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Brain Tumor Invasion and Angiogenesis

Written By

Almos Klekner

Submitted: April 17th, 2012 Published: February 27th, 2013

DOI: 10.5772/52309

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1. Introduction

It is a well-known fact that effectiveness of oncotherapy in brain tumors remains under the expectations in comparison to anaplastic tumors of other organs. Knowing the very modest survival rates enormous efforts of neuro-oncological researches has been made, but only partial success is produced. Beside the extremely high proliferation rate of high grade glioma cells researches established the highly intensive invasiveness and angiogenesis as the main reasons of treatment failure. In this chapter the main molecular mechanisms of brain tumor invasion and angiogenesis will be discussed followed by the hopeful treatment possibilities that are already in studies and will be achievable in the near-future.

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2. General a spects of glioma invasion

Malignant gliomas are the most common primary brain tumors. They are associated with the shortest survival time explained by their early recurrence due to their deep invasion of the normal brain, which makes them practically impossible to remove completely. Invasive anaplastic gliomas are almost invariably fatal, recurring close to the resection margin in almost all cases. Interestingly, primary brain tumors have a strong tendency to invade their environment, but with rare exceptions, do not metastasize outside the brain. [1-3].

To understand the invasion behaviour of gliomas, the cellular and molecular events of peritumoral infiltration have to be discussed. The most important medium for this process is the extracellular matrix (ECM). The ECM comprises a considerable proportion of the normal brain volume. The extracellular space (ECS) of the healthy brain tissue volume is approximatley 20%. The extracellular volume fraction in the majority of primary brain tumors is significantly increased, representing about 48% of the total tumor tissue volume especially in high grade gliomas. The structure and compounds of the ECM of the brain tissue have many specific differences from other human organs. The ECM of the brain contains mainly macromolecules like glycosaminoglycans (GAGs) and proteoglycans (PGs), and only moderately express fibrillary glycoproteins (e.g. collagens, fibronectin, elastin or reticulin). The compounds of ECM glycoproteins play a crucial role in peritumoral invasion forming structural elements for cellular attachment and migration. There is much evidence that ECM components can modulate brain tumor growth, proliferation, and invasion by many different mechanisms. Thus extracellular matrix plays a pivotal role in the tumorous infiltration of the surrounding tissue. The presence and functions of hyaluronic acid (hyaluronan, HA), PGs and various types of GAGs have already been intensively investigated to clarify the molecular mechanisms of invasion, and a positive correlation has been established many times. To allow cell adhesion and migration, the ECM components interact with specific receptors on the cell membrane, such as integrins, CD44, or CD168. Some proteases and synthases also strongly influence invasiveness because of their capacity to alter the actual levels of the ECM molecules or to degrade the pericellular network. [4-16]

Using the ECM macromolecules to their active movement, glioma cells infiltrate the enviroment and form it similar to the tumor tissue. The process of the peritumoral invasion depends on the confrontation zone of the tumor cells and the non-neoplastic cells and ECM. Glioma cells express mainly adhesion receptors and proteases, while host cells produce macromolecules to maintain original structure and to inhibit invading cell movement. Since brain ECM has no strong fibrillar, collagen-rich network, the brain parenchyma remains soft, that can not hinder significantly the migration of tumor cells.

In case of glial cell tumors there are two main factors that significantly promote peritumoral infiltration. First is the normal structure of the brain parenchyma composed mainly by tracts in the white matter and basement membranes, which are suitable for guiding cell migration. Second is the increased ability of glia cells to migration. Both factors are special for the brain and they can be easily understood knowing the connection of development, structure and function. [17, 18]

From neuro-oncological point of view the increased glioma cell mobility and extensive peritumoral infiltration leads to the following problems:

  1. A. Total extirpation of a low grade tumor is not an easy and evident technical tool of therapy. This is one main reason why these tumors are “semi-benign” tumors. Thus in spite of the macroscopically radical surgical removal, the recurrence rate of these tumors is very high, and full recovery is not a general event.

  2. B. In case of high grade tumors, neither open surgery, nor stereotactic radiosurgery can achieve radical tumor removal. This experience can explain the local recurrence that appears in almost every case.

  3. C. Local chemotherapeutical treatment (intraparenchymal or post operatively administered intracavital drug) has low effectiveness.

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3. Molecular aspects of glioma invasion

Molecules that are responsible for the cell migration are divided in three groups:

  1. Cell-membrane associated molecules (receptors and adhesion molecules).

  2. Extracellular matrix (ECM) components (targets for the receptors).

  3. Enzymes that are synthesizing or lysating the ECM components.

3.1. Cell-membrane associated molecules (receptors and adhesion molecules)

Molecules with evident role in peritumoral invasion are located either on the cell surface, or form transmembrane structure. The main representatives of this group are the receptors and adhesion molecules as detailed below.

The Ig superfamily contains molecules in the cell membrane consisted of immunoglobulin-like and fibronectin type III domains involved in cell–cell adhesion. The superfamily includes the integrins, a variety of cell adhesion molecules (CAMs) with distinct ligand-binding specificities, namely ICAM (intercellular), NCAM (neural), Ep-CAM (epithelial), L1-CAM, VCAM (vascular), ALCAM (activated leukocyte), and JAM (junctional adhesion molecule), among others. [19]

The integrins are the most common molecules that serve for glioma cells to adhere to ECM. These molecules are heterodimeric transmembrane glycoproteins consisting of non-covalently linked α and β chains, which both determine ligand binding strength and specificity. Eight distinct α and 18 β chains combine to form about 24 different heterodimers. They can interact with two groups of ligands: some of the ECM proteins, such as fibrinogen, fibronectin, vitronectin, and cell surface molecules, that are members of the immunoglobulin superfamily. Regarding the many different heterodimers, each cell type maintains a specific and activation-dependent integrin repertoire and consequence ligand preference. The cytoplasmic integrin domains connect to signalling proteins and to the actin-cytoskeleton mediating intracellular signal transduction and cell movement. This function definietly demonstrate the dynamics of cell–ECM interaction as cells move along a substrate. Thus, integrins are prominently important mediators for cell adhesion and migration. They also interact with growth hormone receptors and contribute to cell–cell contacts due to direct interactions with counterpart cell receptors. On the other hand, focal contacts mainly depend on the ECM-compartment and on the cell type. Different integrins are known to be involved in that process. Integrin α5β1 binds to fibronectin, α6β1 or β4 binds to laminin, αvβ3 binds to fibronectin, vitronectin and tenascin-C and α2β1 binds to fibrillar collagen. Some of the integrins are directly connected to malignant behavior of gliomas. Neutralizing antibodies to β1- and αvβ5-integrin lead to decreased glioma migration in vitro. It was also demonstrated, that tenascin increases in vitro motility of human gliomas through interaction with β1-integrins. Inhibition of β1-integrins leads also to decreased motility, whereas inhibition of αv-integrin causes increased motility. The integrin αvβ3 plays a central role in glioma invasion. Increased expression of integrin αvβ3 results in increased motility of glioma cells with a decrease in apoptosis sensitivity. Furthermore, inhibition of integrin αvβ3 decreases glioma cell motility. Integrins αvβ3 and αvβ6 interacting with tenascin was proved to mediate adhesion rather than migration. Expression of β5-integrin is correlated with in vitro invasiveness and migration of human glioma cells. However α-actin expression and linkage of integrins to the cytoskeleton is related to glioma aggressiveness and poor prognosis in WHO II and III astrocytoma. [20-33]

Integrins mediate also activation of focal adhesion kinase (FAK) that associates with β1- and β3-integrins, which can trigger FAK phosphorylation. It is a non receptor tyrosine kinase overexpressed in invasive glioma cells, and its expression correlates with tumor recurrence and invasiveness in many tumor types. FAK is activated either by integrin mediated adhesion to ECM or by growth factor stimulation and it induces cell migration. Induction of FAK can protect cells from apoptosis. [34-41]

The neural cell adhesion molecule (NCAM) is expressed mainly by developing neurons. It is downregulated during embryogenesis and re-expressed again once differentiation is initiated. Overexpression of NCAM decreases glioma cell motility in vitro. In drug-resistant glioma cell lines NCAM expression is reduced and integrin-expression is increased that help to explain decreased chemosensitivity in invading glioma. [42- 45]

CD44 is the most important HA-receptor expressed by every nucleated cells in vertebrates. CD44 is a transmembrane glycoprotein belonging to the immunoglobulin receptor superfamily. Besides the standard form (CD44s), multiple splice variants encoded by variable exons v1–10 (CD44v1–10) can be identified depending on the cell differentiation and activation state. Interactions of CD44 with numerous other molecules, such as collagens, laminins and fibronectin, have been proved in vitro. CD44 is consisted of four functional domains: amino terminal domain, stem structure, transmembrane domain and cytoplasmic domain. The amino terminal domain can link to the ECM components such as HA and other GAGs. The stem structure domain binds the amino-terminal domain and transmembrane domain. The transmembrane region is probable responsible for the association of CD44 with lipid rafts. The cytoplasmic domain of CD44 is connected to the cytoskeleton via ankyrin and other proteins that is necessary to cell adhesion and motiliy. CD44 can be cleaved to two parts, and both the extracellular and intracellular components of CD44 promote cell migration. CD44 also interacts with various regulatory mediators to cell signaling pathways. Through these connections CD44 promotes MMP-mediated matrix degradation, tumor cell growth, migration and invasion and its expression correlates well with invasion potential of glioblastoma. [46-54]

The receptor for hyaluronate-mediated motility (RHAMM) is also a HA-binding protein expressed on the cell surface and also in the cytoplasm, cytoskeleton and nucleus. Interaction of HA with RHAMM induces many cellular signaling pathways in connection to protein kinase-C, FAK, MAP kinases, NFκB, RAS, phosphatidylinositol kinase (PI3K), tyrosine kinases and cytoskeletal components. CD44 and RHAMM probably have redundant or overlapping functions, but it is evident that interactions of HA with CD44 and RHAMM are necessary for tumorigenesis and tumor progression. [55-58]

Syndecans are a family of transmembrane heparan sulphate proteoglycans with four members, syndecans 1 to 4. Syndecans are co-receptors by binding their ECM ligands in conjunction with other receptors, mainly integrins. Through their heparan sulphate side chains, syndecans may further take part in other ligand binding, like VEGF, fibronectin and antithrombin-1. Linking syndecan to fibronectin is modulated by tenascin-C. Syndecan-1, -3, and syndecan -2, -4 bild two different structural subgroups. Syndecan-1 is expressed generally in fibroblasts and epithelial cells (especially in keratinocytes), but normally there is only a moderate presence in endothel and neural cells. Syndecan-3 dominates in neural cells, but not in epithelial cells, and syndecan-4 can be found mainly in epithel cells and fibroblasts, while it is poorly expressed by endothel and neural cells. Syndecans have four main function: 1. activation of growth hormon receptors; 2. cell adhesion to ECM components such as collagens type I, III, V, fibronectin, thrombospondin and tenascin; 3. cell-to-cell adhesion (e.g. syndecan-4 and integrin linkage takes part in intercellular interactions; 4. tumor suppression (anti-invasive effect by keeping tumor cells together) or tumor progression (depending on tumor histology and growth phase). [59-62]

Cadherin superfamily is also an important group of adhesion molecules regarding glioma invasion. Cadherins are transmembrane proteins compound of several tandemly repeated cadherin domains that interact in calcium-dependent homophilic cell–cell contacts. The cadherin superfamily consists of more than 100 different members, with E- (epithelial) and N- (neural) and P-cadherin, most intensively expressed in epithelial and neural tissues, respectively. Desmosomal cadherins (desmoglein and desmocollin) provide a linkage to the intermediate filament network through connection with cytosolic proteins (desmoplakin, plakoglobin and plakophilin). Adherens junctions play a pivotal role in embryonic development as well as in the maintenance of tissue architecture in adults. Cadherins are linked to the actin-cytoskeleton network through catenins (α-, β-catenin, plakoglobin and p120ctn), thereby providing molecular lines of communication to other cell–cell junctions and to cell-substratum junctions. Cadherin cluster forms a transmembrane core of adherens junctions at sites of the cell–cell contacts. During tumor progression decreased cadherin function is correlated with de-differentiation, metastasis and poor prognosis. In glioblastoma N-cadherin cleavage is regulated by ADAM-10 that promotes tumor cell migration. Furthermore, aberrantly processed proN-cadherin promotes cell migration and invasion in vitro, and in human glioma the level of proN-cadherin is elevated that directly correlates with the invasion potential. [63-68]

Dystroglycan is a transmembrane glycoprotein expressed mainly in sceletal muscle cells, but it can be also found in brain tissue as well. Its main function is to creat contact between the ECM macromolecules and the intracellular cytosceleton. It is linked intracellularly to dystrophin, a protein coded on the X-chromosome (lack of dystrophin causes the herediter muscle disease named dystrophia musculorum Duchenne). Dystroglycan is a heterodimeric complex consisting of non-covalently associated α and β subunits. The α-subunit connects α2-laminin, agrin and perlecan (components of the lamina basalis), the β-subunit is the transmembrane part that binds to dystrophin. Overexpression of dystroglycan decreased the growth rate of glioma cell lines so it was found to be involved in the progression of primary brain tumors. [69-71]

3.2. Extracellular Matrix (ECM) components (targets for the receptors)

Various components of brain ECM, like GAGs and PGs are overexpressed in gliomas. These molecules are binding sites for tumor cell receptors or they can inhibit cell migration, so they take an important part in peritumoral glioma invasion, and consequently could also serve as targets for anti-tumor therapy.

Proteoglycans (PGs) are composed of a protein core and glycosaminoglycan side chains (GAGs). GAGs are carbohydrate polymers containing N-acethylglucosamine or N-acethylgalactosamine and uronic acid (glycuronacid or iduronacid).

Depending on the GAG side chains the main types of PGs are chondroitin-sulphate (glycuronacid and N-acethylgalactosamine polymer and protein core), dermatan-sulphates (former name chondroitin-sulphate-B, composed of iduronacid and N-acethylgalactosamine polymer and protein core), heparansulphate (glycuronacid and N-sulphoglucosamine polymer and protein core) and keratansulphate (galactose and N-acethylgalactosamine polymer and protein core). Hyaluronic acid (hyaluronan, HA) is consisted of only GAGs (glycuronacid and N-acethylglucosamin polymer) that has no covalent bind to a protein, so it is not a PG by definition, but due to its tight relation to the PGs in general it is discussed together with them.

One of the most frequent adhesion glycoprotein in the ECM is fibronectin. It has a pivotal role in cell attachment, migration, differentiation and proliferation. Although its protein fragment is coded by only one gene, more isoform exits due to alternative splicing. The main cell surface receptors for fibronectin are the integrins, but it can also bind collagens, fibrin and heparan-sulphates. It is structured of two different subunits linked by disulphid bridges to each other. Fibronectin appears in two different forms: the solubile molecule can be found in the plasma, produced by hepatocytes, it accumulates at wessel wall damage and has an evident role in clot-building. The insolubile form of fibronectin is expressed by fibroblasts and mainly localized in the intercellular ECM. In tumor stroma production of fibronectin is reduced and its degradation is increased. Paralel to these changes on tumor cell surface, the expression of the fibronectin receptor α5β1 integrin is also decreased. ECM components such as fibronectin and collagen type IV are mostly produced by the host tissue and are associated dominantly with the vessel walls in gliomas. Fibronectin is mainly degraded by MMP-2 that is specifically active in gliomas explaining partly the moderate presence of extracellular fibronectin in glioma ECM. [72-74]

Another common component of the ECM is the molecular family of laminins. This glycoprotein has many variants, and it is the main component of lamina basalis. It is thought to take part in cell differentiation, adhesion, migration and cell survival. Each molecule of laminin consits three different chains (α, β, and γ chain) which has 5, 4 and 3 genetic variants, respectively. Recently at least fifteen different chain-combinations have been detected in human tissues. In the lamina basalis laminins promote cell-to-cell linkage, and it forms a specific network with connection to enactin, fibronectin and perlecan. These molecules can also bind to cell surface receptors such as integrins or dystroglycans, etc. Laminins regulate glioma cell adhesion to ECM proteins in specific manner leading to cell proliferation or cell migration and up-regulation of laminin is associated with the invasiveness activity. [75-77]

Agrin is also an ECM forming PG with the capability to collect acetylcholin receptors. Normally it is indispensible in developing neuromuscular junctions during embryogenesis. Agrin is secretaed at the end of the moto-neurons, and it is also a main component of membrana basalis in various human organs taking part in cell-ECM interactions. Together with neurocan, tenascin-C and versican it is responsible for the peritumoral infiltration of gliomas. [78]

Hyaluronan(HA) is a non-sulphated, linear, high-molecularweight GAG. It differs evidently of other GAGs, because of its extremely large molecular weight (103–104 kDa) composed of 10,000 or more disaccharide repeating units, the lack of sulfate groups or epimerized uronic acid residues and because HA is synthesized at the inner face of the plasma membrane as a free linear polymer without any protein core. It has a significant waterbinding capacity, so it controls the water content of the brain interstitium. HA comprises a substantial fraction of brain ECM and is involved in many physiological and pathological processes. In normal ECM, HA sustain tissue homeostasis, biomechanical integrity, structure and some kind of tissue cohesion. In malignant tumor tissues, HA transmit signals into cytoplasm and induces cell proliferation, motility and invasion. HA binds tenascins, lecticans, the cell surface receptors including CD44, RHAMM or ICAM-1, which together contribute to ECM organization and cell–matrix interaction. Through elevating the level of MMP-9 HA also promotes peritumoral invasion by activating the protease system. Glial tumors have increased amounts of HA which facilitates invasion activity of glioma cells. [79-84]

Lecticans comprise also a family of chondroitin sulphate proteoglycans with four members (brevican, versican, neurocan, and aggrecan), whereby brevican and neurocan are brain-specific molecules. Lecticans contain HA and tenascin binding sites and thus mediates linkage in protein–PG-GAG networks. [85-86]

Brain enriched hyaluronan binding (BEHAB) molecule,also known as brevican, a brain-specific chondroitin sulfate PG shows dramatic upregulation in gliomas and it is also induced during periods of increased glial cell motility in development and following brain injury. Gliomas express unique brevican isoforms and the processing of this specific isoform is important for its proinvasive role. In experimentally induced tumors brevican accumulates at the invasive borders and it associates with high infiltrative profiles. Furthermore, brevican up-regulation correlates well with short survival periods of patients with high grade gliomas. Brevican expression in gliomas is restricted to membrane localization, and its presence in high-grade gliomas suggests that it plays a significant role in glioma progression. Brevican promotes activation of epidermal growth factor receptor (EGFR), increases the synthesis of cell adhesion molecules and facilitate fibronectin microfibrill presence on the cell membrane. The effect of brevican on glioma cells motility is mediated not only via EGFR signaling but also by fibronectin-dependent adhesion, and increased expression of CAMs. This motogenic signals could not be worked in the normal neural ECM, where fibronectin is almost absent but it is effective in the microenvironment of glioma cells, which co-express large amounts of brevican and fibronectin in vivo. This interaction explains the distinct ability of these tumors spreading in the central nervous system. Overexpression of brain-specific isoforms of brevican proved to be correlated with ability to peritumoral invasion of gliomas. [73, 87-89]

Neurocan is a large brain specific chondroitin-sulphate PG that interacts with heparan-sulphate proteoglycan (HSPG) molecules, such as syndecan-3 and glypican-1. It has influence on cell adhesion and migration. Neurocan has two HSPG-binding domain with different affinity. In cell culture neurit outgrowth is increased by C-terminal part of neurocan. HSPGs serve also as cell-surface receptors for neurocan, and connection of neurocan to the HSPGs is necessary for the neurit growth. It was found on clinical samples that higher expression of neurocan is associated with the invasive activity of astrocytomas. [89-90]

The ECM glycoprotein tenascin, which forms a hexabrachion structure, can be detected in both the ECM and the perivascular tissues of high-grade gliomas. Tenascin R, a brain-specific member of the tenascin family comprising also tenascin C, X, and W, is a homotrimer with both lectican and integrin binding sites forming an adhesion link between the ECM and cells. The developed brain does not contains tenascin, but in normal brain tissue distinguishable deposits of this glycoprotein can be found in the glia limitans externa, and some tenascin was also detected in the ECS of white matter. Theres is a positive correlation between tenascin production and the malignancy or angiogenesis of astrocytomas and there is a prognostic utility of its immunohistochemical detection in ependymomas. The accumulation of tenascin in the ECS in high grade glial tumors can be one of the major factors leading to the critical increase in ECS tortuosity and the simultaneous enlargement of the ECS. It has been arised that the ECM distribution is modified at the brain-tumor zone of confrontation and the presence of tenascin in this zone represents a negative prognostic factor in pediatric ependymomas. Tenascin-C is overexpressed in both low and high grade astrocytomas as well. In cultured brain-tissue tenascin-C is produced by the endothelial cells. It takes an important part in various cellular mechanisms like heamagglutination, T-cell immunsuppression, angiogenesis, chondrogenesis and it also has some antiadhesive effect. Tenascin subunits contain EGF- and fibronectin-like repeated sequences that are responsible for the growth inducing effect. Tenascin-C enhances migration of endothelial cells and phosphorylation of focal adhesion kinase (FAK). Tenascin-C signaling is mainly mediated by integrin-β1 which interacts with FAK. Tenascin-C is produced by the glioma cells rather than by the invaded brain and it improves aggressive behaviour and invasion activity of grade II astrocytoma cells in vitro and in vivo. Furthermore, expression of tenascin-C can be used as prognostic factor in grade II astrocytomas showing correlation with ability of tumor recurrence. Beside this, low tenascin-C expression was found to be associated with prolonged average survival time in glioblastomas and highest tenascin-C expression could be detected at the border of the malignant gliomas. [91-104]

Versican (also known as VCAN or CSPG2), a chondroitin sulfate PG, is one of the main components of the ECM, expressed almost in all human tissues. Versican takes part in normal tissue development, but its increased expression can be also detected in most malignancies. Elevated versican production occurs in either the tumor cells or the stromal cells surrounding the tumor. Increased versican expression strongly correlates with poor outcomes for many different tumor types. Versican regulates a wide variety of intracellular processes including cell adhesion, proliferation, apoptosis, migration and invasion via the chondroitin and dermatan sulfate side chains. In addition, the versican G1 and G3 domains can interact with various intracellular or extracellular molecules. In addition to HA, versican associates with tenascin-R, fibulin-1 and -2, fibrillin-1, fibronectin, P- and L-selectin, and many chemokines. It also binds to cell surface proteins including epidermal growth factor receptor (EGFR), CD44, and integrin β1.

A number of proteinase families are capable of generating the proteolytic fragments of versican. Matrix metalloproteinase (MMP)-1, -2, -3, -7, and -9, ADAMTS-1, -4, -5 and -9 cleave versican and generates proteolytic fragments.The accumulation of proteolytic fragments of versican play an important role in cancer progression. The regulation of G1 and G3 versican levels by proteases is known to be important in regulating cancer cell motility and metastasis. Through the EGF-like motifs in the G3 domain versican can stimulate cell proliferation and its G1 domain destabilizes cell adhesion and promotes cell growth. Versican expression is associated with a high rate of proliferation and it is localized in HA-rich tissues and also accumulated in perivascular elastic tissues involved in peritumoral invasion. These features of versican make it a proliferative, anti-adhesive and pro-migratory molecule that facilitates tumor cell motility. In clinical samples the association of versican to invasiveness of astrocytoma could be evidently demonstrated. On the other side, the decreased expression of versican V0 and V1 isoforms in glioma ECM can be related to the marked local invasivity and rarity of extracranial metastasis of gliomas. [105-111]

3.3. Enzymes that are synthesizing or lysating the ECM components

Matrix metalloproteinases (MMPs) are the most common proteases that degrade ECM to create the space for invading glioma cells. MMPs belong to the zinc-dependent endopeptidase together with adamalysins, serralysins and astacins. MMPs take part in remodelling after tissue damage, cell migration, differentiation and angiogenesis. At least 28 different types of MMPs are identified composing a protease family that is able to degrade practically every component of the ECM. Due to their function, MMPs also play evident role of activating mechanism by cleavage metabolits of inactive molecules. MMPs are overexpressed in glioma cells compared with normal brain tissue. MMP-2, MMP-3 and MMP-9 activity correlates well with glioma cell migration and invasion. [46, 112, 113]

Cathepsin-B is a cystein protease involved in protein degradation primarily within intracellular lysosomes but it takes evidently part in degradation of ECM-proteins. In order to be able to interact with ECM proteins, the lysosomal enzyme is secreted from its intracellular localization. Thus cathepsin B appears on the surface of glioma cells, where the enzyme can interact with the surrounding matrix components. Cathepsin-B is overexpressed in gliomas. Downregulation of cathepsin B in human glioma cells leads to decreased invasiveness in matrigel-assay and coculture experiments. Furthermore, downregulation of cathepsin-L in human glioma cells correlates with decreased invasiveness and increased sensitivity to apoptotic stimuli. [114-118]

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4. Invasion process of tumor cells

Knowing the invasion potential of primary brain tumors, many of the molecular mechanisms of peritumoral infiltration have been already studied and some of the invasion processes have been defined. During malignant transformation, invasiveness is determined by the complex functions of tumor cells of distinct histological types. A four-step model of invasion has been applied, that is also valid for brain tumors. This model contains the following steps: 1) the tumor cells at the invasive site detach from the growing primary tumor mass; 2) they adhere to the extracellular matrix (ECM) via specific recebptors; 3) proteases secreted by the glioma cells locally degrade the ECM components, forming a pathway migration into the surrounding tissue, and 4) tumor cell movement due to cytosceletal processes. Each step of the peritumoral invasion requires a harmonized cooperation of numerous molecules resulted in active cellular movement into the normal brain parenchyma. [119, 120]

The detachment of invading glioma cells from the primary tumor mass is a complex process comprising the following steps: 1) Destabilization and disorganization of the cadherin mediated junctions that hold the primary mass together. 2) Decrease expression of cell adhesion molecule which provides adhesion to the primary tumor mass. This leads to a reduction in gap junction formation. Cell–cell communication is necessary for growth control and differentiation, and it is mainly achieved through gap junctions. Increased malignancy of gliomas is accociated with reduced in situ gap junction formation, and invasion of gliomas. 3) Cleavage of CD44, which anchors the primary mass to the ECM. This process is mediated by metalloproteinase ADAM. [119-123]

Tumor cell adherence to the ECM components is mediated by specific cell surface or transmembrane receptors like integrins binding to laminins, fibronectins and collagens or CD44 to hyaluronan.

Degradation of ECM components occurs due to the local enhancement and activation of protease suc as MMPs, hyaluronidase, cathepsins and chondroitin suphatase.

Due to migration the glioma cell must interact with the surrounding ECM, which forms a mechanical barrier to the cells, and serves as a substratum for traction for the moving cells. For cell movement changes in cell morphology occur: the cell becomes polarized and membrane protrusions develop, including the extensions at the leading edge of pseudopodia, lamellipodia, filopodia, and invadopodia. These extensions contain filamentous actin and various structural and signaling molecules. The formation of membrane anchors needs cytoskeletal contraction, which finally results a cell forward displacement. Glioma cell motility and contractility also require A and B isoforms of myosin II. Myosin II is the major source of cytoplasmic contractile force. Myosin II allows glioma cells to squeeze through pores smaller than their nuclear diameter, which is especially important for gliomas because the human brain tissue has particularly narrow extracellular spaces. The connection of ECM macromolecules and cytosceleton is mediated by dystroglycans. [69, 124]

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5. The possible agents for antiinvasive therapy

Tumor cell invasion into the surrounding brain tissue is mainly responsible for the failure of radical surgical resection and successful treatment, with tumor recurrence as microdisseminated disease. ECM related molecules and their receptors predominantly participate in the invasion process, including the cell adhesion to the surrounding microenvironment and cell migration. Determination of the key molecules of invasion process can help toprovide possible targets for antiinvasive therapy. Regarding peritumoral infiltration activity of glioma cells, the following molecules are supposed to serve as antitumor agents.

Cilengitide is a cyclic peptide targeting the RGD-motif of integrins blocking αvβ3- and αvβ5-integrin mediated interaction between endothelial cells and ECM. By targeting these integrins cilengitide could inhibit both glioma invasion and angiogenesis. Cilengitide causes significant regression of glioma xenograftsand induces apoptosis in U87 glioma cells cultured on tenascin and vitronectin. In clinical trials targeting glioma invasion, in a randomized phase II study cilengitide proved to be safe and was associated with a median survival of 10 months in recurrent glioma patients. The North American Brain Tumor Consortium (NABTC) study aimed to determine cilengitide penetration rate into GBM in human patients. This study confirmed that cilengitide is effectively delivered into primary human GBM tumors with good retention. The effect of combination therapy, such as cilengitide with XRT or with another chemotherapeutic agent, is likely to be cumulative. [125-129]

Knowing the evident role of versican proteolytic fragments in cancer progression, its possible role as target for anti-cancer therapy has been arised. Although there are only a few results regarding anti-versican therapy in glioma patients, some possible agents are notable to mention for their potential future role.The tyrosine kinase inhibitor genistein has been shown to block versican expression in malignant mesothelioma cell lines and in vascular smooth muscle cells. Versican G3 fragments facilitate cancer cell growth, invasion and metastasis through EGFR signaling. The selective EGF receptor inhibitor, AG1478 prevents G3 fragment enhanced cell growth, migration, invasion and chemical resistance in vitro. Galardin, an antibody against the ADAMTS specific versican cleavage site inhibits glioma cell migration. GM6001, a MMP and ADAMT proteases inhibitor, also decreases cancer cell invasion and metastasis in several kinds of carcinoma. Other protease inhibitors such as catechin gallate esters, present in natural sources (green tea) selectively inhibit ADAMTS-1, -4 and -5 catabolism. [130-137]

Tumor formation of the pericellular matrix with HA and versican can be inhibited by treatment with HA oligomers, which can block the interaction between HA and versican, serving as inhibitors of cancer dissemination. Furthermore, disruption of the HA CD44 interaction with HA oligomers could also inhibit the growth of B16F16 melanoma cells, Therefore the application of HA oligomers can be an effective agent for inhibiting the formation of vesicant-HA-CD44 complexes, providing valuable targets against tumor progression. [138-140]

Emodin (3-methyl-1,6,8-trihydroxyanthraquinone) has evident anti-invasive effect on HA-induced glioma invasion. In glioma cells emodin inhibits the TGFbeta and FGF-2 induced expression of syndecan-1. It decreses the expression of MMP-2 and MMP-9 at both transcriptional and translational levels suggesting that emodin can be a clinically valuable anti-cancer agent against glioma invasion. [141, 142]

Since increased MMP levels are associated with glioma invasion and angiogenesis, marimastat, an orally active drug that can reduce MMP levels in patients with gliomas could inhibit growing of tumor. A phase II study evaluated marimastat combined with temozolomide (TMZ) in patients with recurrent malignant glioma and good outcome was documented, but joint and tendon pain was reported in 47% of patients. [143, 144]

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6. General aspects of angiogenesis

Rapidly growing tumors need to develop their own vasculature. The hypervascularisation of high grade gliomas can be visualized well on radioimaging and it can be a preoperative characteristic of glioblastoma. Furthermore, glioma angiogenesis is necessary for tumor expansion and survival, so its inhibition could be a potential tool in anti-tumor therapy.

There are two main angiogenic and invasive glioma phenotypes. Clusters of glioma cells perform single cell infiltrations into normal parenchyma independent of vasculature. Another group of glioma cells can be found around newly developed vessels in the normal brain parenchyma near to the tumor margin. These two different angiogenic and invasive phenotypes are called angiogenesis-dependent and angiogenesis independent invasions. High grade astrocytomas content both invasion phenotypes in a mixture of subclones present in different intratumoral regions. Molecular mechanisms of single cell migration were detailed above, but the role of neo-angiogenesis forms also a very important way to glioma expansion. [145]

In expanding, highly proliferate gliomas angiogenesis is activated when the pro-angiogenic stimuli dominates over the anti-angiogenic stimuli. These stimuli are mediated by factors secreted from glioma, endothelial or microglia cells, or arise from the extracellular matrix or other environmental sources like hypoxia induced cell productions. The pro- and anti-angiogenic forces are influenced strongly by tissue hypoxia and genetic alterations. The summation of these stimulileads to the so-called “angiogenic switch” in glioma angiogenesis.The most effective activator of angiogenesis in brain tumors is hypoxia that downregulates anti-angiogenic pathways and induces many pro-angiogenic ones. A well-known pathway is the HIF-1/VEGF-A pathway, which play a significant role in endothelial cell proliferation and migration. Another pathway mediator is interleukin-8, which is produced by microglia cells as a reaction to hypoxia. It is important to mention, that genetic instability of high grade gliomas provides the way of angiogenesis independently of hypoxia (such as chronic HIF activation via phosphoinositide 3-kinase (PI3K) or mitogenactivated protein kinase (MAPK) pathways. [146-152]

After activating the “angiogenic switch”, the tumor produces new vessels. The modes of new blood vessel formation in glioma occur by one of three different methods: 1) angiogenesis; 2) vasculogenesis; or 3) arteriogenesis. Angiogenesis is the formation of new blood vessels by rerouting or remodeling existing tumor vessels, and is supposed to be the main stream of neo-angiogenesis. Vasculogenesis means de novo production of blood vessels from circulating marrow-derived endothelial progenitor cells originally as the method of vasculature development in embryonic process. Since these progenitor cells have been also identified in tumors, they role in tumor angiogenesis cannot be denied. Vasculogenesis is probably regulated by tumor-secreted stromal-derived factor 1 under the control of the hypoxia-induced transcription factor hypoxia-inducible factor 1α (HIF1α). Arteriogenesis is the third mode of arteriolar networks formation representing a moderate proportion of tumor angiogenesis. [153-156]

6.1. Neoangiogenesis

The most significant way to form new blood vessels in gliomas is neoangiogenesis. Formation of new vessels from native vessels begins with breaking down the original vessel wall. The process of blood vessel breakdown is composed of three main phases. The first event in forming new vessels from existing ones is the disintegration of the vessel wall. Angiopoietin-1 (Ang-1) and its receptor Tie-2 play a pivotal role in this phase. Normally, Ang-1 binds to Tie-2 achieving a close association between pericytes and endothelial cells that is necessary for vasculature stability. In rapidly proliferating tumors like glioblastoma, tissue hypoxia increases and it induces Ang-2 upregulation in endothelial cells whereas Ang-1 is accumulated tumor cells. Increased Ang-2 expression, which is an antagonist of Tie-2, leads to the initial regression of blood vessels. Beside these, matrix-metalloproteinase (MMP)-2 expression is induced via Tie-2 signaling, and in conjunction with VEGF promotes angiogenesis. The second phase is the breakdown of ECM to provide place for the migration of endothel cells to form new blood vessels. Following dissolution of native vessel wall, degradation of the vessel basement membrane and relating ECM is the necessary condition for endothelial cells for invasion the surrounding microenvironment. MMPs play an integral role in this phase. In case of glioma angiogenesis, the collagenases MMP-2 and MMP-9 are involved in this process and their expression correlates with a poor prognosis in gliomas. Expression of MMP-2 and MMP-9 is also induced by hypoxia and through their proteolytic activity interaction of endothelial cells and tumor-ECM contents like VEGF and fibroblast growth factor (FGF) occurs. [157-166]

The third phase to form new blood vessels is the migration of endothelial cells. After dissolution of the basement membrane of the blood vessels and decomponent ECM, endothelial cells begins to proliferate and migrate toward tumor cells that expresses pro-angiogenic factors. Due to this process cell surface adhesion and migration molecules, such as integrins and CD44 upregulates.The activated endothelial cells secrets platelet-derived growth factor (PDGF) that induces pericytes to participate in creating a new basement membrane. For this reason beside migration of endothelial cells, pericyte migration also occurs as a necessary event of vasculogenesis. [167-169]

At the end of tumor blood vessel formation a significant change occurs in the extracellular environment, caused by increased expression of embryonic ECM molecules, such as tenascin-C. Elevation of VEGF and Ang-2 levels can be also detected, that probably explains the leakiness and pathologic structure of the new vessels. The result of glioma angiogenesis are highly tortuous dilated vessels and lots of small diameter vessels with alterations in endothelial cell adhesion molecule expression and disrupted basement membrane. [170-174]

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7. Molecular aspects of glioma angiogenesis

Angiogenesis is mainly induced through growth hormone receptors, especially through the vascular endothel growth factor receptor (VEGFR). This is a transmembrane receptor with an extracellular antibody-binding domain (for vascular endothel growth factor (VEGF)) and an intracellular tyrosin kinase domain stimulating the PI3K/Akt pathway. In tumor angiogenesis the effect of VEGFR can be increased either by receptor overexpression on the cell surface or by mutation of the receptor that without a hormone-ligand or by only a moderate ligand connection it keeps on a permanent stimulus.

Regarding glioma angiogenesis not only VEGFR but the hormone ligand VEGF has also an evident role in the process. There are more types of VEGF. Specifically, VEGF-A is upregulated in glioblastoma and it is produced by many cell types, such as tumor cells, stromal, and inflammatory cells. VEGF-A is primarily induced by tissue hypoxia and it regulates endothelial cell survival, proliferation, permeability and migration mainly through the VEGF-receptor 2 (VEGFR2). VEGF can also be derived from the tumor-ECM. Beside the increased amount of VEGF, the receptors VEGF-R1, VEGF-R2 and VEGF-R3 are upregulated on endothelial cells in glioma in comparison to normal brain. [175- 182]

Other growth factors have also influence on angiogenesis. Epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and platelet derived gfrowth factor (PDGF) facilitates VEGF expression. The result of pathologic increased VEGF signaling in tumors is immature, highly permeable blood vessels with deteriorated blood-brain-barrier (BBB) function and subsequent parenchymal edema. In glioma, bFGF is expressed by tumor cells and endothelial cells but it can be also accumulated and stored in the extracellular matrix of glioma. [183-186]

In rapidly proliferating anaplastic gliomas oxigene supply remains constantly under the necessity, thus hypoxia remains a permanent stimuli for angiogenic factors. It seems to induce not only the secretion of growth factors, but also interleukin-8 (Il-8), a chemokine released by microglia, and Il-8 is expressed in adult glioma at levels correlating to tumor grade. In glioma the interleukin-8 mediated angiogenesis is regulated by the tumor suppressor protein ING4 through the transcription factor NFĸB. [187-189]

Interestingly, there are some molecules involved in neuronal pattering during embryogenesis that have similar functions in vascular pattern during tumor angiogenesis. One of these molecules is the semaphorin, that induces signal pathway through neuropilins and plexins. Neuropilins are expressed on vascular endothelial cells and function as receptors for VEGF. Their activation leads to pro-angiogenic responses even in the absent of the classical VEGF-R2 signaling and blocking neuropilin-1 can decrease tumor angiogenesis and growth. [183, 190-192]

Beside growth factors and their receptors, there are some ECM components that are overexpressed in glioma vessels in comparison to normal brain tissue, and have some stimulating effect on angiogenesis. One of the most important ECM proteins with an evident role in angiogenesis is tenascin-C, which is normally not expressed in the adult brain, but in glioma it can be found at the invading tumor border in the region of angiogenesis. Tenascin-C facilitates endothelial cell migration and induces VEGF expression and focal adhesion kinase phosphorylation, which are both important for angiogenesis. Another ECM protein involved in angiogenesis is fibronectin. The oncofetal form of fibronectin is typically only expressed during embryogenesis, but it is also produced in GBM, and it is localized to the tumor vessels. Laminin-8 a member of the laminin family in ECM is expressed in vascular basement membrane of GBM. Its blocking in an animal model of GBM resulted in decreased tumor microvessel density and increased survival. Versican is also an important ECM component of the tumor angiogenesis process. The versican G3 domain facilitates endothelial cell adhesion, proliferation, and migration in vitro and blood vessel formation in nude mouse tumors. Furthermore, G3-domain expressing cells produce increased levels of fibronectin and VEGF, suggesting their common functions in angiogenesis. [193-197]

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8. The possible agents for anti-angiogenic therapy

Since VEGFR play the most significant role in tumor angiogenesis, its inhibition bears the most effective possibility for decrease tumor growth. The VEGFR is a transmembrane tumor cell receptor, so blocking antibodies could close down its effect. On the other side blocking the intracellular tyrosine-kinase domain could also inhibit the activation of the signaling pathways. The latest way came into the front in past few years, when small-molecular tyrosine kinase inhibitors proved to be effective in vitro against glioma cell lines. Beside these, blocking the VEG-factor itself can also definitely decrease the stimulating effect of the receptor.

8.1. VEGF-blocking

The most known VEGF neutralizing antibody is the bevacizumab that is already a possible tool of the oncotherapy for glioblastoma. In recurrent glioma patients treated with bevacizumab combined with the chemotherapy agent irinotecan the median survival can be prolonged. As the result of a significant antitumor effect 63% radiographic response, 6-month progression-free survival in 32% of GBM patients could be achieved. Based on these favorable observations further clinical trials have been initiated to combine bevacizumab with temozolomide, the current standard of care for newly diagnosed glioblastoma patients. Another clinical trial suggests that the presence of tumor hypoxia markers predicts probable radiographic response and better survival of patients treated with combinant chemotherapy of bevacizumab and irinotecan. Gliomas treated with bevacizumab often appear as nonenhancing infiltrating laesions on MRI proving the reduced vascularity beside the ongoing invasion, so induction of anti-angiogenic therapy combined with anti-invasive therapy seems to be a possible treatment method in the future. [198-203]

8.2. VEGF-receptor blocking

Anti-angiogenic therapy with VEGF receptor inhibitor sunitinib normalizates tumor vasculature, so it elevates intratumoral level of temozolomide due to the improved vessel functions. Cediranib is a pan-VEGFR tyrosine kinase inhibitor, while enzastaurin is a protein kinase-C inhibitor. Both agents are already in studies. Sorafenib is a multikinase inhibitor, that suppresses angiogenesis by inhibiting VEGFR and PDGFR activities in endothelial cells. Sorafenib-treated mice showed significant suppression of glioblastoma cell proliferation, increased apoptosis and autophagy, and reduction of angiogenesis in vivo, phase II trials of sorafenib in patients with malignant gliomas were inducted. Imatinib is a kinase inhibitor of PDGFR, c-kit, and bcr-abl. In vitro studies of imatinib on glioma cell proliferation describe, that it is cytostatic agent at low concentration whereas at high concentrations it has cytotoxic effect. Imatinib monotherapy against malignant gliomas has failed to show any significant clinical benefits probable because of the moderate drug penetration across BBB and the inhibition of PDGFR alone can be insufficient to inhibit growth of malignant gliomas. In spite of these its use in combination therapy is still an interesting theme. [204-211]

8.3. Other target molecules for anti-angiogenic therapy

Tenascin-C is mainly expressed in hyperplastic vessels and it promotes migration of endothelial cells in astrocytic tumors. Therefore, blocking tenascin with an antibody to inhibit angiogenesis seems biologically reasonable, so a tenascin-specific antibody radiolabeled with I-131 was tested in patients with high-grade gliomas. The phase II studies with tenascin-blocking antibody in malignant glioma reported about a slight increase in survival time. [101, 195, 212-214]

Another ECM protein that has anti-angiogenic effect in glioma is secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or BM-40. Osteonectin takes part in a number of basic biologic functions, including migration, proliferation, and survival. Expression of SPARC in the nervous system is restricted normally to the angiogenic microvasculature, such as in the region of locus coeruleus and retinal astrocytes, but is not expressed in the cerebral cortex. In contrast, osteonectin is present in both tumor cells and endothelial cells in gliomas of all grades, and it is also expressed by endothelial cells and astrocytes in the adjacent tissue. Osteonectin suppresses tumor angiogenesis via inhibition of VEGF expression and secretion. [215-221]

8.4. Endogenous anti-angiogenic factors

A number of endogenous anti-angiogenic factors have been described that play pivotal role in tumor angiogenesis. Identifying these factors could offer some anti-cancer agent for neuro-oncological therapies. One of the best known endogenous anti-angiogenic proteins is angiostatin. It is mainly derived from degradation of plasminogen by proteases cathepsin-D and MMPs. In vivo studies in mice proved that angiostatin inhibits glioma angiogenesis and growth. The thrombospondins (TSPs) are another family of proteins that serves as an anti-angiogenic factor. In normal tissue TSP1 is produced by platelets, endothelial cells, and smooth muscle cells. Similar to angiostatin, endostatin is also an anti-angiogenic molecule created in glioblastoma basement membrane by proteolytic cleavage of collagen-18 by elastase, cathepsin-L, and specific MMPs. The endostatin-mediated signaling has more angiogenic inhibitory mechanism by binding to a5b1 integrin, inhibition of VEGF-R2, reduction of focal adhesion kinase-mediated endothelial cell migration, and suppression of pro-angiogenic MMP-2. A further factor is the angiogenesis inhibitor-1 (BAI1), also known as vasculostatin, that is produced only in glial cells and neurons of normal brain but not in blood vessels. Since vasculostatin is defnietly reduced in glioblastomas, its role in suppressing angiogenesis is glioma is strongly supposed. [222-231]

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9. Conclusion

There are no simple and evidently succesful protocols for therapy of primary brain tumors. The intensive proliferation activity, the significant peritumoral infiltration and increased angiogenesis altogether are responsible for the extremely high recurrence rate of gliomas. The failure of recently administered chemotherapy arises the requirement of combination therapy. Thus besides searching a highly specific tumor marker, establishing the molecular spectrum of these tumors can be suggested. Supporting this theory, the mRNA expression pattern of the invasion-related molecules was found to be highly specific for various different histological tumor groups. So determination of the genetic signature of invasion of a glioma is thought to help in screening exact molecules as targets for individual chemotherapy. [89] Furthermore, complexity of oncotherapy with combination of antiproliferation, antiinvasive and antiangiogenic drugs could bring benefits in treatment effectiveness against brain tumors in the future.

References

  1. 1. Burger PC, Scheithauer BW. Tumors of the central nervous system. Atlas of Tumor Pathology, third series, fascicle 1994; 10: 349-369
  2. 2. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathol 2007; 114: 197-109
  3. 3. Miliaras G, Tsitsopoulos PP, Markoula S, Kyritsis A, Polyzoidis KS, Malamou-Mitsi V. Multifocal glioblastoma with remote cutaneous metastasis: a case report and review of the literature. Cen Eur Neurosurg 2009; 70: 39-42
  4. 4. Czirok A, Zamir EA, Filla MB, Little CD, Rongish BJ.Extracellular matrix macroassembly dynamics in early vertebrate embryos. Curr Top Dev Biol 2006; 73: 237-258
  5. 5. Hirose J, Kawashima H, Yoshie O,Tashiro K, Miyasaka M. Versican interacts with chemokines and modulates cellular responses. J Biol Chem 2001; 276: 5228-5234
  6. 6. Jung S, Moon KS, Kim ST, Ryu HH, Lee YH, Jeong YI, Jung TY, Kim IY, Kim KK, Kang SS. Increased expression of intracystic matrix metalloproteinases in brain tumors: relationship to the pathogenesis of brain tumor-associated cysts and peritumoral edema. J Clin Neurosci 2007; 14:1192-1198
  7. 7. Leivonen M, Lundin J, Nordling S, von Boguslawski K, Haglund C.Prognostic Value of Syndecan-1 Expression in Breast Cancer. Oncology 2004; 67: 11-18
  8. 8. Pakula R, Melchior A, Denys A, Vanpouille C, Mazurier J, Allain F. Syndecan- /CD147 association is essential for cyclophilin B-induced activation of p44/42 mitogen-activated protein kinases and promotion of cell adhesion and chemotaxis. Glycobiology 2007; 17:492-503
  9. 9. Shibata Sh, Fukada K, Suzuki Sh, Ogawa T, Yamashita Y. Histochemical localisation of versican, aggrecan and hyaluronan in the developing condylar cartilage of the fetal rat mandible. J Anat 2001; 198: 129-135
  10. 10. Bellail AC, Hunter SB, Brat DJ, Tan C, Van Meir EG. Microregional extracellular matrix heterogeneity in brain modulates glioma cell invasion. Int J Biochem Cell Biol 2004; 36:1046–1069
  11. 11. Gladson CL. The extracellular matrix of gliomas: modulation of cell function. J Neuropathol Exp Neurol 1999; 58:1029–1040
  12. 12. Goldbrunner RH, Bernstein JJ, Tonn JC. Cell-extracellular matrix interaction in glioma invasion. Acta Neurochir (Wien) 1999; 141:295–305
  13. 13. Nicholson C, Sykova. Extracellular space structure revealed by diffusion analysis. Trends Neurosci 1998; 21:207–215
  14. 14. Novak U, Kaye AH. Extracellular matrix and the brain: components and function. J Clin Neurosci 2000; 7:280–290
  15. 15. Paulus W. Brain extracellular matrix, adhesion molecules and glioma invasion. In: Mikkelsen T, Bjerkvig R, Laerum OD, Rosenblum ML (eds) Brain tumor invasion: biological, clinical and therapeutic considerations. Wiley-Liss, New York, 1998; pp 301–322
  16. 16. Zamecnik J, Vargova L, Homola A, Kodet R, Sykova E. Extracellular matrix and diffusion barriers in human astrocytic tumors. Neuropathol Appl Neurobiol 2004; 30:338–350
  17. 17. Langley RR, Fidler IJ. The seed and soil hypothesis revisited - the role of tumor–stroma interactions in metastasis to different organs. Int J Cancer 2011; 128: 2527–2535.
  18. 18. Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nature Rev Cancer 2003; 3: 422–433.
  19. 19. Rougon G, Hobert O. New insights into the diversity and function of neuronal immunoglobulin superfamily molecules. Annu Rev Neurosci 2003; 26: 207–238.
  20. 20. Robinson EE, Zazzali KM, Corbett SA, et al . Alpha5beta1 integrin mediates strong tissue cohesion. J Cell Sci 2003; 116: 377–386.
  21. 21. Humphries JD, Byron A, Humphries MJ. Integrin ligands at a glance. J Cell Sci 2006; 119: 3901–3903.
  22. 22. Schmidt S, Friedl P. Interstitial cell migration: integrin-dependent and alternative adhesion mechanisms. Cell Tissue Res 2010; 339:83–92.
  23. 23. Anthis NJ, Campbell ID. The tail of integrin activation. Trends Biochem Sci 2011; 36: 191–198.
  24. 24. Schweitzer T, Vince GH, Herbold C, et al . Extraneural metastases of primary brain tumors. J Neurooncol 2001; 53: 107–114.
  25. 25. Shapiro L, Love J, Colman DR. Adhesion molecules in the nervous system: structural insights into function and diversity. Annu Rev Neurosci 2007; 30: 451–474.
  26. 26. Gingras MC, Roussel E, Bruner JM, et al . Comparison of cell adhesion molecule expression between glioblastoma multiforme and autologous normal brain tissue. J Neuroimmunol 1995; 57:143–153.
  27. 27. Calogero A, Pavoni E, Gramaglia T, et al . Altered expression of alpha-dystroglycan subunit in human gliomas. Cancer Biol Ther 2006; 5: 441–448.
  28. 28. Paulus W, Baur I, Schuppan D, et al . Characterization of integrin receptors in normal and neoplastic human brain. Am J Pathol 1993; 143: 154–163.
  29. 29. Kawataki T, Yamane T, Naganuma H, et al . Laminin isoforms and their integrin receptors in glioma cell migration and invasiveness: evidence for a role of alpha5-laminin(s) and alpha3beta1 integrin. Exp Cell Res 2007; 313: 3819–3831.
  30. 30. Jahn O, Tenzer S, Werner HB. Myelin proteomics: molecular anatomy of an insulating sheath. Mol Neurobiol 2009; 40: 55–72.
  31. 31. Nakada M, Kita D, Futami K, et al . Roles of membrane type 1 matrix metalloproteinase and tissue inhibitor of metalloproteinases 2 in invasion and dissemination of human malignant glioma. J Neurosurg 2001; 94: 464–473.
  32. 32. Leavesley DI, Ferguson GD, Wayner EA et al. Requirement of the integrin beta 3 subunit for carcinoma cell spreading or migration on vitronectin and fibrinogen. J Cell Biol 1992; 117:1101–1107
  33. 33. Platten M, Wick W, Wild-Bode C et al. Transforming growth factors beta(1) (TGF-beta(1)) and TGF-beta(2) promote glioma cell migration via up-regulation of alpha(V)beta(3) integrin expression. Biochem Biophys Res Commun 2000; 268:607–611
  34. 34. Guan JL, Shalloway D: Regulation of focal adhesionassociated protein tyrosine kinase by both cellular adhesion and oncogenic transformation. Nature 358: 690–692, 1992
  35. 35. Owens LV, Xu L, Craven RJ, Dent GA, Weiner TM, Kornberg L, Liu E T, Cance W G: Overexpression of the focal adhesion inase (p125FAK) in invasive human tumors. Cancer Res 55: 2752–2755, 1995
  36. 36. Jones G, Machado J Jr, Merlo A: Loss of focal adhesion kinase (FAK) inhibits epidermal growth factor receptordependent migration and induces aggregation of nh(2)- terminal FAK in the nuclei of apoptotic glioblastoma cells. Cancer Res, 61: 4978–4981, 2001
  37. 37. Zagzag D, Friedlander DR, Margolis B, Grumet M, Semenza GL, Zhong H, Simons JW, Holash. J, Wiegand, SJ, Yancopoulos GD: Molecular events implicated in brain tumor angiogenesis and invasion. Pediatr Neurosurg 33: 49–55, 2000
  38. 38. Cary LA, Guan JL: Focal adhesion kinase in integrinmediated signaling. Front: Biosci, 4: D102–113, 1999
  39. 39. Hauck CR, Hsia DA, Schlaepfer DD: The focal adhesion kinase – a regulator of cell migration and invasion. IUBMB Life 53: 115–119, 2002
  40. 40. Frisch SM, Vuori K, Ruoslahti E, Chan-Hui PY: Control of adhesion-dependent cell survival by focal adhesion kinase. J Cell Biol 134: 793–799, 1996
  41. 41. Xiong W, Parsons JT: Induction of apoptosis after expression of PYK2, a tyrosine kinase structurally relatedto focal adhesion kinase. J Cell Biol 139: 529–539, 1997
  42. 42. Graham CH, Connelly I, MacDougall JR, Kerbel RS, Stetler-Stevenson WG, Lala PK: Resistance of malignant trophoblast cells to both the anti-proliferative and antiinvasive effects of transforming growth factor-beta. Exp Cell Res 214: 93–99, 1994
  43. 43. Merzak A, Koocheckpour S, Pilkington GJ: CD44 mediates human glioma cell adhesion and invasion in vitro. Cancer Res 54: 3988–3992, 1994
  44. 44. Prag S, Lepekhin EA, Kolkova K, Hartmann-Petersen R, Kawa A, Walmod PS, Belman V, Gallagher H, C, Berezin V, Bock E, Pedersen N: NCAM regulates cell motility. J Cell Sci 115: 283–292, 2002
  45. 45. Hikawa T, Mori T, Abe T, Hori S: The ability in adhesion and invasion of drug-resistant human glioma cells. J Exp Clin Cancer Res 19: 357–362, 2000
  46. 46. Varga I, Hutóczki G, Petrás M, Kenyeres A, Scholtz B, Mikó E, Hanzély Z, Tóth J, Bognár L, Zahuczky G, Klekner A: Expression of invasion-related extracellular matrix molecules in human glioblastoma versus intracerebral lung adenocarcinoma metastasis. Cen Eur Neurosurg, 2010 Nov;71(4):173-80
  47. 47. Naor D, Wallach-Dayan SB, Zahalka MA, et al . Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol 2008; 18: 260–267.
  48. 48. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nature RevMol Cell Biol 2003; 4: 33–45.
  49. 49. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nature reviews. Cancer.2004;4:528–539.
  50. 50. Toole BP. Hyaluronan promotes the malignant phenotype. Glycobiology. 2002;12:37–42.
  51. 51. Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the giant. J Biol Chem.2002;277:4585–4588.
  52. 52. Tsukita S, Oishi K, Sato N, Sagara J, Kawai A. ERM family members as molecular linkers between the cell surface glycoprotein CD44 and actin-based cytoskeletons. J Cell Biol. 1994;126:391–401.
  53. 53. Lokeshwar VB, Fregien N, Bourguignon LY. Ankyrin-binding domain of CD44 (GP85) is required for the expression of hyaluronic acid-mediated adhesion function. J Cell Biol. 1994;126:1099–1109.
  54. 54. Li H, Guo L, Li JW, Liu N, Qi R, Liu J. Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression. Int J Oncol. 2000;17:927–932.
  55. 55. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nature reviews. Cancer.2004;4:528–539.
  56. 56. Ponta H, Sherman L, Herrlich P. CD44: from adhesion molecules to signalling regulators. Nature Rev Mol Cell Biol. 2003;4:33–45.
  57. 57. Fieber C, Plug R, Sleeman J, Dall P, Ponta H, Hofmann M. Characterisation of the murine gene encoding the intracellular hyaluronan receptor IHABP (RHAMM) Gene. 1999;226:41.
  58. 58. Thorne RF, Legg JW, Isacke CM. The role of the CD44 transmembrane and cytoplasmic domains in coordinating adhesive and signaling events. J Cell Sci. 2004;117:373–380.
  59. 59. Morgan MR, Humphries MJ, Bass MD. Synergistic control of cell adhesion by integrins and syndecans. Nature Rev Mol Cell Biol 2007; 8: 957–969.
  60. 60. Xian X, Gopal S, Couchman JR. Syndecans as receptors and organizers of the extracellular matrix. Cell Tissue Res 2010; 339: 31–46.
  61. 61. Kim C W et al., “Members of the syndecan family of heparan sulfate proteoglycans are expressed in distinct cell-, tissue-, and development-specific patterns. Molecular Biology of the Cell 5, no. 7 (July 1994): 797–805.
  62. 62. Anttonen A et al., “Syndecan-1 expression has prognostic significance in head and neck carcinoma. British Journal of Cancer 79, no. 3-4 (February 1999): 558–564.
  63. 63. Maret D, Gruzglin E, Sadr MS, Siu V, Shan W, Koch AW, Seidah NG, Del Maestro RF, Colman DR. Surface expression of precursor N-cadherin promotes tumor cell invasion. Neoplasia. 2010 Dec;12(12):1066-80.
  64. 64. Kohutek ZA, diPierro CG, Redpath GT, Hussaini IM. ADAM-10-mediated N-cadherin cleavage is protein kinase C-alpha dependent and promotes glioblastoma cell migration. J Neurosci. 2009 Apr 8;29(14):4605-15.
  65. 65. Nollet F, Kools P, van Roy F: Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. J Mol Biol 299: 551–572, 2000
  66. 66. Shapiro L, Weis WI. Structure and biochemistry of cadherins and catenins. Cold Spring Harbor Perspect Biol 2009; 1: a003053.
  67. 67. Shapiro L, Love J, Colman DR. Adhesion molecules in the nervous system: structural insights into function and diversity. Annu Rev Neurosci 2007; 30: 451–474.
  68. 68. Nollet F, Kools P, van Roy F. Phylogenetic analysis of the cadherin superfamily allows identification of six major subfamilies besides several solitary members. JMol Biol 2000; 299: 551–572.
  69. 69. Bozzi M, Morlacchi S, Bigotti MG, et al . Functional diversity of dystroglycan. Matrix Biol 2009; 28: 179–187.
  70. 70. Calogero A, Pavoni E, Gramaglia T, D'Amati G, Ragona G, Brancaccio A, Petrucci TC. Altered expression of alpha-dystroglycan subunit in human gliomas. Cancer Biol Ther. 2006 Apr;5(4):441-8.
  71. 71. Gee SH, Montanaro F, Lindenbaum MH, Carbonetto S. Dystroglycan-alpha, a dystrophin-associated glycoprotein, is a functional agrin receptor. Cell 1994; 77 (5): 675–86.
  72. 72. Pankov R, Yamada KM. Fibronectin at a glance. J Cell Sci 2002; 115 (Pt 20): 3861–3
  73. 73. Hu B., Kong L. L., Matthews R. T., Viapiano M. S. The proteoglycan brevican binds to fibronectin after proteolytic cleavage and promotes glioma cell motility. J. Biol. Chem. 2008; 283(36):24848-59
  74. 74. Yamagata M, Yamada KM, Yoneda M, Suzuki S, Kimata K: Chondroitin sulfate proteoglycan (PG-M-like proteoglycan) is involved in the binding of hyaluronic acid to cellular fibronectin. J Biol Chem 1986, 261(29):13526-13535.
  75. 75. Timpl R et al. Laminin – a glycoprotein from basement membranes. J Biol Chem 1979; 254 (19): 21. 9933
  76. 76. Guo P, Imanishi Y, Cackowski FC, et al. Up-regulation of angiopoietin- 2, matrix metalloprotease-2, membrane type 1 metalloprotease, and laminin 5 gamma 2 correlates with the invasiveness of human glioma. Am J Pathol 2005; 166:877– 890
  77. 77. Aguiar CB, Lobão-Soares B, Alvarez-Silva M, Trentin AG.Glycosaminoglycans modulate C6 glioma cell adhesion to extracellular matrix components and alter cell proliferation and cell migration. BMC Cell Biol. 2005 Aug 19;6:31.
  78. 78. Sanes JR, Lichtmann JW: Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2001; 2(11): 791-805
  79. 79. Delpech B, Maingonnat C, Girard N, Chauzy C, Maunoury R, Olivier A, Tayot J, Creissard P. Hyaluronan and hyaluronectin in the extracellular matrix of human brain tumour stroma. Eur J Cancer 1993; 29A:1012–1017
  80. 80. Sadeghi N, Camby I, Goldman S, Gabius HJ, Baleriaux D, Salmon I, Decaesteckere C, Kiss R, Metens T. Effect of hydrophilic components of the extracellular matrix on quantifiable diffusion-weighted imaging of human gliomas: preliminary results of correlating apparent diffusion coefficient values and hyaluronan expression level. AJR Am J Roentgenol 2003; 181:235–241
  81. 81. Itano N. Simple primary structure, complex turnover regulation and multiple roles of hyaluronan. J Biochem 2008; 144: 131–137.
  82. 82. Fidler IJ. The role of the organ microenvironment in brain metastasis. Semin Cancer Biol 2011; 21: 107–112.
  83. 83. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nature Reviews. Cancer.2004;4:528–539.
  84. 84. Kim MS, Park MJ, Moon EJ, Kim SJ, Lee CH, Yoo H, Shin SH, Song ES, Lee SH. Hyaluronic acid induces osteopontin via the phosphatidylinositol 3-kinase/AKT pathway to enhance the motility of human glioma cells. Cancer Res. 2005;65:686–691.
  85. 85. Viapiano MS, Matthews RT. From barriers to bridges: chondroitin sulfate proteoglycans in Neuropathology. Trends Mol Med 2006; 12: 488–496.
  86. 86. Yamaguchi Y. Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 2000; 57: 276–289.
  87. 87. Nutt CL, Matthews RT, Hockfield S. Glial tumor invasion: a role for the upregulation and cleavage of BEHAB/brevican. Neuroscientist 2001; 7: 113-122
  88. 88. Viapiano MS, Bi WL, Piepmeier J, Hockfield S, Matthews RT. Novel tumor-specific isoforms of BEHAB/brevican identified in human malignant gliomas. Cancer Res 2005; 65: 6726-6733
  89. 89. Varga, G. Hutóczki, Cs. D. Szemcsák, G. Zahuczky, J. Tóth, Zs. Adamecz, A. Kenyeres, L. Bognár, Z. Hanzély, A. Klekner: Brevican, neurocan, tenascin-C and versican are mainly responsible for the invasiveness of low-grade astrocytoma. Pathol Oncol Res, Pathol Oncol Res. 2012 Apr;18(2):413-20.
  90. 90. Akita K., Toda M., Hosoki Y., Inoue M., Fushiki S., Oohira A., Okayama M., Yamashina I., Nakada H. Heparan sulphate proteoglycans interact with neurocan and promote neurite outgrowth from cerebellar granule cells. Biochem J. 2004; 383(Pt 1):129-38
  91. 91. Kim C. H., Bak K. H., Kim Y. S., Kim J. M., Ko Y., Oh S. J., Kim K. M., Hong E. K. Expression of tenascin-C in astrocytic tumors: its relevance to proliferation and angiogenesis. Surg. Neurol. 2000; 54(3):235-40
  92. 92. Swindle C. S., Tran K. T., Johnson T. D., Banerjee P., Mayes A. M., Griffith L., Wells A. Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J. Cell Biol. 2001; 154(2):459-68
  93. 93. Fischer D., Brown-Lüdi M.,Schulthess T., Chiquet-Ehrismann R. Concerted action of tenascin-C domains in cell adhesion, anti-adhesion and promotion of neurite outgrowth. J. Cell Sci. 1997; 110(Pt13):1513-22
  94. 94. Hirata E., Arakawa Y., Shirahata M., Yamaguchi M., Kishi Y., Okada T., Takahashi J. A., Matsuda M., Hashimoto N. Endogenous tenascin-C enhances glioblastoma invasion with reactive change of surrounding brain tissue. Cancer Sci. 2009; 100(8):1451-9
  95. 95. Maris C., Rorive S., Sandras F., D'Haene N., Sadeghi N., Bièche I., Vidaud M., Decaestecker C., Salmon I. Tenascin-C expression relates to clinicopathological features in pilocytic and diffuse astrocytomas. Neuropathol. Appl. Neurobiol. 2008; 34(3):316-29
  96. 96. Gladson CL, Cheresh DA. Glioblastoma expression of vitronectin and the alpha v beta 3 integrin. Adhesion mechanism for transformed glial cells. J Clin Invest 1991; 88:1924– 1932
  97. 97. Joester A, Faissner A. The structure and function of tenascin in the nervous system. Matrix Biol 2001; 20:13–22
  98. 98. Mahesparan R, Read TA, Lund-Johansen M, Skaftnesmo KO, Bjerkvig R, Engebraaten O. Expression of extracellular matrix components in a highly infiltrative in vivo glioma model. Acta Neuropathol 2003; 105:49–57
  99. 99. Oz B, Karayel FA, Gazio NL, Ozlen F, Balci K. The distribution of extracellular matrix proteins and CD44S expression in human astrocytomas. Pathol Oncol Res 2000; 6:118–124
  100. 100. Zamecnik J, Chanova M, Tichy M, Kodet R. Distribution of the extracellular matrix glycoproteins in ependymomas— an immunohistochemical study with follow-up analysis. Neoplasma 2004; 51:214–222
  101. 101. Zagzag D, Friedlander DR, Dosik J, Chikramane S, Chan W, Greco MA, Allen JC, Dorovini-Zis K, Grumet M: Tenascin-C expression by angiogenic vessels in human astrocytomas and by human brain endothelial cells in vitro. Cancer Res, 56: 182–189, 1996
  102. 102. Kostianovsky M, Greco MA, Cangiarella J, Zagzag D: Tenascin-C expression in ultrastructurally defined angiogenic and vasculogenic lesions. Ultrastruct Pathol 21: 537– 544, 1997
  103. 103. Zagzag D, Capo V: Angiogenesis in the central nervous system: a role for vascular endothelial growth factor/vascular permeability factor and tenascin-C. Common molecular effectors in cerebral neoplastic, and non-neoplastic ‘angiogenic diseases’. Histol Histopathol 17: 301– 321, 2002
  104. 104. Plopper GE, McNamee HP, Dike LE, Bojanowski K, Ingber DE: Convergence of integrin and growth factor receptor signaling pathways within the focal adhesion complex. Mol Biol Cell 6: 1349–1365, 1995
  105. 105. Mauri P, Scarpa A, Nascimbeni AC, Benazzi L, Parmagnani E, Mafficini A, Della Peruta M, Bassi C, Miyazaki K, Sorio C: Identification of proteins released by pancreatic cancer cells by multidimensional protein identification technology: a strategy for identification of novel cancer markers. Faseb J 2005, 19(9):1125-1127.
  106. 106. Voutilainen K, Anttila M, Sillanpaa S, Tammi R, Tammi M, Saarikoski S, Kosma VM: Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. Int J Cancer 2003, 107(3):359-364.
  107. 107. Aspberg A, Binkert C, Ruoslahti E: The versican C-type lectin domain recognizes the adhesion protein tenascin-R. Proc Natl Acad Sci U S A 1995, 92(23):10590-10594.
  108. 108. Aspberg A, Adam S, Kostka G, Timpl R, Heinegard D: Fibulin-1 is a ligand for the C-type lectin domains of aggrecan and versican. J Biol Chem 1999, 274(29):20444-20449.
  109. 109. Isogai Z, Aspberg A, Keene DR, Ono RN, Reinhardt DP, Sakai LY: Versican interacts with fibrillin-1 and links extracellular microfibrils to other connective tissue networks. J Biol Chem 2002, 277(6):4565-4572.
  110. 110. Kawashima H, Hirose M, Hirose J, Nagakubo D, Plaas AH, Miyasaka M: Binding of a large chondroitin sulfate/dermatan sulfate proteoglycan, versican, to L-selectin, P-selectin, and CD44. J Biol Chem 2000, 275(45):35448-35456.
  111. 111. Perides G, Asher RA, Lark MW, Lane WS, Robinson RA, Bignami A: Glial hyaluronate-binding protein: a product of metalloproteinase digestion of versican? Biochem J 1995, 312 ( Pt 2):377-384.
  112. 112. Van Lint P, Libert C (December 2007). Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J. Leukoc. Biol. 82 (6): 1375–81.
  113. 113. Wild-Bode C, Weller M, Wick W. Molecular determinants of glioma cell migration and invasion. J Neurosurg 2001; 94:978–984
  114. 114. Demchik LL, Sameni M, Nelson K, Mikkelsen T, Sloane BF: Cathepsin B and glioma invasion. Int J Dev Neurosci 17: 483–494, 1999
  115. 115. Rempel SA, Rosenblum ML, Mikkelsen T, Yan. PS, Ellis KD, Golembieski WA, Sameni M, Rozhin J, Ziegler G, Sloane BF: Cathepsin B expression and localization in glioma progression and invasion. Cancer Res 54: 6027–6031, 1994
  116. 116. Sivaparvathi M, Sawaya R, Wang SW, Rayford A, Yamamoto M, Liotta LA, Nicolson GL, Rao JS: Overexpression and localization of cathepsin B during the progression of human gliomas. Clin Exp Metastasis 13: 49–56, 1995
  117. 117. Mohanam S, Jasti SL, Kondraganti SR, Chandrasekar N, Lakka SS, Kin Y, Fuller GN, Yung AW, Kyritsis AP, Dinh DH; Olivero WC, Gujrati M, Ali-Osman F, Rao JS: Down-regulation of cathepsin B expression impairs the invasive and tumorigenic potential of human glioblastoma cells. Oncogene 20: 3665–3673, 2001
  118. 118. Levicar N, Dewey RA, Daley E, Bates TE, Davies D, Kos J, Pilkington GJ, and Lah TT: Selective suppression of cathepsin L by antisense cDNA impairs human braintumor cell invasion in vitro and promotes apoptosis. Cancer Gene Then 10: 141–151, 2003
  119. 119. Manabu O, Tomotsugu I,Kazuhiko K,Isao D. Angiogenesis and invasion in glioma. Brain Tumor Pathol 2011; 28:13–24
  120. 120. Calogero A, Pavoni E, Gramaglia T, D'Amati G, Ragona G, Brancaccio A, Petrucci TC. Altered expression of alpha-dystroglycan subunit in human gliomas. Cancer Biol Ther. 2006 Apr;5(4):441-8.
  121. 121. Demuth T, Berens ME. Molecular mechanisms of glioma cell migration and invasion. J Neurooncol 2004; 70:217–228
  122. 122. Goodenough DA, Goliger JA, Paul DL. Connexins, connexons, and intercellular communication. Annu Rev Biochem 1996; 65:475–502
  123. 123. Soroceanu L, Manning TJ Jr, Sontheimer H. Reduced expression of connexin-43 and functional gap junction coupling in human gliomas. Glia 2001; 33:107–117
  124. 124. Beadle C, Assanah MC, Monzo P, Vallee R, Rosenfeld SS, Canoll P. The role of myosin II in glioma invasion of the brain. Mol Biol Cell 2008;19:3357–3368.
  125. 125. Tonn JC, Wunderlich S, Kerkau S, Klein CE, Roosen K: Invasive behaviour of human gliomas is mediated by interindividually different integrin patterns. AnticancerRes 18: 2599–2605, 1998
  126. 126. Taga T, Suzuki A, Gonzalez-Gomez I, Gilles FH, Stins M, Shimada H, Barsky L, Weinberg KI, Laug WE: alpha v- Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin. Int J Cancer 98: 690–697, 2002
  127. 127. MacDonald TJ, Taga T, Shimada H, Tabrizi, P, Zlokovic BV, Cheresh DA, Laug WE: Preferential susceptibility of brain tumors to the antiangiogenic effects of an alpha(v) integrin antagonist. Neurosurgery 48: 151–157 2001
  128. 128. Etienne-Manneville S, Hall A: Rho GTPases in cell biology. Nature 420; 629–635, 2002
  129. 129. Reardon DA, Fink KL, Mikkelsen T, et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008;26:5610 –5617.
  130. 130. Arslan F, Bosserhoff AK, Nickl-Jockschat T, Doerfelt A, Bogdahn U, Hau P: The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-beta2. Br J Cancer 2007, 96(10):1560-1568.
  131. 131. Syrokou A, Tzanakakis GN, Hjerpe A, Karamanos NK: Proteoglycans in human malignant mesothelioma. Stimulation of their synthesis induced by epidermal, insulin and platelet-derived growth factors involves receptors with tyrosine kinase activity. Biochimie 1999, 81(7):733-744.
  132. 132. Du WW, Yang BB, Shatseva TA, Yang BL, Deng Z, Shan SW, Lee DY, Seth A, Yee AJ: Versican G3 promotes mouse mammary tumor cell growth, migration, and metastasis by influencing EGF receptor signaling. PLoS One, 5(11):e13828
  133. 133. Casey RC, Koch KA, Oegema TR, Jr., Skubitz KM, Pambuccian SE, Grindle SM, Skubitz AP: Establishment of an in vitro assay to measure the invasion of ovarian carcinoma cells through mesothelial cell monolayers. Clin Exp Metastasis 2003, 20(4):343-356
  134. 134. Nakamura JL, Haas-Kogan DA, Pieper RO: Glioma invasiveness responds variably to irradiation in a co-culture model. Int J Radiat Oncol Biol Phys 2007, 69(3):880-886.
  135. 135. Almholt K, Juncker-Jensen A, Laerum OD, Dano K, Johnsen M, Lund LR, Romer J: Metastasis is strongly reduced by the matrix metalloproteinase inhibitor Galardin in the MMTV-PymT transgenic breast cancer model. Mol Cancer Ther 2008, 7(9):2758-2767.
  136. 136. Vankemmelbeke MN, Jones GC, Fowles C, Ilic MZ, Handley CJ, Day AJ, Knight CG, Mort JS, Buttle DJ: Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters. Eur J Biochem 2003, 270(11):2394-2403
  137. 137. Schonherr E, Kinsella MG, Wight TN: Genistein selectively inhibits platelet-derived growth factor-stimulated versican biosynthesis in monkey arterial smooth muscle cells. Arch Biochem Biophys 1997, 339(2):353-361.
  138. 138. Evanko SP, Angello JC, Wight TN: Formation of hyaluronan- and versican-rich pericellular matrix is required for proliferation and migration of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999, 19(4):1004-1013.
  139. 139. Ween MP, Hummitzsch K, Rodgers RJ, Oehler MK, Ricciardelli C: Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides. Clin Exp Metastasis, 28(2):113-125.
  140. 140. Zeng C, Toole BP, Kinney SD, Kuo JW, Stamenkovic I: Inhibition of tumor growth in vivo by hyaluronan oligomers. Int J Cancer 1998, 77(3):396-401.
  141. 141. Kim MS, Park MJ, Kim SJ, Lee CH, Yoo H, Shin SH, Song ES, Lee SH. Emodin suppresses hyaluronic acid-induced MMP-9 secretion and ivnasion of gliomas cells. Int J Oncol. 2005;27:839–846.[
  142. 142. Arata Watanabe A, Mabuchi T, Satoh E, Furuya K, Zhang L, Maeda S, Maeda S, Naganuma H. Expression of syndecans, a heparin sulfate proteoglycan, in malignant gliomas: participation of nuclear factor-kappaB in upregulation of syndecan-1 expression. J Neurooncol. 2006;77:25–32.
  143. 143. Levin VA, Phuphanich S, Yung WK et al. Randomized, double-blind, placebo-controlled trial of marimastat in glioblastoma multiforme patients following surgery and irradiation. J Neurooncol 2006; 78:295–302
  144. 144. Groves MD, Puduvalli VK, Hess KR et al. Phase II trial of temozolomide plus the matrix metalloproteinase inhibitor, marimastat, in recurrent and progressive glioblastoma multiforme. J Clin Oncol 2002; 20:1383–1388
  145. 145. Sakariassen PO, Prestegarden L, Wang J et al.Angiogenesis- independent tumor growth mediated by stem-like cancer cells. Proc Natl Acad Sci USA 2006; 103:16466–16471
  146. 146. Wang D, Anderson JC, Gladson CL. The role of the extracellular matrix in angiogenesis in malignant glioma tumors. Brain Pathol 2005;15:318 –326.
  147. 147. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4:437– 447.
  148. 148. Kaur B, Brat DJ, Calkins CC, Van Meir EG. Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 2003; 162:19 –27.
  149. 149. Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 2005;7:122–133.
  150. 150. Desbaillets I, Diserens AC, de Tribolet N, Hamou MF, Van Meir EG. Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma. Oncogene 1999;18:1447–1456.
  151. 151. Fischer I, Gagner JP, Law M, Newcomb EW, Zagzag D. Angiogenesis in gliomas: biology and molecular pathophysiology. Brain Pathol 2005;15:297–310.
  152. 152. Kaur B, Tan C, Brat DJ, Post DE, Van Meir EG. Genetic and hypoxic regulation of angiogenesis in gliomas. J Neurooncol 2004;70:229 –243.
  153. 153. Aghi M, Chiocca EA. Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors. Mol Ther 2005; 12:994 –1005.
  154. 154. Jouanneau E. Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery 2008;62:31–50.
  155. 155. Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA. Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes. Cancer Res 2006;66:9054 –9064.
  156. 156. Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell 2008;13: 206–220.
  157. 157. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 2005;7:452– 464.
  158. 158. Reiss Y, Machein MR, Plate KH. The role of angiopoietins during angiogenesis in gliomas. Brain Pathol 2005;15:311–317.
  159. 159. Zagzag D, Amirnovin R, Greco MA, et al. Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 2000;80: 837–849.
  160. 160. Stratmann A, Risau W, Plate KH. Cell type-specific expression of angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. Am J Pathol 1998;153:1459 –1466.
  161. 161. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994 –1998.
  162. 162. Hu B, Guo P, Fang Q, et al. Angiopoietin-2 induces human glioma invasion through the activation of matrix metalloprotease- 2. Proc Natl Acad Sci U S A 2003;100:8904–8909.
  163. 163. Rooprai HK, McCormick D. Proteases and their inhibitors in human brain tumours: a review. Anticancer Res 1997;17:4151– 4162.
  164. 164. Raithatha SA, Muzik H, Rewcastle NB, Johnston RN, Edwards DR, Forsyth PA. Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas. Neuro Oncol 2000;2:145– 150.
  165. 165. Rao JS, Yamamoto M, Mohaman S, et al. Expression and localization of 92 kDa type IV collagenase/gelatinase B (MMP-9) in human gliomas. Clin Exp Metastasis 1996;14:12–18.
  166. 166. Lakka SS, Gondi CS, Rao JS. Proteases and glioma angiogenesis. Brain Pathol 2005;15:327–341
  167. 167. Jouanneau E. Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery 2008;62:31–50.
  168. 168. Bergers G, Song S. The role of pericytes in blood-vessel formation and maintenance. Neuro Oncol 2005;7:452– 464.
  169. 169. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature 2005;438:967–974.
  170. 170. Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med 2008;10:e23.
  171. 171. Jouanneau E. Angiogenesis and gliomas: current issues and development of surrogate markers. Neurosurgery 2008;62:31–50.
  172. 172. Herold-Mende C, Mueller MM, Bonsanto MM, Schmitt HP, Kunze S, Steiner HH. Clinical impact and functional aspects of tenascin-C expression during glioma progression. Int J Cancer 2002;98:362–369.
  173. 173. Baluk P, Morikawa S, Haskell A, Mancuso M, McDonald DM. Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors. Am J Pathol 2003;163:1801–1815.
  174. 174. Vitolo D, Paradiso P, Uccini S, Ruco LP, Baroni CD. Expression of adhesion molecules and extracellular matrix proteins in glioblastomas: relation to angiogenesis and spread. Histopathology 1996;28:521–528.
  175. 175. Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353–364.
  176. 176. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature 2000;407:249 –257.
  177. 177. Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 2002;20: 4368–4380.
  178. 178. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 2004;25:581– 611.
  179. 179. Machein MR, Plate KH. VEGF in brain tumors. J Neurooncol 2000;50:109 –120.
  180. 180. Plate KH, Breier G, Weich HA, Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992;359:845– 848.
  181. 181. Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. J Biol Chem 1996;271: 10079–10086.
  182. 182. Grau SJ, Trillsch F, Herms J, et al. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol 2007;82:141–150.
  183. 183. Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT. Angiogenesis in brain tumours. Nat Rev Neurosci 2007;8:610–622.
  184. 184. Kaur B, Brat DJ, Calkins CC, Van Meir EG. Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 2003; 162:19 –27.
  185. 185. Jain RK. Molecular regulation of vessel maturation. Nat Med 2003;9:685– 693.
  186. 186. Karcher S, Steiner HH, Ahmadi R, et al. Different angiogenic phenotypes in primary and secondary glioblastomas. Int J Cancer 2006;118:2182–2189.
  187. 187. Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol 2005;7:122–133.
  188. 188. Melder RJ, Koenig GC, Witwer BP, Safabakhsh N, Munn LL, Jain RK. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat Med 1996;2:992–997.
  189. 189. Garkavtsev I, Kozin SV, Chernova O, et al. The candidate tumoursuppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature 2004;428:328 –332.
  190. 190. Mamluk R, Klagsbrun M, Detmar M, Bielenberg DR. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis 2005;8:217–227.
  191. 191. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998;92:735–745.
  192. 192. Miao HQ, Klagsbrun M. Neuropilin is a mediator of angiogenesis. Cancer Metastasis Rev 2000;19:29 –37.
  193. 193. Wang D, Anderson JC, Gladson CL. The role of the extracellular matrix in angiogenesis in malignant glioma tumors. Brain Pathol 2005;15:318 –326.
  194. 194. Castellani P, Viale G, Dorcaratto A, et al. The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int J Cancer 1994;59:612– 618.
  195. 195. Zagzag D, Shiff B, Jallo GI, et al. Tenascin-C promotes microvascular cell migration and phosphorylation of focal adhesion kinase. Cancer Res 2002;62:2660 –2668.
  196. 196. Mariani G, Lasku A, Balza E, et al. Tumor targeting potential of the monoclonal antibody BC-1 against oncofetal fibronectin in nude mice bearing human tumor implants. Cancer 1997;80:2378– 2384.
  197. 197. Fujita M, Khazenzon NM, Ljubimov AV, et al. Inhibition of laminin-8 in vivo using a novel poly(malic acid)-based carrier reduces glioma angiogenesis. Angiogenesis 2006;9:183–191.
  198. 198. Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352:987–996
  199. 199. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253–1259.
  200. 200. Vredenburgh JJ, Desjardins A, Herndon JE, 2nd, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007;25:4722– 4729.
  201. 201. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 2008;70:779 –787.
  202. 202. Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther 2007; 7:1537–1560.
  203. 203. Sathornsumetee S, Cao Y, Marcello JE et al. Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan. J Clin Oncol 2008; 26:271–278
  204. 204. Roberts WG, Whalen PM, Soderstrom E, et al. Antiangiogenic and antitumor activity of a selective PDGFR tyrosine kinase inhibitor, CP-673,451. Cancer Res 2005;65:957–966.
  205. 205. Batchelor TT, Sorensen AG, di Tomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83–95.
  206. 206. Tabatabai G, Frank B, Wick A, et al. Synergistic antiglioma activity of radiotherapy and enzastaurin. Ann Neurol 2007;61:153–161.
  207. 207. Zhou Q, Guo P, Gallo JM. Impact of angiogenesis inhibition by sunitinib on tumor distribution of temozolomide. Clin Cancer Res 2008;14:1540 –1549.
  208. 208. Wong ML, Prawira A, Kaye AH et al. Tumour angiogenesis: its mechanism and therapeutic implications in malignant gliomas. J Clin Neurosci 2009; 16:1119–1130
  209. 209. Siegelin MD, Raskett CM, Gilbert CA, Ross AH, Altieri DC (2010) Sorafenib exerts anti-glioma activity in vitro and in vivo. Neurosci Lett 478:165–170
  210. 210. Ranza E, Mazzini G, Facoetti A, Nano R. In vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation. J Neurooncol 2010; 96:349–357
  211. 211. Wen PY, Yung WK, Lamborn KR et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 2006; 99-08. Clin Cancer Res 12:4899–4907
  212. 212. Akabani G, Reardon DA, Coleman RE, et al. Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study. J Nucl Med 2005;46:1042–1051.
  213. 213. Bigner DD, Brown M, Coleman RE et al. Phase I studies of treatment of malignant gliomas and neoplastic meningitis with 131I-radiolabeled monoclonal antibodies anti-tenascin 81C6 and anti-chondroitin proteoglycan sulfate Me1-14 F(ab0)2––a preliminary report. J Neurooncol 1995; 24:109–122
  214. 214. Reardon DA, Akabani G, Coleman RE et al. Phase II trial of murine (131)I-labeled antitenascin monoclonal antibody 81C6 administered into surgically created resection cavities of patients with newly diagnosed malignant gliomas. J Clin Oncol 2002; 20:1389–1397
  215. 215. Yunker CK, Golembieski W, Lemke N, et al. SPARC-induced increase in glioma matrix and decrease in vascularity are associated with reduced VEGF expression and secretion. Int J Cancer 2008;122:2735–2743.
  216. 216. Rempel SA, Golembieski WA, Ge S, et al. SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas. J Neuropathol Exp Neurol 1998;57:1112–1121.
  217. 217. Bornstein P, Sage EH. Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 2002;14:608–616.
  218. 218. Lane TF, Iruela-Arispe ML, Johnson RS, Sage EH. SPARC is a source of copper-binding peptides that stimulate angiogenesis. J Cell Biol 1994;125:929 –943.
  219. 219. Yan Q, Sage EH, Hendrickson AE. SPARC is expressed by ganglion cells and astrocytes in bovine retina. J Histochem Cytochem 1998;46:3–10.
  220. 220. Lane TF, Sage EH. The biology of SPARC, a protein that modulates cell-matrix interactions. FASEB J 1994;8:163–173.
  221. 221. Anderson JC, McFarland BC, Gladson CL. New molecular targets in angiogenic vessels of glioblastoma tumours. Expert Rev Mol Med 2008;10:e23.
  222. 222. Kaur B, Brat DJ, Calkins CC, Van Meir EG. Brain angiogenesis inhibitor 1 is differentially expressed in normal brain and glioblastoma independently of p53 expression. Am J Pathol 2003; 162:19 –27.
  223. 223. Wahl ML, Kenan DJ, Gonzalez-Gronow M, Pizzo SV. Angiostatin’s molecular mechanism: aspects of specificity and regulation elucidated. J Cell Biochem 2005;96:242–261.
  224. 224. O’Reilly MS, Holmgren L, Shing Y, et al. Angiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma. Cell 1994;79:315–328.
  225. 225. Kirsch M, Strasser J, Allende R, Bello L, Zhang J, Black PM. Angiostatin suppresses malignant glioma growth in vivo. Cancer Res 1998;58:4654–4659.
  226. 226. Joe YA, Hong YK, Chung DS, et al. Inhibition of human malignant glioma growth in vivo by human recombinant plasminogen kringles 1-3. Int J Cancer 1999;82:694–699.
  227. 227. Adams JC, Lawler J. The thrombospondins. Int J Biochem Cell Biol 2004;36:961–968.
  228. 228. Strik HM, Weller M, Frank B, et al. Heat shock protein expression in human gliomas. Anticancer Res 2000;20:4457– 4462.
  229. 229. Folkman J. Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Exp Cell Res 2006;312:594–607.
  230. 230. Heljasvaara R, Nyberg P, Luostarinen J, et al. Generation of biologically active endostatin fragments from human collagen XVIII by distinct matrix metalloproteases. Exp Cell Res 2005; 307:292–304.
  231. 231. Sudhakar A, Sugimoto H, Yang C, Lively J, Zeisberg M, Kalluri R. Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by alpha v beta 3 and alpha 5 beta 1 integrins. Proc Natl Acad Sci U S A 2003;100:4766–4771.

Written By

Almos Klekner

Submitted: April 17th, 2012 Published: February 27th, 2013