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| REVIEW |
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| Year : 2018 | Volume
: 1
| Issue : 2 | Page : 43-49 |
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Angiogenesis in glioma
Fei-Yi-Fan Wang, Xue-Jun Li
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| Date of Web Publication | 30-Apr-2018 |
Correspondence Address:
Dr. Xue-Jun Li
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, Hunan
China
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/glioma.glioma_9_18
Despite aggressive surgery, radiotherapy, and chemotherapy, malignant gliomas remain uniformly fatal. To progress, these tumors stimulate the formation of new blood vessels through processes driven primarily by angiogenesis factors. However, the resulting vessels are structurally and functionally abnormal and contribute to a hostile microenvironment that is highly selective for a more malignant phenotype with increased morbidity and mortality. Emerging preclinical and clinical data indicate that antiangiogenesis therapies are potentially effective regarding glioblastoma, and can transiently normalize tumor vessels. This creates a window of opportunity for optimally combining chemotherapeutics and radiation.
Keywords: Angiogenesis, gliomas, targeted therapy, vasculogenic mimicry
How to cite this article:
Wang FY, Li XJ. Angiogenesis in glioma. Glioma 2018;1:43-9 |
| Introduction | |  |
Glioma is a common central nervous system (CNS) tumor that accounts for 30% of intracranial tumor incidences.[1] In 2016, the World Health Organization (WHO) broke a century-long reliance on classical pathology by associating molecular biomarkers with CNS tumors. The WHO classified brain gliomas into four grades based on its malignancy and biological characteristics. Under this classification system, glioblastoma multiforme (GBM) is a Grade IV tumor with the highest invasion, tumor vascularization, and malignancy rate, often resulting in poor prognoses and high resistance rates to combination therapies. As a result, the average survival time of patients is only 12–15 months.[2] Over the past 20 years, despite the innovation of surgery, radiotherapy, and chemotherapy regarding GBM treatment, its dismal prognosis has not been significantly improved. More recently, GBM molecular pathogenesis has received a great amount of academic attention. At present, exploring the molecular pathogenesis of GBM has become an important research direction for many scholars.
Tumor angiogenesis is an extremely complex process involving multiple steps: (1) vascular endothelial (VE) matrix degradation, (2) endothelial cell migration, (3) endothelial cell proliferation, (4) endothelial cell tubing branching to form vascular rings, and (5) the formation of new basement membranes. Since neovascular is ill-structured and incompetent with the insufficient matrix, it has a high tendency for vascular leakage, which may lead to distant tumor metastasis. More and more studies have shown that benign tumor has rather scarce and slow angiogenesis, compared to malignant tumor angiogeneses demonstrating intensive and rapid growth. Therefore, angiogenesis plays an important role in the growth and metastasis of tumors, and the inhibition of it would help control such an effect. In 1971, Folkman published his famous saying, "tumor growth must rely on its vascular," which was then gradually accepted by subsequent researchers.[3],[4] Since then, inhibition of angiogenesis has become a key point in cancer therapy. In recent years, studies have indicated that tumor blood vascular is the morphological basis of tumor growth and metastasis. Tumor blood vessels not only provide nutrition for tumor cells but also continuously deliver tumor cells to other parts of the body, leading to the growth and metastasis of malignant tumors.[5],[6],[7] Furthermore, studies have confirmed that tumor angiogenesis has three major types: (1) vasculogenesis: in the early stage of tumor growth, neovascular is generated from angioblast cells, and endothelial progenitor cells; (2) angiogenesis: small tumor vascular could also be generated by endothelial cell proliferation and migration from existing mature vascular;[8] and (3) vasculogenic mimicry (VM): tumor vascular could be generated from the tumor cell.[9]
This review aims to explain the biological function of angiogenesis associated patterns in GBM pathogenesis.
| Angiogenesis In Glioma | | |
Angiogenesis
Physiological angiogenesis occurred mostly in the embryonic period, which is also observed in the ovarian cycle, pregnancy, traumatic repair, and endometrial regeneration. The vascular system in normal mature tissue is relatively static, with only very limited endothelial cell updates.[10] However, pathological conditions such as inflammation, stroke, and the presence of tumors could lead to extreme activation of the endothelial cells with a significantly shortened proliferation period.[11] Similar to other solid malignancies, glioma angiogenesis is also a multi-step process, which includes (1) endothelial cell activation, proliferation, and migration; (2) basement membrane and extracellular matrix degradation; and (3) endothelial cell remodeling and interaction with surrounding cells, which contributes to the formation of lumen-like structures.
Glioma angiogenesis can be divided into three stages. (1) In the early stage, once the tumor diameter is larger than 1–2 mm, diffusion cannot completely meet the nutritional demands of tumor growth, especially in its central core. Led by subsequent hypoxia and local inflammation, local angiogenic factors accumulate abundantly and thereby induce angiogenesis. (2) In the proliferation stage, protease degradation of extracellular matrix may cause endothelial cells to release and inhibit surrounding tissue adhesion, which then mediates endothelial cell proliferation, migration, and infiltration. (3) In the late differentiation stage, through vascular lumen formation, endothelial cell differentiation, and apoptosis, the vascular structure finishes its pruning and reconstruction, which subsequently generates the complete capillary network.
During the angiogenesis process, the balance between angiogenic factors and antiangiogenic factors in the human body is broken, which initiates and promotes the generation of tumor blood vessels. At the same time, a series of proangiogenic factors and extracellular matrix play a key role in promoting angiogenesis. Furthermore, endothelial activation and proliferation are prerequisites of angiogenesis, regardless of its physiological or pathological presence, which represents the central part of endothelial cells.[12] Within the glioma microenvironment, the endothelial cells also act as the main target for various angiogenesis factors generated by intra- and para-tumor tissues, which include tumor cells and surrounding inflammation.[13] Based on this consensus, further research regarding the interaction between glioma cells, endothelial cells, and inflammatory cells would facilitate an improved understanding of glioma angiogenesis.
Vasculogenic mimicry
In 1999, Maniotis et al.[14] proposed a new tumor microcirculation model in their uveal malignant melanoma research. This is independent of the classical tumor angiogenesis pathway for general endothelial cells, known as VM. It has been well accepted that an endothelial cell-dependent pathway was the only available angiogenesis process for the tumor. VM challenges this concept completely. Recently, the recognition of tumor angiogenesis pathways has been largely extended. In subsequent studies, VM has also been found in liver, prostate, ovarian cancer, and double differentiated tumors, which has a close relationship with growth, differentiation, and invasion.[15]
In gliomas, the formation of VM is closely related to glioma stem cells and several bioactive molecules, including miRNA, epithelial cell kinase (EphA2), VE-cadherin, transforming growth factor-β (TGF-β), VE growth factor R-2 (VEGFR-2), and Galectin-1.[16],[17] Furthermore, studies have indicated that glioma patients with VM generally have a worse prognosis and higher rates of antivascular drug resistance.
Studies have shown that glioma patients with VM often have poor prognoses. Liu et al.[18] conducted a retrospective study of 101 cases of glioma patients, and found that tumor pathological grade was proportional to incidences of VM. They also reported that VM-positive patients had shorter survival times relative to VM-negative patients. Wang et al.[19] (among other studies) have shown that VM is an independent factor affecting the prognosis of patients with glioma. In their study, among the 86 patients with malignant gliomas, 23 patients were found with VM, and the median survival time of VM-positive patients was significantly shorter than that of VM-negative patients. VM can benefit a tumor's blood supply, and its tumor cell-composed structure comes into contact with blood directly, which makes it easier for hematogenous tumor spread. Previous studies have found antivascular therapies to cause tumor hypoxia, in turn promoting VM generation in these malignant tumors. As a result, classical vascular and its nutrition supply function are replaced by VM, which accelerate tumor metastasis largely. Xu et al.[20] demonstrated that Bevacizumab treatment of ovarian cancer models confirmed short-term anti-VEGF treatments could cause VM formation, and accelerate tumor metastasis. Therefore, combination treatment regimens of anti-vascular therapy and anti-VM therapy may improve glioma and other tumor treatment. At present, studies have shown that alpha statin may inhibit the phosphorylation of EphA2 protein and matrix metalloproteinases 2 (MMP2) protein activation, thereby reducing the formation of VM in gliomas. This kind of anti-VM-based anti-tumor therapy is very promising.[21],[22]
| Glioma Angiogenesis Factor | | |
Studies have confirmed that a variety of bioactive substances can regulate tumor angiogenesis [Table 1]. These angiogenesis factors are mainly a large class of either growth factors or cytokines with a peptides presence, including fibroblast growth factors (FGFs), interleukin-1 (IL-1), IL-8, as well as various lipids, nucleotides, and vitamins.
Hypoxia response is the initiator of tumor angiogenesis and the promoter in its later developmental processes. The hypoxia-inducible factor-1 (HIF-1) gene plays a central regulatory role in promoting tumor angiogenesis and invasiveness within tumor microenvironments.[23] Gliomas share the same biological characteristics as other tumors: a continued growth until the tumors nutrient demand cannot be met, thus leading to localized hypoxia. In this pathological situation, the HIF-1 gene has been shown to be largely activated. Downstream products include angiogenesis factors which are then activated. As a result given that glioma becomes more invasive, HIF-1 could specifically binds to the hypoxia response element 5'-TACGTG-3', which belongs to the hypoxia-inducible gene promoter. Target genes under this transcription regulation would then be able to control the expression of VEGF at the gene level.[24]
VEGF, also known as vascular permeability factor, functions as a direct stimulation of endothelial cell proliferation. It also could enhance vascular permeability and induce the generation of plasminogen activator and its inhibitor.[25] Five VEGF isomers have been recognized: VEGFl21, VEGFl65, VEGFl45, VEGFl89, and VEGF206. In particular, VEGF165 is the most important, due to its dominant role in glioma. VEGF is one of the most important tumor angiogenic factors, and its main biological functions are as follows: (1) promoting VE cell proliferation, thereby enhancing the formation of vascular. VEGF is a VE cell-specific mitogen, with a strong effect on promoting VE proliferation. (2) Increasing vascular permeability. VEGF has 5000 times stronger pharmacological effects than histamine. (3) Causing endothelial cell elongation and replication to stimulate endothelial cell migration.
VEGF is nonexpressed or sparsely expressed in normal nerve tissue, and expressed more in low-grade gliomas. However, it has a high expressing rate in high-grade gliomas. Under this physiological situation, the half-life of VEGF mRNA is about 30–40 min, which can be increased to 8 h under hypoxic conditions.[26] VEGF presents its biological function only when it binds to VEGF receptor (VEGFR). Five VEGF isomers have been recognized: VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flt-2), VEGFR-3 (Flt-4), NP-1, and NP-2. Among these VEGFRs, Flt-1, KDR, and Flt-4 are all tyrosine kinase transmembrane receptors, with VEGFR-1 mainly expressed in VE cells and VEGFR-3 mainly in lymphatic endothelial cells. NP-1 and NP-2 are nontyrosine kinase transmembrane receptors, containing long extracellular segments, and short intracellular segments, which are expressed in endothelial cells and several kinds of tumor cells. Wojtukiewicz et al.[27] found that VEGFR-2 plays a major role in VEGF-induced angiogenesis and vascular permeability and suggested that KDR inhibitors could block VEGF and basal membrane fibroblast growth factor (bFGF)-induced angiogenesis.
The bFGF belongs to the fibroblast growth factor family (FGFs) and is the first identified angiogenesis promoting factor. Human bFGF gene is located on chromosome 4q26–27.[28] A single copy of the bFGF gene can encode various forms of bFGF with 18–34 kD size, due to differences in transcription start site and gene splicing. At present, most research is performed with respect to the 18 kD subtype. The biological activity of bFGF is mainly mediated by high-affinity receptors on the cell membrane (FGFR1 and low-affinity receptor heparin sulfate proteoglycan). Moreover, the Cysteine-Rich FGF receptor and FGF binding proteins are worth being concerned, both of which are related to the regulation of bFGF secretion and biological activity.
Tumor angiogenesis is a complex process, which is finished only when the lumen-like structure built by the endothelial cells is shown. Recently, a new endothelial cell growth factor called epidermal growth factor domain 7 (EGF-like domain 7, EGFL7) has been discovered, which is highly expressed in most human malignant tumors, and could enhance tumor invasiveness and metastasis ability.[29] In most normal mature tissue, EGFL7 is sparsely expressed or not expressed at all. However, EGFL7 is highly expressed in some vascular-rich organs, such as lung, heart, and uterus. Due to its distribution, EGLF7 was at first thought to be a kind of vasoactive factor involved in physiological vascular development and injury repair, thus importantly participating in the formation of vascular lumen-like structure. The role of EGFL7 has been gradually recognized in recent years.
EGFL7 is a kind of EGF related protein. Its structure determines the diversity of its function: Signal peptide sequence indicates that it is a secretory protein, and its amino-terminal emilin-like domain (EMI) structure indicates that it can be secreted to the extracellular matrix for further function. The EGF-like structure is the key structure of protein-to-protein recognition. Studies have shown that DSLs-similar structure is found in the first EGF-like structure of EGFL7 and that DSL structure is present in Notch receptors. Previous studies have shown that EGFL7 is a natural Notch receptor antagonist.[30] The second EGF-like structure on EGFL7 has a Ca2+ site, and the EGF-like family function is thought to be associated with Ca2+. The integrins are mostly heterophilic cell adhesion molecules, which also rely on Ca2+, so as both have extracellular matrix components, they may affect each other. EGFL7 and integrin ligand talin can form a complex to regulate the activity of integrin αPS2 βPS in Drosophila, and may also activate local focal adhesion kinase (FAK) signaling pathways. In gliomas, EGFL7 may bind extracellular matrix-integrin ανβ3 binding, involved in angiogenesis.[31]
Furthermore, many oncogenes are involved in glioma angiogenesis, which can promote downstream target genes and abnormal expressions such as MMP, integrin, and VEGF. These factors promote multiple invasion processes including cell matrix degradation, abnormal adhesion, and tumor angiogenesis. All in all, glioma angiogenesis is a complex and orderly process involving many factors. At present, its molecular mechanism, regulatory manner, and signal transduction pathway remain largely unknown, and deeper research is needed to improve glioma therapy.
| Angiogenesis Inhibitory Factor | | |
In most adult normal tissues, angiogenesis factors and their inhibitors are in a relatively balanced state. If this balance is broken, it may lead to physiological or pathological angiogenesis. At present, dozens of endogenous angiogenesis inhibitors have been found. Among them, Angiostatin and Endostatin are particularly interesting. Currently, these two endogenous angiogenesis inhibitory factors have been in phase I and II clinical trials in the US and may become the next generation of anti-tumor drugs.[32]
Endostatin is the C-terminal fragment of XVIII collagen that specifically inhibits endothelial cell proliferation and promotes apoptosis. Endostatin can inhibit the function of angiogenic factors such as VEGF and bFGF. It also inhibits the migration and adhesion of endothelial cells by binding to MMPs, integrins ανβ3, and ανβ5. It has a high ability to inhibit neovascularization, which is currently known to be the strongest endogenous angiogenesis inhibitory factor that plays a significant role in the regulation of tumor angiogenesis. Experiments have shown that Endostatin has significant anti-tumor activity and antiangiogenic abilities. Mouse Lewis lung tumor transplantation can be significantly suppressed by systemic Endostatin treatment that follows a dose-effect relationship. Daily injection of doses of 20 mg/kg has been shown to almost entirely suppress primary tumors. Endostatin treatment could also suppress several other kinds of mice malignant tumor transplantation, including B16F10 malignant tumors, T241 fibrosarcomas, and mouse endothelial hemangioendothelioma (EOMA) endometrial tumors, where a rapid size reduction is often observed. These effects are mediated by the inhibition of endothelial cell proliferation and neovascular formation.In vitro animal experiments also suggest endostatin could inhibit endothelial cell proliferation.[33]
In recent years, brain-specific angiogenesis inhibitor 1 (BAI1) has gained interest due to its brain tissue-specific expression and angiogenesis inhibition function. It is expected to become a potentially new direction for glioma gene therapy. The structure of the BAI1 gene has been partially confirmed: at least 80 kb, not <28 exons and the binding site of P53 is in the 9th intron (tGGCT-GCCTGGACATGTTC). This 11 kDa glycoprotein has a seven transmembrane protein structure of 1584 aa, including the extracellular domain of 95l aa, the seven transmembrane regions of 233 aa, and the intracellular domain of 400 aa. The extracellular domain contains five thrombospondin type 1 repeats and one Arg-Gly-Asp integrin recognition structure.[34] The extracellular domain adjacent to the first transmembrane region is a G protein-coupled receptor proteolytic site, and the C-terminus of its intracellular domain is the Gln-Thr-Glu-Val (QTEV) domain. Due to structural similarities, BAI1 is thought to be a member of the G-protein coupled receptor family.
BAI1 could inhibit basal membrane fibroblast growth factor (bFGF)-induced angiogenesis in vitro, as one functional p53 binding sequence on it induces p53 activation has been confirmed to play the role of a tumor suppressor gene. Cork et al.[35] have shown that BAI1 is widely expressed in normal brain tissue but not in glioma samples. Nishimori et al.[36] suggested that BAI1 is a p53 target gene. The biological function of p53 is achieved by affecting downstream genes, such as apoptosis-related GML, p53-induced protein, STAG1, p53R2 associated with DNA repair, growth related to BAI1, and so on.
Collagen is a highly specialized soluble fibrin macromolecule that is widely distributed in the animal extracellular matrix. In 2000, Colorado et al.[37] found that the three noncollagen ends of Type IV collagen corresponded to three different angiogenesis inhibitors, namely arresten, constantin, and tumstatin. The study found that α1 (IV) NCl chain exists in the basal, vascular, alveolar, and glandular basement membranes. It has a significant inhibitory effect on malignant melanoma cells. Arresten can inhibit the proliferation and migration of endothelial cells in human veins. It can induce endothelial cell apoptosis, and prevent vascularization in endothelial cells. It owns 3–10 times stronger effects than Endostatin. Thus, arresten is considered to be a novel potential for angiostatin after endostatin.
The underlying mechanism of above-mentioned factors is to interfere with every stage of tumor neovascularization: endothelial cell membrane degradation; endothelial cell proliferation; and endothelial cell tube formation. MMPs can degrade the basement membrane around the vascular, tissue inhibitors of metalloproteinases can inhibit the MMPs' function; growth factor antagonists can bind-free growth factor, thereby inhibiting the growth factor-mediated vascular growth; angiostatin and endostatin can inhibit endothelial cell proliferation, and tumstatin binds to subunits of CD47/IAP and ανβ3 proteins on the surface of tumor cells to activate FAK and phosphatidylinositol kinase 3 (PI3K).[38] Activation of PI3K then activates adenylate cyclase so that intracellular cAMP increases, which can initiate cAMP-dependent protein kinase A. As a result, the proliferation of tumor cells is inhibited.[39] Through the up-regulation of these factors in the tumor, a novel available glioma treatment strategy can be achieved. However, before clinical implementation, further research is required to understand its function regarding the inhibition of endothelial cells and tumor cells.
| The Role of Glioma Stem Cells in Angiogenesis | | |
Parallel to the role that normal stem cells play in organogenesis, GBM stem cells are thought to be crucial for tumorigenesis. Investigating the relationship between glioma stem cells and angiogenesis can help to develop better treatment strategies. We reviewed a series of recent studies and found that highly malignant glioblastoma stem cells rely on angiogenic mimicry and can further stimulate this effect. These results have important implications for glioma studies, show similarities between normal stem cells and GBM stem cells, and define new target therapies for tumor microenvironments.
Severely disordered angiogenesis is a hallmark of glioblastoma. It is often presumed that this abnormal blood vessel distribution is indispensable to meet the rapidly growing nutritional needs of tumors. However, the presence of GBM stem cells and the discovery of vascular stem cell niches in normal brain tissue suggest further complex interactions within the tumor vascular network: the formation of abnormal stem cell niches that maintain glioblastoma stem cells. In the 1940s, a study regarding the normal intracerebral migration of tumor cells in vascular microenvironments (peripheral satellite lesions) revealed that GBM stem cells may have a special relationship with peripheral vascular tissue.[40] A subsequent series of studies have supported such a view, that the number of capillaries in glioblastoma is related to the prognosis of patients,[41] and these tumors are very sensitive to the treatment of VEGF antibodies (i.e., bevacizumab).[42] However, until Bao et al.[43] demonstrated that high levels of VEGF produced by CD133+ glioma cells might contribute to its ability to initiate tumors, the functional relationship between tumor vessels and GBM stem cells was elucidated. They demonstrated that freshly resected CD133+, but not CD133-, human glioblastoma cells readily form highly vascular and hemorrhagic tumors in the brains of immunocompromised mice. In addition, treatment of CD133+ GBM stem cells with bevacizumab was shown to block the ability to induce endothelial cell migration and tube formation in culture and to inhibit tumors in vivo. Therefore, similar to normal neural stem cells, glioma stem cells appear to have potent angiogenic properties and can recruit angiogenic factors during tumorigenesis. It is worth noting that necrosis and hypoxia traits of glioblastoma provide a strong angiogenic driving force by inducing VEGF, VEGFR-2, Tie2, and angiopoietin-2, allowing the microenvironment of glioblastoma lesions to induce an abnormally rich vascular network.
| Antiangiogenic Therapy in Glioma | | |
At present, the research of angiogenesis inhibitors mainly has the following four strategies: (1) blocking the ability of endothelial cells to degrade the surrounding matrix; (2) directly inhibiting the function of endothelial cells; (3) blocking the synthesis and release of angiogenic factors; and (4) blocking the integrin on endothelial cell surfaces [Figure 1].
It has been found that EGFR inhibition can suppress the differentiation of GBM stem cells into endothelial cells, thereby reducing tumor growth, and eliminating blood vessels. This suggests that glioma endothelial cells (GECs) can promote tumor growth and vascular system development. Furthermore, GECs behave as aging rather than apoptosis when undergoing chemotherapy or radiotherapy, which indicates a resistance to standard temozolomide (TMZ)-based therapy. This has been found to be correlated with EHFR-mediated tumor micro VE cell (tMVECs) generation. Borovski et al.[44] suggested that tMVECs may participate in the expression of O 6-methylguanine DNA methyltransferase (MGMT), which generates GBM stem cell TMZ resistance by interfering with its DNA repair system.
There is a generally positive view regarding combination therapy with Nimotuzumab and chemotherapy, such that the two may benefit each other: (1) postoperation chemotherapy could enhance glioma patient outcomes. However, most patients still face the challenge of tumor recurrence and progression. For this reason, drugs that could enhance or recover chemotherapy sensitivity may contribute to better patient outcomes. Data have shown that sensitivity to chemotherapy can be regulated by the activation of growth factors, key points of special signal transduction pathways, and DNA repair and apoptosis-related proteins. EGFR inhibitors may also play a role in this process. (2) Since the EGFR monoclonal antibody is a 150 kDa protein, normal blood–brain barrier hinders its transmission to brain lesions. However, EGFR monoclonal antibodies can cross the blood–brain barrier when the patient has undergone surgery, radiotherapy, or has suffered certain types of tumors that have damaged the integrity of the blood–brain barrier. Gmeiner Stopar et al.[45] used radioimmunoassays to visualize the 99 mTC biomarkers, and found monoclonal antibody positive uptake at the site of the tumor after combination therapy, suggesting that rituximab can enter the brain of glioma patients and is specific.
Bevacizumab is a recombinant human anti-VEGF monoclonal antibody, sold under the trade name Avastin that acts primarily by neutralizing VEGF to block its binding to VEGF receptors on endothelial cells. Avastin was approved by the US Food and Drug Administration in 2004 for the treatment of advanced colorectal cancer. In colorectal cancer patients, the infusion of Bevacizumab alone can significantly inhibit angiogenesis, which can then reduce blood perfusion, vascular volume, microvascular density, interstitial fluid, and circulatory endothelial cell load.[46] Recent studies have found that bevacizumab-irinotecan (a chemotherapy drug) can increase the effect of glioma radiotherapy.[47] At present, Bevacizumab for malignant glioma treatment has already started as part of phase II clinical trials.[48]
| Prospects | | |
As with other malignant tumors, glioma angiogenesis is an extremely complex process that included multiple steps and multiple factors. Both positive and negative regulators contribute to the sophisticated regulation of this process. An imbalance between these regulators may initiate subsequent angiogenesis, thus shifting a relatively static tumor into an active phase. Thus, glioma angiogenesis has already been identified as a newly found, hopeful glioma treatment target. Antiangiogenic therapy has achieved remarkable results in the clinical practice of many malignant tumors, but the therapeutic effect in GBM is currently not satisfactory. Many clinical studies provide further evidence that the development of gliomas is not only a cellular intrinsic process driven by epigenetic or genetic mutations in tumor cells but also a process that depends on the tumor microenvironment. Targeting cancer stem cells in vascular microenvironments may be a key component. Therefore, new treatment methods, (especially immunotherapies that target angiogenesis key markers, such as DC vaccine [VXM01] against VEGFR-2) have currently completed clinical trials in the treatment of pancreatic cancer and may play a potential role in the treatment of glioma.
Nowadays, for a given glioma patient, surgical resection therapy has been replaced by molecular biology comprehensive diagnosis and treatment in the age of precision medicine, which covers the prophylactic, test, diagnosis, and later treatment of glioma. If we take the final solution for glioma treatment as a mountain, now we are quite close to the peak of it, where we have never arrived before.
The principle of glioma treatment has changed from traditional surgical resection to comprehensive treatment of molecular biology. The prevention, detection, diagnosis and treatment of gliomas will enter a new era with the advent of precision medicine. In an attempt to develop new therapeutic strategies and identify the molecular mechanism involved in glioma growth and progression, there has been extraordinary scientific interest in the past few years in angiogenic responses associated with gliomas. We believe these efforts will certainly bring new hope for the treatment of gliomas.
Financial support and sponsorship
This work was supported financially by grants from the National Natural Science Foundation of China (81472594 and 81770781) and the Fundamental Research Funds for the Central Universities of Central South University.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1]
[Table 1]
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