VEGF, VM has been demonstrated to play a critical role in angiogenesis of GBM. Furthermore, AGR2, miRNA-7, miRNA-16, and miRNA-137 may provide a new target for GBM treatments.


  Conclusions and Perspectives Top


Glioblastoma is the most common primary malignant tumor of the central nervous system in adults. In this review, we discussed a series of studies on angiogenesis in glioblastoma, including associated genes, signaling pathways, mechanism of resistance to antiangiogenic therapy, and new strategy to antiangiogenesis. The current antiangiogenic treatments targeting VEGF, such as bevacizumab, have not shown obvious improvement in the overall survival of GBM patients due to the presence of VEGF-independent angiogenic pathway in GBM cells. What's more, the resistance to antiangiogenic therapies has become the new challenge, and the molecular mechanisms of the resistance to antiangiogenic strategy remain to be further explored. VM may be a new potential target for antiangiogenic therapy. The more we understand the mechanisms of glioblastoma angiogenesis, the greater our chances to develop a successful antiangiogenic therapy in GBM patients that effectively improve their quality of life are.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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