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Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

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Vascular Endothelial Growth Factor in Malignant Disease of the Central Nervous System


Vascular Endothelial Growth Factor (VEGF) is a major contributor to the growth of malignant tumors of the central nervous system. It stimulates tumor angiogenesis and vascular proliferation characteristic of high grade gliomas. Elevated expression of VEGF is one the factors responsible for the virulent nature of these tumors. The production of VEGF by malignant glial cells in response to ionizing radiation contributes to treatment failure. The rat C6 glioma is similar to human gliomas with respect to VEGF pathophysiology. Interruption of VEGF-Receptor signaling in preclinical models effectively suppresses tumor growth and demonstrates the potential for anti-angiogenic therapy.

VEGF in the Normal Brain

Intact VEGF-Receptor signaling is required for maturation of the central nervous system (CNS). Mutant mice heterozygous for VEGF die in utero and develop multiple anomalies including failure of vascularization of the neuroepithelium, disorganization of neuroepithelial cells, and underdevelopment of the forebrain.1 A single mutant allele can bring this about. In mature brain tissue VEGF is distributed in areas surrounding the microvasculature where it may assist in maintaining the differentiated state.2 VEGF is also produced in response to CNS trauma. In response to cold thermal injury, VEGF isoform A is upregulated in astrocytes, inflammatory cells, and neovascular endothelium in the rat brain. Increased production of VEGF mRNA was demonstrated as early as six hours after injury by in situ hybridization.3

VEGF Is Upregulated in Malignant Disease of the CNS

Human brain tumors comprise a group of diseases which vary in their natural history, histopathology, and response to treatment. Heterogeneity also exists within each histopathologic category of tumor. In adults, the most common tumors arise from cells which comprise the supportive stroma of the CNS.4 Collectively, they are called gliomas. These include astrocytomas, oligodendrogliomas, and ependymomas. Up-regulation of VEGF and its receptors has been demonstrated in each.57 Astrocytomas are the most common glial tumors. They are subdivided on the basis of how undifferentiated the tissue appears microscopically. Grade I tumors bear the closest resemblance to normal brain. Grade IV are the most undifferentiated. Low grade astrocytomas progress more slowly than their high grade counterparts whose growth can be explosive. Grade IV astrocytoma is also known as glioblastoma multiforme, one of the deadliest of all malignant diseases. Figure 1 is a CT (computerized tomography) scan of a patient with glioblastoma multiforme. It demonstrates a large parietal lobe mass which “enhances” after the intravenous administration of iodinated molecules of high molecular weight. The iodinated reagent accumulates in the perivascular space around leaky capillaries allowing the vascular rim of the tumor to stand out in contrast to other tissue. A region of hypodensity indicative of edema surrounds the area of enhancement. While multiple growth factors are potentially operative in glioma angiogenesis, only VEGF is known to induce vascular permeability. Angiogenesis increases markedly from the low grade tumors (grades I and II) to the high grade lesions (grades III and IV). VEGF and its receptors are upregulated in most, but not all, astrocytomas.8 Production of VEGF parallels the angiogenic phenotype, with high grade tumors being more likely to produce VEGF. Furthermore, low grade astrocytomas which produce VEGF have the same dismal prognosis as high grade lesions.9

Figure 1. Contrast enhancement: the signature of VEGF.

Figure 1

Contrast enhancement: the signature of VEGF. Iodinated molecules of high molecular weight pool in the perivascular space due to capillary leakage. A typical CT scan for high grade glioma at the time of presentation or upon disease recurrence.

Elevated VEGF production has also been demonstrated in CNS tumors of non glial origin. These include craniopharyngiomas, meningiomas, pituitary adenomas, and hemangioblastomas. 1013 In these nonglial tumors, VEGF production is variable. VEGF is elevated in virtually all hemangioblastomas. In meningioma VEGF content correlates with the degree of differentiation. The most undifferentiated lesions produce the greatest amount of VEGF. However, Lamszus et al found no correlation between VEGF content and vascularity or invasiveness.11 Taken together these findings suggest that VEGF is a factor in the evolution of nonglial tumors, but not the only one. Of historical note, an early isolate of VEGF came from cultured pituitary folliculostellate cells.14 Tumors which metastasize to the brain also produce VEGF.15

Fortunately, brain tumors are rare in children. The majority of CNS tumors in children arise from astrocytes ( astrocytomas) or from the granular layer of the cerebellum (medulloblastomas). Both are associated with enhanced VEGF production.16,17

Gliomas are the most common malignant tumors of the central nervous system. They have been studied extensively with regard to VEGF. The remaining discussion will focus on them.

Angiogenesis in Glioma

One of the major differentiating features between low grade and high grade gliomas is the degree of vascularity. The progression to high grade is characterized by increased vascularity and the presence of endothelial cell proliferation. Swollen endothelial cells become prominent, and abnormal vascular channels resembling glomerular structures develop in the most undifferentiated lesions.

Neoangiogenesis in human glioma is driven by multiple molecules including VEGF, angiopoietins, fibroblast growth factors, platelet derived growth factor, epidermal growth factor, and transforming growth factors.18 Macrophages, themselves capable of releasing multiple modulators of vascular remodeling including VEGF, play a role.19 Down-regulation of negative modulators of angiogenesis is also seen in the progression of glioma. The anti-angiogenic molecule, thrombospondin, is shut off in high grade lesions.20 Folkman has advanced the concept of the “angiogenic switch” in tumor progression. A major tenet is that neoangiogenesis is dependent upon the local balance between pro and anti-angiogenic forces.21 Gliomas, with multi-factorial pro and anti-angiogenic molecules, are a classical illustration of this concept.

Aberrant VEGF production plays a significant role in the pathophysiology of glioma progression. VEGF is produced in at least four isoforms. Three isoforms, VEGF,121 VEGF165 and VEGF,189 have been demonstrated in glioblastoma multiforme.22 In situ hybridiziation demonstrates a progressive increase in VEGF mRNA from very low levels in normal brain to a fifty fold elevation in glioblastoma where expression is detected in palisading cells around areas of necrosis.23 Likewise, VEGF expression correlates strongly with neovascularization and tumor progression in oligodendroglioma.24

VEGF is produced by malignant glial cells which are distributed both centrally and peripherally within tumors.25,26 In situ hybridization experiments demonstrate mRNA for VEGF in malignant glial cells often juxtaposed to areas of necrosis. Cells producing VEGF also infiltrate the normal brain adjacent to tumor. The receptors for VEGF are up-regulated in the developing microvasculature of gliomas.2729 Increased expression of mRNA for VEGFR-1 (Flt-1, fms-like tyrosine kinase) and VEGFR-2 (Flk-1/KDR, Fetal liver kinase 1, murine homologue of human Kinase insert Domain-containing Receptor) is found in endothelial cells of the tumor neovasculature and in normal brain adjacent to tumors but not in the established vasculature of the normal brain. VEGF can be demonstrated on or within the newly developing blood vessels. Taken together, these findings support the hypothesis that VEGF is produced and secreted by malignant glial cells and is then sequestered by receptors on activated endothelium. Figure 2 is an immunohistochemical evaluation of human glioblastoma which demonstrates VEGF in the glial cells surrounding capillaries and in the capillary walls themselves.

Figure 2. Immunohistochemistry of glioblastoma multiforme: the brown stain indicates the presence of VEGF in malignant glial cells surrounding “glomeruloid” vessels.

Figure 2

Immunohistochemistry of glioblastoma multiforme: the brown stain indicates the presence of VEGF in malignant glial cells surrounding “glomeruloid” vessels. VEGF is also present in the endothelial cells themselves.

VEGFR-1 (Flt-1) is also present on macrophages. Recruitment of macrophages is mediated in part by VEGF-Flt-1 receptor signaling.30 The presence of macrophages further contributes to neoangiogenesis and correlates with poor prognosis in malignant tumors of the central nervous system.31

VEGF is one of a number of growth factors capable of stimulating endothelial cell proliferation in brain tumors.18 Angiopoietin-Tie2/Tek receptor signaling is an important early event along the angiogenic pathway.32 Vascular remodeling in glioma is dependent upon signals generated by both VEGF and the angiopoietins. When glioma cells are implanted into the brains of rats or mice, tumor “take” is facilitated by co-option of existing vessels.33 The co-opted vasculature initially regresses under the influence of angiopoietin-2. Tumor cell death occurs in areas of central necrosis. VEGF becomes upregulated in peripheral regions in response to hypoxia. Consequently, a robust angiogenic response occurs in the peripheral rim. In their elegant work, Holash et al studied the co-ordinated expression of Angiopoietin-2 and VEGF in specimens of C6 gliomas as well as human glioblastoma.33 They identified Angiopoietin-2 as an early signal which destabilizes vascular endothelium. The coincident expression of Angiopoietin-2 and VEGF produces neoangiogenesis. Angiopoietin-2 expression in the absence of VEGF leads to endothelial cell death and vascular regression. Other studies have documented the involvement of PDGF (platelet derived growth factor), the FGF's (fibroblast growth factors), and EGF (epidermal growth factor) in glioma angiogenesis.3436 The picture which emerges has VEGF as a major contributor to angiogenesis in malignant disease of the CNS albeit with co-ordinated input from a number of other growth factors.

Integrins present on the surface of endothelial cells are important for cell to cell signaling and attachment to the extracellular matrix. Friedlander et al have identified two separate angiogenic pathways.37 VEGF drives a pathway in which alphavbeta5 integrin is up-regulated whereas bFGF (basic fibroblast growth factor) drives a pathway mediated by alphavbeta3 integrin. In situ hybridization of glioblastoma demonstrates mRNA for both beta3 and beta5 subunits in contrast to normal brain microvasculature where neither was present.38 These findings support the concept that VEGF and bFGF both contribute to angiogenesis in high grade glioma.

Factors Influencing VEGF Production

VEGF exists in four major isoforms of 121, 165, 189, and 206 amino acids. The isoforms are created by alternative splicing of a single gene found on chromosome six in humans.39 VEGF165, the predominant species, is a weakly acidic heparin binding protein. It is present on cell surfaces and secreted. VEGF121 is the most soluble. VEGF189 and VEGF206 bind more avidly to heparin and are sequestered in the extracellular matrix. Proteolytic cleavage of the longer isoforms by plasmin produces biologically active fragments which contribute to angiogenesis.

The gene for VEGF is regulated by hypoxia. The promoter region contains a 28 base pair sequence under control of the transcriptional activator, Hypoxia Inducible Factor I (HIF-1).40 VEGF expression is increased in response to hypoxia in cultured cells of human gliomas.23 Post transcriptional stabilization of mRNA coding for VEGF also contributes to elevated VEGF concentrations in response to hypoxia.41 In situ hybridization of glioblastoma multiforme demonstrates the presence of VEGF producing cells in close proximity to necrotic (hypoxic) regions. 23 Evidence from multiple sources points to the importance of hypoxic up-regulation of VEGF expression in malignant disease of the CNS.

Acidosis also contributes to VEGF production independently of hypoxia.42 Fukumura et al used fluorescence ratio imaging microscopy to evaluate VEGF production in human gliomas growing in a mouse cranial window. They mapped out regions of VEGF production in relation to the pO2 and pH of the tissue. The highest levels of VEGF were found in acidotic regions independent of the degree of local oxygenation. They concluded that VEGF is up-regulated by hypoxia and acidosis via different mechanisms.42

Growth factors including bFGF, PDGF-BB, and EGF stimulate VEGF production by cultured glioma cell lines.43 Stimulation of the VEGF promotor by activation of the EGF Receptor occurs under hypoxic and normoxic conditions.44

Activation of oncogene pathways can stimulate VEGF production. Src stimulates VEGF production.45 Ras up-regulates VEGF under both normoxic and hypoxic conditions.46 Inhibition of the ras pathway by genetic or pharmacologic manipulation results in decreased VEGF expression.47 Wild type p53 suppresses VEGF expression.45 Malignant progression in glioma is associated with loss of function of the tumor suppressor gene p16. Restoration of p16 activity inhibits VEGF expression and angiogenesis.48 In hemangioblastomas the von Hippel-Lindau (VHL) tumor suppressor gene is mutated.49 The function of wild type (normal) VHL is to dampen expression of hypoxia inducible genes including HIF-1. Hemangioblastomas, as their name suggests, are highly vascular tumors which express high levels of VEGF.

Radiation stimulates VEGF expression in cultured glioma cells. VEGF was elevated in the conditioned media of human glioblastoma T98 and U87 cells following radiation exposure.50 The underlying mechanism involves activation of the Mitogen Activated Protein Kinase (MAPK) pathway. Ionizing radiation stimulated the MAPK pathway in both primary and malignant astrocytes of rat origin.51 MAPK activation was most pronounced in malignant cells, and multiple doses of radiation had a greater effect than single doses.

C6 Glioma Is an Excellent Model for the Study of High Grade Human Glioma with Regard to VEGF

C6 glioma is a highly vascular tumor of rat origin similar in histologic appearance to human high grade glioma.52 “Palisading cells” producing VEGF surround areas of necrosis in both. As in human tumors, VEGF receptors are up-regulated on endothelial cells within tumor and at the interface between tumor and normal brain but not in the normal brain. Hypoxia stimulates VEGF production by C6 cells, and mRNA encoding VEGF is stabilized post transcriptionally.53 Similar to human gliomas, angiogenesis in C6 tumors depends upon the interaction between VEGF and angiopoietin-2.33,54 Angiogenesis in C6 tumors is dependent on VEGF production. VEGF withdrawal leads to endothelial cell apoptosis and secondary tumor necrosis.55

VEGF Is Responsible for the Virulent Nature of High Grade Gliomas

While multiple growth factors influence angiogenesis in glioma, none is more crucial to the process than VEGF. Glial cell lines vary in their production of VEGF, and tumorigenicity correlates with VEGF production.56 Furthermore, cell lines of low virulence can be converted to high virulence by engineering them to express more VEGF.57 Studies where cells are “re-engineered” with respect to VEGF-receptor signaling clearly demonstrate that glioma growth and VEGF signaling go hand in hand. Benjamin and Keshet transfected C6 cells with a plasmid expressing VEGF under control of a tetracycline sensitive promotor.55 Tetracycline inhibited the promotor, and production of VEGF was repressed by the addition of tetracycline to the animals' drinking water. C6 tumors were allowed to grow to as large as one centimeter in diameter when VEGF was shut off. Microscopic evaluation of the VEGF deprived tumors demonstrated endothelial cell detachment and regression of both newly formed and mature vessels indicating that VEGF serves as a survival factor for established vasculature in this tumor model. Marked tumor necrosis was seen around areas of vascular involution.

Cheng et al transfected the human glioblastoma line U87MG with an antisense construct of the gene expressing VEGF.58 The cells produced less VEGF but retained their usual growth characteristics in vitro. However, they exhibited diminished ability to stimulate the migration of endothelial cells. Untransfected wild type cells readily formed large tumors when inoculated in the flanks of immunocompromised mice. They also grew intracranially. The antisense transfected cells showed marked impairment of growth when implanted subcutaneously or intracranially. Microvascular density was diminished in the small tumors which developed from the antisense-transfected cell line. Transfected cells which spontaneously lost the antisense expression reverted to the highly malignant and vasculogenic phenotype. Similar results were obtained using antisense VEGF transfected C6 cells and by directly injecting established tumors with a recombinant adenovirus expressing antisense VEGF.59,60

Millauer et al created a retrovirus expressing a mutated form of VEGFR-2 (Flk-1).61 Cells infected by the virus produced receptors for VEGF which were defective in VEGF signal transduction but which retained normal signal transduction pathways for other growth factors such as PDGF. Such cells were under the influence of a “dominant negative Flk-1 mutant.” The growth of C6 cells was unaltered in vitro by exposure to conditioned media from cell lines producing the “dominant negative” retrovirus. However, C6 tumor growth was inhibited in vivo in nude mice when the tumors were exposed to the retrovirus expressing truncated Flk-1 either at the time of tumor inoculation or five days afterwards. Microscopic examination of the treated tumors revealed a central necrotic core surrounded by a rim of viable cells with fewer capillaries.

The studies by Benjamin, Cheng, and Millauer clearly demonstrate that intact VEGF-receptor signaling is required for tumorgenicity in glioma.55,58,61 When otherwise virulent U87MG or C6 cells are re-engineered to produce less VEGF, they are no longer killers. Likewise, when the VEGFR-2 (Flk-1/KDR) receptor can be silenced by creating one that doesn't function, angiogenesis and tumor growth is profoundly inhibited. All tumors contain multiple molecular derangements; none is more crucial to the growth of high grade glioma than overexpression of VEGF.

Interrupting VEGF-Receptor Signaling Inhibits Glioma Growth in Preclinical Models

Glioma growth has been inhibited in preclinical models by strategies which target VEGF-receptor signaling in tumors which have not been re-engineered or epi-genetically modified. These include treatments with monoclonal antibodies directed against VEGF, monoclonal antibodies to VEGFR-1 and VEGFR-2, VEGF conjugated with diptheria toxin, soluble decoy receptors for VEGF (VEGF-Trap), and low molecular weight tyrosine kinase inhibitors (SU6668, SU5416).6269

Intra-peritoneal administration of the VEGF neutralizing antibody, 4.6.1, caused growth inhibition in a variety of human tumor xenografts including the G55 glioblastoma cell line.62 The antibody had no effect on cell proliferation in vitro. However, established G55 tumors treated in vivo with anti-VEGF had 20% of the weight of tumors treated with a control antibody. Microscopic evaluation showed a decrease in the vasculature of those tumors treated with 4.6.1. The antibody inhibited but did not eradicate the growth of G55 tumors. The authors speculated that additional angiogenic factors such as the Fibroblast Growth Factors might be responsible for growth. Yuan et al observed the effects of 4.6.1 on U87 growth in dorsal skinfold and cranial window chambers of mice.70 The antibody caused a reduction in vascular permeability within six hours of intravenous administration. The same effect was observed four days after intra-peritoneal administration of antibody. Other anti-VEGF antibodies besides 4.6.1 have slowed the growth of xenografted gliomas.63,65

Antibodies directed against both VEGFR-1 and VEGFR-2 have likewise demonstrated a capacity to impede the growth of gliomas. DC101 is a monoclonal antibody against VEGFR-2 which inhibited the growth of human GBM-18 tumors in a mouse xenograft.64 Regression of established glioblastomas was observed with DC101. The antibody inhibited tumor growth throughout the duration of treatment . However, progressive tumor growth took place upon cessation of treatment. Tumors treated with DC101 became pale and avascular.64 A monoclonal antibody to VEGFR-1 inhibited the growth of C6 tumors in mice.65 Tumors treated with the antibody to VEGFR-1 accumulated fewer macrophages in comparison to tumors treated with a control antibody. They also showed impaired vascular maturation.

VEGF-Trap is a molecule designed as a “decoy receptor” for VEGF. It consists of portions of the receptors for VEGF fused to the constant (Fc) region of IgG1. As implied by its name, it traps VEGF before binding to true receptors can occur. VEGF-Trap effectively inhibited the growth of C6 tumors in mice.67 Neoangiogenesis was markedly inhibited, but some viable tumor cells survived by “co-opting” the underlying host microvasculature.

SU6668 is a low molecular weight tyrosine kinase inhibitor capable of blocking receptors for VEGF, FGF, and PDGF.68 It can be administered either intra-peritoneally or orally. It demonstrated growth inhibition against a wide variety of tumors tested in a mouse xenograft. The A431 human epidermoid tumor was particularly susceptible with 97% growth inhibition. Half of all A431 tumors were permanently eradicated. SU6668 did well, albeit less spectacularly, against C6 tumors which showed 81% growth inhibition and the human glioma, SF763T, whose growth was inhibited by 79%. Intravital videomicroscopy revealed diminished tumor vessel density in C6 tumors treated with SU6668. However, even treated tumors showed an increase in vessel density from day 10 to day 22.

Collectively, the preclinical studies targeting VEGF signaling share the following common denominators: (1) tumor growth is impeded, and the magnitude of the effect is impressive. However, gliomas are not completely eradicated in the process. (2) microvascular density is decreased; it is not eliminated. Following cessation of treatment, tumor growth resumes.

Current Therapy of Glioma: VEGF Contributes to Treatment Failure

Treatment of glioma generally consists of subtotal resection followed by radiation therapy. Tumors infiltrate normal brain parenchyma, and total removal is rarely achievable. Fractionated radiation is delivered postoperatively to doses in the order of 6000 to 6500 cGy in daily fractions of 180-200 cGy. Chemotherapy is often given concurrent with and following radiation in high grade lesions. The prognosis depends largely upon the grade of tumor and the extent of resection.71,72 Grade I and II tumors have few mitotic figures, little cellular pleomorphism, and sparse normal appearing neovasculature. Median survival with grade I/II tumors is measured in years. Grade III/IV lesions are a different matter. These tumors have a high mitotic index, much cellular pleomorphism, and abundant abnormal appearing neovasculature. Despite the aggressive treatment outlined above, median survival is measured in months for high grade gliomas. The vast majority of recurrences happen “locally,” that is, within the original tumor volume. Autopsy specimens demonstrate VEGF expression in cells spread throughout the recurrent tumor and in normal-appearing astrocytes in the adjacent normal brain.73 Why does aggressive treatment fail to control high grade glioma? Cell lines derived from gliomas are not intrinsically “radioresistant.”74 They exhibit the same sensitivity to radiation as “radiocurable” cell lines in clonogenic assays. The answer may be that gliomas produce VEGF in response to ionizing radiation.50,51 Gorski et al demonstrated that VEGF is a survival factor which protects endothelial cells from the lethal effects of radiation in vitro.50 Conversely, blocking VEGF enhances the ability of radiation to kill endothelial cells. The authors put forth the hypothesis that “radiation resistance” is mediated by the protective effect of VEGF on the microvasculature. Geng et al validated this hypothesis by observing the growth of tumor vasculature in a vascular window model.75 They grew the murine glioma cell line, GL261, in the hindlimbs of mice and measured vascular growth in response to radiation alone or in combination with VEGF receptor blockade. They found that VEGF receptor blockade sensitized the endothelium to ionizing radiation and “eliminated the resistance phenotype.”

Radiation has been combined with anti-VEGF approaches in the treatment of established glioma xenografts. Monoclonal antibodies to VEGF and VEGFR-2 have been employed in combination with radiation.49,76,77 The low molecular weight tyrosine kinase inhibitor, SU5416, has also been used with radiation.75 Combined therapy demonstrates improvement over radiation alone. The growth of tumors is delayed by combined therapy, however, eradication of tumors has not been reported.

Summary and Future Directions

High grade gliomas are incurable by current methods of treatment. They possess the ability to regenerate by mounting a vigorous angiogenic response. VEGF is central to the process. It is the main “accelerant” which fuels tumor growth before and after conventional treatment. In preclinical models, blockade of VEGF-receptor signaling disrupts angiogenesis which causes tumor shrinkage and growth delay. The magnitude of the effect is impressive. However, secondary growth factors (FGF's, PDGF, TGF etc) capable of stimulating angiogenesis are operative in high grade glioma. They can drive the angiogenic engine in the face of VEGF blockade.

True believers (the author is one) in the concept of cancer control by blockade of tumor angiogenisis must understand that the process is multi-factorial. Strategies which complement VEGF blockade must be identified. Potential avenues of approach include: (1) Disrupting the process of “vascular co-option” whereby tumor cells engage the existing host vasculature. This phenomenon seems to be a common feature of early disease development as well as tumor regrowth following treatment. (2) Targeted therapy to disrupt signaling of the secondary growth factors. (3) Disruption of integrin signaling.

It has been only two decades since the discovery that “tumor cells secrete a vascular permeability factor”.78 We know it now as Vascular Endothelial Growth Factor. Since then the central role of VEGF in the pathophysiology of malignant disease has been elucidated. Molecules capable of blocking its effects have gone from the preclinical to the clinical stage of investigation. Unfortunately, angiogenesis inhibitors have had a disappointing track record in early clinical trials. Large potentially unstable molecules have been used as single agents. Often, doses employed in human trials have been significantly smaller on a milligram for kilogram basis than those employed in mice. The “true believer” must not be deterred. We are looking for the right combination of anti-angiogenic molecules. Single agents won't do the trick against a multi-factorial process. In the future, heretofore uncontrollable tumors such as glioblastoma will be cured by the delivery of a “cocktail” of angiogenesis inhibitors. The cocktail will include at least one potent blocker of VEGF-receptor signaling. Take it to the bank. Keep looking for the ingredients.


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