Journal of the National Cancer Institute Advance Access published online on October 30, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm187
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© The Author 2007. Published by Oxford University Press.
REVIEW |
Autocrine Factors That Sustain Glioma Invasion and Paracrine Biology in the Brain Microenvironment
Affiliation of authors: Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ
Correspondence to: Michael E. Berens, PhD, Cancer and Cell Biology Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ 85004 (e-mail: mberens{at}tgen.org).
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ABSTRACT |
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 Top Abstract Autocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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Invasion is a defining hallmark of glioblastoma multiforme, just as metastasis characterizes other high-grade tumors. Glial tumors invariably recur due to the regrowth of invasive cells, which are unaffected by standard treatment modalities. Drivers of glioma invasion include autocrine signals propagated by secreted factors that signal through receptors on the tumor. These secreted factors are able to diffuse through the peritumoral stroma, thereby influencing parenchymal cells that surround the tumor mass. Here we describe various autocrine motility factors that are expressed by invasive glioma cells and explore the effects that they may have on normal cells present in the path of invasion. Conversely, normal brain parenchymal cells secrete ligands that can stimulate receptors on invasive glioma cells and potentially facilitate glioma invasion or create a permissive microenvironment for malignant progression. Parallel observations have been made for solid tumors of epithelial origin, in which parenchymal and stromal cells either support or suppress tumor invasion. Most autocrine and paracrine interactions involved in glioma invasion constitute known signaling systems in stages of central nervous system development that involve the migration of precursor cells that populate the developing brain. Key paracrine interactions between glioma cells and the brain microenvironment can influence glioma pathobiology and therefore contribute to its poor prognosis. Current therapies for glioma that could have an impact on paracrine communication between tumors and normal cells are discussed. We suggest that cells in the normal brain parenchyma be considered as potential targets for adjuvant therapies to control glioma growth because such cells are less likely to develop resistance than glioma cells.
Tumors of the central nervous system can arise from several different cellular lineages that include glia, such as astrocytes and oligodendrocytes. Astrocytic tumors (astrocytomas) fall into two distinct categories based on how they interact with their immediate microenvironment: diffuse and localized astrocytomas. Localized astrocytomas have a circumscribed pattern of growth and limited invasive potential, whereas diffuse astrocytomas are characterized by their cellular infiltration of the peritumoral margin and disperse to distant sites, regardless of tumor grade. There are three grades of diffuse astrocytic tumors (1): astrocytoma (World Health Organization [WHO] grade II), anaplastic astrocytoma (WHO grade III), and glioblastoma multiforme (WHO grade IV). Although astrocytic tumors of all three grades are invasive, the higher-grade tumors (i.e., grades III and IV) are progressively more proliferative and result in a shorter time to tumor recurrence than lower-grade tumors. All glial tumors (except for pilocytic astrocytomas [WHO grade I]) recur at high frequency after treatment with surgery, radiation, and chemotherapy and are essentially incurable. Recurrence is due mainly to the highly invasive behavior of even low-grade (i.e., WHO grade II) astrocytomas, which allows the active egress of glioma cells from the main tumor mass into the surrounding normal brain tissue. Therefore, invasive glioma cells are essentially beyond the reach of current therapies, which are localized to the tumor and immediate peri-tumoral environment. However, the survival of patients with tumors with similar degrees of invasiveness (such as low-grade and high-grade astrocytoma) differs dramatically (median survival ranges from 10–15 years in patients with low-grade astrocytomas to 15 months in patients with glioblastoma multiforme) for reasons that are still unknown.
Glioblastoma multiforme is the most common and most malignant of all glial tumors: it accounts for 60% of all glial tumors and occurs at a frequency of 5 cases per 100000 people (2). Although molecular markers for glioblastoma multiforme have helped to identify patients responsive to current therapies (3), the overall survival of responsive patients has not changed substantially in the last 20 years (4). Glioblastoma multiforme cell invasion is not random; transformed glial cells preferentially invade along anatomic features such as myelinated axons, vascular basement membranes, and the subependyma (5), which suggests that they interact with specific features in their immediate microenvironment. These interactions may also play a role in patient survival: patients with glioblastoma multiforme located in the deep gray matter survive statistically significantly longer than patients with lobar gliomas (regardless of tumor size at diagnosis) (6). It has been theorized (6) that these differences in survival reflect the differential invasion capacity of glioma cells that are located in different microenvironments. Indeed, mounting evidence indicates that normal peritumoral cells play active roles in tumor progression in other carcinomas (7,8).
Glioblastoma multiforme invasion is likely triggered by signals that prompt tumor cells to egress from the tumor mass, including signals that are activated by an acidic and hypoxic tumor environment. The best documented of these signals is the transcription factor hypoxia inducible factor-1, which increases the expression of invasion-related genes such as proteases and transforming growth factor-
(TGF-) (9). As cells exit the tumor mass, they encounter a different set of microenvironmental cues, including a disrupted extracellular matrix and normoxic physiologic conditions. Invasion maintenance may depend on autocrine motility loops and their paracrine effects. As invading glioblastoma cells transit through the brain parenchyma, they interact with a changing landscape of extracellular stimuli that perpetuate the trajectory of invasion much like the signaling systems secreted during neurodevelopmental migration events. The directional motility of neural precursors, glial precursors, and nascent axons through the embryonic central nervous system is achieved and maintained by autocrine signals that are secreted at the leading edges of these cells in response to paracrine cues. For example, embryonic oligodendrocyte migration depends on platelet-derived growth factor (PDGF) secretion as well as on expression of the PDGF receptor (PDGFR) (10). The highly orchestrated migration of neurons of the developing brain is coordinated by autocrine secretion of ligands such as pleiotrophin (PTN) and amphoterin and their receptors syndecan, receptor protein tyrosine phosphatase beta/zeta (RPTP
), and renal tumor antigen (11,12). It is reasonable to anticipate that invasive glioblastoma multiforme cells re-engage developmental migration mechanisms to affect motility and that the microenvironment plays an active role in glioma invasion.
This review describes candidate autocrine–paracrine motility signals in the setting of glioma pathobiology and focuses on how these specific ligand–receptor systems (summarized in Table 1) may contribute to the invasive phenotype of glioblastoma multiforme. We do not address autocrine signaling systems that promote invasion but that do not have documented paracrine effects on cells in the brain parenchyma (such as the receptor tyrosine kinases erb-2 and erb-3 and neuregulin, autocrine motility factor and its receptor angiopoietin-2, as well as the angiogenic factor cysteine-rich 61, the hormone ghrelin, and their respective signal transducing systems).
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Autocrine Signals in Glioma Invasion |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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Glioblastoma multiforme cells secrete several factors that result in autocrine motility signaling. These factors have been the focus of research that seeks to understand the basis for the pervasive invasive capacity of diffuse astrocytomas as well as research to identify points of vulnerability in invasive cells that might yield specific anti-invasive therapies. In this section, we list representative autocrine motility signaling systems that play a role in enhancing glioma invasion.
Epidermal growth factor receptor (EGFR) signaling is one of the salient drivers of glioma proliferation. However, autocrine proliferation signaling can also stimulate glioma invasion. In 1997, Chicoine and Silbergeld (13) speculated that the growth factors EGF and TGF- might also be the motogens that drive glioblastoma multiforme invasion. Recently, both TGF- and heparin-binding EGF (HB-EGF) have been confirmed to participate in autocrine loops in glioma (14). TGF- and HB-EGF secretion is likely to have pleiotropic effects on the microenvironment of the tumor, given that EGFR is expressed by neurons, astrocytes, microglia, and reactive astrocytes. The most common hallmark of glioblastoma multiforme biology is aberrant EGF/EGFR signaling, followed by dysregulation in PDGF/PDGFR signaling. PDGF and PDGFR expression increases are observed during progression of astrocytic tumors from lower grades to glioblastoma multiforme (10). Although PDGF and its receptor PDGFR are most frequently linked to the proliferation of glial tumors and to angiogenesis (10,15), several reports (16,17) suggest that signaling through this autocrine pair results in increased glioblastoma multiforme cell motility in vitro.
Glioblastoma multiforme cells also secrete hepatocyte growth factor/scatter factor (HGF/SF), which binds to its receptor, the Met tyrosine kinase; the expression of both players in this ligand–receptor system increases with increasing grade of malignancy (18). Although the proliferative and angiogenic potentials of this autocrine loop have been well documented (19), HGF/SF expression is also associated with invasion. Indeed, both Met and HGF/SF are expressed in invasive cells from primary human glioma samples (18). In addition, an in vitro study (20) that analyzed the effect of a panel of chemokines on glioma motility found that HGF/SF was the most potent chemotactic factor for the cell lines tested, suggesting that Met–HGF/SF signaling could also represent an autocrine motility loop. A number of cell types in the brain express Met (Table 1) and may therefore be responsive to glioma-generated HGF/SF signaling.
In addition to kinases, phosphatases can also drive glioblastoma invasion. RPTP is expressed in the central nervous system during development (21) and was initially associated with the modulation of neuronal and glial cell adhesion (22). Although various cell adhesion molecules and components of the extracellular matrix are known to interact with RPTP (23,24), PTN is the only soluble ligand that has been shown to bind RPTP (25). PTN binding to RPTP induces inactivation of the phosphatase activity of RPTP (26), which results in a net increase in the phosphorylation of beta-catenin, beta-adducin, and Fyn, proteins that increase cell motility by disrupting the stability of the cytoskeleton (27). Gene expression profiling has revealed overexpression of the genes encoding RPTP and PTN in a subset of glioblastoma multiforme tumors compared with normal brain (28). Migration assays confirmed that PTN stimulated the motility of these glioblastoma multiforme cell lines in an RPTP-dependent manner (29).
Chemokines also play a role in glioblastoma invasion. The chemokine (CXC motif) receptor 4 (CCR4) was initially found to be overexpressed in glioblastoma multiforme compared with normal brain tissue during a cDNA microarray screen (30); in this study it was thought to be a proliferation marker. Subsequent studies confirmed expression of CXCR4 protein in glioblastoma multiforme, as well as persistent co-expression of its ligand chemokine (C-X-C motif) ligand 12 (CXCL12) (31–33). CXCL12 stimulates the invasiveness of glioma cell lines in vitro (34,35). The increased transcription of both CXCR4 and CXCL12 in laser-capture microdissected invasive cells in a rat C6 glioma model provided the first clue that these proteins mediate glioma cell invasiveness in vivo (34). This chemokine–receptor pair also plays a role in breast cancer progression (36) and metastasis and has been shown to contribute to the homing of breast cancer cells to secondary organs such as the lung (37).
More complex autocrine motility signals are represented by a three-part signaling system that involves glial cell line–derived neurotrophic factor (GDNF), which signals through two extracellular proteins, the GDNF receptor 1 (GDNFR1) (the ligand-binding moiety) and its signal transducing partner, rearranged during transfection protooncogene (c-Ret). This autocrine trio is overexpressed in glioblastoma multiforme compared with normal brain as well as in the rat C6 glioma cell line compared with rat brain (38). Stimulation of rat C6 glioma cells that overexpressed GDNFR1 and GDNF resulted in increased cell migration compared with unstimulated cells, whereas a low-grade glioma cell line that expressed lower amounts of GDNFR1 reacted to stimulation with a modest increase in GDNF-dependent cell motility (39). GDNF, which is nearly universally expressed throughout the brain, could foster the maintenance of glioma cell invasion through its receptors that are expressed on invasive glioma cells.
In addition to conventional autocrine loops, there are autocrine motility signals that engage in phospholipid signaling. One such signaling system involves autotaxin (ATX), lysophosphatidic acid (LPA), and the LPA receptors (LPA1, LPA2, LPA3, and LPA4). ATX is a secreted motogenic protein that was first identified in conditioned medium from a human melanoma cell line (40); ATX is also expressed by other tumors that have an invasive phenotype, such as breast cancer (41), non–small-cell lung cancer (42), and glioblastoma multiforme (43,44). The motogenic properties of ATX are linked to its lysophospholipase D activity: it catalyzes the production of LPA, signaling through LPA receptors present on the surface of invasive tumor cells. ATX is expressed by all grades of diffuse astrocytomas and is transcribed at higher levels in glioblastoma multiforme cells that have invaded the brain parenchyma than in cells that remain in the tumor mass. The ATX protein is detectable by immunohistochemistry in all astrocytic tumors but not in normal astrocytes, neurons, or mature oligodendrocytes (43). ATX is secreted by a variety of glioblastoma multiforme cell lines and, when glioblastoma multiforme cells are exposed to the lysophospholipase D substrate lysophosphatidylcholine, ATX promotes cell motility in an LPA1-dependent manner (44). ATX also promotes invasion of glioblastoma multiforme cells into rat brain slices ex vivo (45). This finding echoes the earlier finding of an LPA dose–dependent increase in migration of glioblastoma multiforme cell lines (46). Given that LPA1 is expressed ubiquitously in the brain (47), it is likely that every cell type in the central nervous system would be able to respond to LPA generated by glioblastoma multiforme cells during invasion.
Another bioactive phospholipid that is involved in glioma invasion, sphingosine-1-phosphate (S1P), is secreted by glioblastoma multiforme cells that express sphingosine kinase 1 (SphK1) and sphingosine kinase 2 (48). Van Brocklyn et al. (48) reported that glioblastoma patients whose tumors expressed high levels of SphK1 had statistically significantly shorter survival than patients whose tumors expressed low levels of SphK1 (102 versus 357 days; P = .002). S1P induces cell motility in glioblastoma multiforme cell lines that express S1P receptor-1 and S1P receptor-3; S1P receptor-2 is described as a receptor that inhibits cell motility when activated (49,50). The brain has the highest levels of S1P of various tissues tested (51); however, the only cells in the brain parenchyma that are known to secrete S1P are cerebellar astrocytes (52).
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Paracrine Interactions Between Invasive Tumor Components and Nonneoplasic Cells of the Central Nervous System |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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Microglia and Tumor-Associated Macrophages
Tumors secrete a number of factors that recruit inflammatory cells to the tumor periphery, including cytokines, chemokines, colony-stimulating factors, and growth factors. The effects of these immune cells on the neoplastic process range from the initiation of malignancies to the driving of tumor progression through promotion of angiogenesis, lymphangiogenesis, proliferation, invasion, and metastasis (8). Whereas in extracranial solid tumors it is the tumor-associated macrophage that is closely associated with promotion of malignancies (8,53), in intracranial tumors it is microglia that are the main responders to tumor burden. Both immune cell types respond to nearly identical set of tumor-secreted factors (e.g., EGF, HGF/SF, tumor necrosis factor-, and cytokines) by expressing distinct functional programs that recapitulate normal developmental roles to promote tumor progression (8). However, in histologic sections of the brain/tumor margin, microglia are present at the invasion interface at threefold higher numbers than tumor-associated macrophages (54). The precise function of peritumoral microglia is not fully understood; they may merely represent a reactive immune response to the tumor or they may actively influence tumor growth or invasion through cytokine secretion (55) (Fig. 1). Microglia facilitate glioblastoma multiforme invasion in an ex vivo rat brain slice model by secreting inactive matrix metalloprotease-2 (pro-MMP2) (56). Glioblastoma multiforme cells, on the other hand, produce soluble factors that activate pro-MMP2, thereby increasing the amount of active MMP2, which promotes glioma invasion (56). This intercellular cooperation is reflective of the finding that cocultures of glioblastoma multiforme cells and astrocytes display increased MMP2 activity (57), which suggests that astrocytes are capable of playing a part in glioblastoma multiforme invasion. In addition, microglia secrete multiple cytokines, including tumor necrosis factor- and interleukin 1
(IL-1). The microglial contribution of interleukin 1 to the glioma microenvironment can elicit glioma transcription of TGF-, which, in turn, results in immunosuppression (58), increased expression and secretion of vascular endothelial growth factor (VEGF; which is involved in angiogenesis), EGFR (which is involved in cell proliferation), and matrix metalloproteinase 9 (MMP9; which is involved in invasion) (59), facilitating all three manifestations of the malignant phenotype of glioma cells.
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There are several opportunities for cross-communication between microglia and the invasive tumor cell. Microglia respond to EGF secreted by tumor cells with increased motility, but not by increasing their proliferation (60), which suggests that microglia may be directed to lesions in the central nervous system via paracrine signaling. Activated microglia also secrete EGF, making it likely that glioblastoma multiforme cells that express EGFR can, in turn, respond to the presence of microglia with heightened invasion. This scenario is likely also true for Met–HGF/SF signaling between glioblastoma multiforme and microglia, given that both cell types express the receptor and the ligand (61) and respond to HGF/SF by increasing their migration (55). Because microglia are frequently found surrounding the tumor mass, it is possible that HGF/SF causes microglial migration toward the tumor. The same could also hold true for GDNF and GDNFR, which are thought to attract microglia to sites of brain injury to stimulate axonal sprouting (62,63).
Most tumors secrete chemokines, which frequently results in the recruitment of a host of inflammatory cells. In glioblastoma multiforme, chemokine signaling through CXCR4 and CXCL12 not only induces microglial migration (64) and potentially recruits microglia to the peritumoral area but also influences T-regulatory cell motility. Like many other tumor types, gliomas create an immunosuppressed zone in their immediate vicinity (65). Among the factors that contribute to this phenomenon, T-regulatory cell recruitment to and accumulation at the tumor and its periphery appears to be the most important (58,66). CXCR4–CXCL12 signals are also known effectors of T-regulatory cell homing to bone marrow (33). Therefore, it is possible that glioma-secreted CXCL12 may attract natural T-regulatory cells as well as CD4-positive T-lymphocytes, which are then converted to T-regulatory cells by tumor-secreted TGF- (58), to gliomas, where they could actively suppress immune responses to the tumor.
Microglia and most astrocytomas secrete ATX, which suggests that they are capable of generating the phospholipid motogen LPA. Both tumor and immune cells also express receptors for LPA such as LPA1 and LPA2 (45). This finding suggests that phospholipid signaling through ATX could contribute to microglial cell motility in both an autocrine (microglia driving its own motility) and paracrine (microglia motility being driven by glioblastoma-secreted ATX) manner. This possibility is supported by the observation that LPA enhances chemokinetic migration of murine microglial cells in vitro (67).
Glial and Neuronal Progenitors
Among the growth factors that are known to drive glioma tumorigenesis, PDGF has the strongest effect on normal cells in the central nervous system, especially on all stages of neural and glial precursor cells (Fig. 1). Both isoforms of PDGF (PDGFA and PDGFB) are expressed in neurons during embryogenesis (68,69), while their receptor, PDGFR, is expressed in glial cells of the oligodendrocyte lineage (70). This coordinated expression suggests the presence of a paracrine signaling system in which neurons produce the ligand and glial cells of the oligodendrocyte lineage express the receptor. Glial progenitor cells are exquisitely sensitive to PDGF; glial progenitor cells from neonatal mice that were transduced with PDGF-expressing retroviruses and injected into mice proliferated rapidly and formed tumors that resembled oligoastrocytomas (71). Recently, in a glioma mouse model, it was discovered that PDGF-expressing retroviruses could also infect cycling glial progenitor cells from adult mice, which comprise 4% of the cells in the adult white matter (72). PDGF that was secreted by retroviral-infected adult glial progenitor cells had a potent oncogenic effect, and the tumors that arose had proliferative and invasive phenotypes that resembled those of human glioblastoma multiforme cells (72). Surprisingly, however, the newly formed tumors consisted of a mixture of infected and noninfected cells; this finding suggests that the PDGF-expressing cells can recruit and transform other glial progenitor cells in the vicinity via paracrine signaling, thereby potentially increasing the tumor bulk. Such recruitment of adjacent glial cells may explain the observed extensive genetic heterogeneity of glioblastoma multiforme.
Neural stem cells also respond to HGF/SF and CXCL12 with increased motility (55,73,74), which reflects the effect of these autocrine factors on bone marrow and mesenchymal stem cell migration (75). We speculate that glioma-secreted motility factors are responsible, in part, for the phenomenon of neural stem cell homing to tumors (76). The observation that CXCR4 and CXCL12 are involved in neuronal guidance in the developing brain (77), in microglia migration (64), and in neural stem cell migration toward gliomas (78,79) has sparked interest in the role of this autocrine signaling system in glioma invasion. CXCL12 may be an ontogenetically established guidance cue that is normally active during development but that is re-expressed by glioblastoma multiforme cells to maintain the invasion process.
Invasive glioblastoma multiforme cells secrete PTN and S1P, two additional glioma motility factors with potential paracrine effects on neural precursor cells. Neural stem cells from the embryonic subventricular zone and radial glia express RPTP during the migratory phases of central nervous system development (80). Neural progenitor cells from the embryonic rat brain also express most S1P receptors and thus display increased proliferation and cell–cell aggregation when exposed to S1P (81). Taken together, these two less well known factors in glioma motility represent signaling systems that are similar to the CXCR4–CXCL12 signaling system in that they involve developmental migration cues.
Astrocytes
Glial cells function as a trophic support system for neurons (i.e., they supply growth factors and cytokines). Some of the neurotrophic factors secreted by astrocytes, such as TGF-, CXCL12, S1P, and GDNF, have the potential to increase the invasive capacity of glioblastoma multiforme cells (Fig. 1). However, despite evidence that astrocytes constitutively express EGFR, Met, RPTP, and LPA1 (39,82–85), little is known about the effects of signaling through these receptors on normal astrocytes in vivo. Ligands of the above-mentioned receptors can have a variety of effects on astrocytes in culture. For example, exposure of astrocytes to LPA in vitro results in cell contraction through stress fiber formation (86). It is interesting to note that invasive glioma cells secrete ATX, an extracellular enzyme that catalyzes the production of LPA. In addition, Sharif et al. (87) found that normal mature astrocytes that were exposed to TGF- reverted to a radial glial cell phenotype that was similar to that of glial progenitor cells found in earlier stages of neural development. Prolonged exposure to TGF- resulted in the conversion of mature astrocytes into cells with an even earlier ontogenetic phenotype, neural stem cells. Other studies [reviewed in (88)] indicate that neural stem cells contribute, in part, to the glioblastoma multiforme tumor mass. The capacity of TGF- to dedifferentiate mature astrocytes to radial glia and stem cell phenotypes is similar to the dedifferentiating effect of PDGF on oligodendrocytes (see "Glial and Neuronal Progenitors"). It is interesting that the two best-described growth factor signaling systems that, together, are hallmarks of glioblastoma multiforme biology are able to revert mature cells in the central nervous system to more plastic, pluripotent cells, which may contribute to the aberrant growth and dispersion of glioblastoma multiforme.
Oligodendrocytes
Little is known about how invasive astrocytoma cells might affect oligodendrocytes, which function to support neuronal health and function in the normal brain and to protect neurons from neurotoxic insults. In these capacities, oligodendrocytes secrete HB-EGF (89) and GDNF, which are also expressed by astrocytes (89) and bind to receptors that stimulate glioma motility (14,39). Differentiated oligodendrocytes express S1P receptors (90) and are therefore capable of receiving signals from invasive glioma cells that secrete this phospholipid, but little is known about the effect of S1P signaling on mature oligodendrocytes.
During the myelinating stages of central nervous system development in rat neonates, oligodendrocytes also secrete ATX (91), which has the effect of reducing oligodendrocyte adhesion, presumably to support changes in oligodendrocyte function and morphology that occur during the initial stages of myelination. Glioblastoma multiforme–derived ATX may provoke the de-adhesion of oligodendrocytes found in the path of invading glioblastoma multiforme cells from the extracellular matrix (Fig. 1), creating an environment that is permissive for invasion. In this context, it is interesting that oligodendrocyte-rich white matter tracts are one of the preferred conduits of invasion by glioblastoma multiforme.
Neurons
RPTP is not only expressed by astrocytes throughout the central nervous system but also by certain subsets of neurons (21). The RPTP ligand, PTN, is expressed along pathways of developing axons (92), promotes neurite outgrowth in vitro, and is also expressed in reactive astrocytes following neuronal injury (93). Following experimental injury to the central nervous system, transcription of the RPTP gene increases substantially in areas of axonal sprouting as well as in areas of glial scaring, suggesting that RPTP is part of central nervous system repair mechanisms. These observations imply that cells in the central nervous system may react to injury caused by the physical expansion of the tumor in a manner similar to its reaction to physical injury. This injury response likely includes the secretion of factors such as PTN which could ultimately stimulate glioblastoma multiforme dispersion away from the tumor mass. Neurons may also be sensitive to glioma-derived phospholipid signaling: they undergo growth cone collapse in response to LPA (94) and express S1P receptors (95), indicating that they are capable of receiving signals from invasive glioma cells that secrete these phospholipids (Fig. 1).
Vasculature
The role of the microenvironment in glioblastoma multiforme invasion was recently and elegantly captured by time-lapse microscopy of rat glioblastoma multiforme invading into a vital rat brain slice (96). In this model system, glioblastoma multiforme cells were observed to travel along blood vessels and to pause at select vascular branch points, where they proliferated, supporting the hypothesis that glioblastoma multiforme cells may respond to endothelial-derived cues (Fig. 1). This study also revealed that the invading glioblastoma multiforme cells disrupt contacts between astrocytic processes called podocytes and endothelial cells. Although the authors of the time-lapse study did not assign a mechanistic basis for the disruption in cell–cell contact (i.e., proteolytic digestion of contacts, paracrine-activated deattachment, or both), their observations demonstrate that, during the process of invasion, glioblastoma multiforme cells cause the disengagement of normal glial cells from their functional context.
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Axonal Guidance Molecules May Be Linked To Glioma Invasion |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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In addition to PTN, other axonal guidance molecules may stimulate glioma invasion. The semaphorins and their receptors, the neuropilins and the plexins, are also expressed by glioblastoma multiforme cells (97) and have been linked to cancer invasion through the observation that semaphorin-3A modulates the migration of neural progenitor cells (98,99). Neuropilin 2 transcription was increased in G112 glioma cells that were stimulated to migrate in vitro compared with stationary cells (100). In addition, we recently found that semaphorin-3B transcription was higher in laser capture microdissected invasive glioblastoma multiforme cells than in noninvasive cells at the tumor core (Demuth T, Reavie L, Hoelzinger D, Rennert J, Nakada M, Berens ME: unpublished observations).
The netrins and their receptors, deleted in colorectal carcinoma (DCC) and the Unc5 homolog, could represent an additional group of axonal guidance factors that are involved in glioblastoma multiforme invasion. For example, netrin 4 transcription was higher in invasive glioblastoma multiforme cells than in stationary cells in the tumor core (43), suggesting that this axonal and glial progenitor guidance system also drives glioblastoma multiforme invasion. During development, netrin 1 (NTN1) expressed in the spinal chord attracts axonal protrusions from neurons that express DCC but repels neurons that express Unc5 (101). NTN1 also elicits directional motility in neuroblastoma cells that express DCC (102). Little is known about netrin signaling in glia, but NTN1 is involved in migration of glial cells of the oligodendrocyte lineage during development (102). In addition, both glial cells of the oligodendrocyte lineage and presumed astrocyte precursors respond to NTN1 and semaphorin-3A concentration gradients in the central nervous system with directional migration along the optic nerve (103).
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Therapeutic Targeting of Autocrine and Paracrine Invasion Signaling |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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A growing understanding of the interplay between a tumor and its microenvironment has generated efforts to therapeutically target the microenvironment. One of the challenges of such an approach is to target the tumor-supporting functions of the microenvironment while leaving intact any tumor-inhibiting functions that it may have. Two reviews have comprehensively addressed this issue in extracranial malignancies (104,105). Glial tumors, however, present a unique type of malignancy: their microenvironment (the brain) is particularly delicate, and the blood–brain barrier poses a substantial hurdle for drug delivery.
The most extensively studied class of targeted agents in glioma are the receptor tyrosine kinase inhibitors, which were developed to target receptor tyrosine kinases that are expressed on tumor cells but may also have additional therapeutic benefit because of their effects on the tumor environment. The most prominent of these agents is the rationally designed drug imatinib, which targets the Bcr–Abl fusion protein and the PDGFR tyrosine kinase in tumor cells (106,107). Imatinib has also been shown to interfere with angiogenesis by decreasing the degree of pericyte coverage of tumor-associated endothelial neovasculature (108). Despite the impressive antitumor activity of imatinib in chronic myelogenous leukemia and against gastrointestinal stromal tumors (109,110), results in glioblastoma multiforme have been disappointing (111) (Table 2). Among the factors thought to contribute to the poor results in glioblastoma multiforme is the limited penetration of the central nervous system by imatinib, combined with active P-glycoprotein–mediated efflux of drug at the blood–brain barrier (112). The blood–brain barrier is likely also the limiting step in the poor efficacy of imatinib in cases of central nervous system relapse of chronic myelogenous and acute lymphoblastic leukemia (113), two normally imatinib-sensitive tumors types.
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The autocrine loop of EGFR and its ligands that is present in brain tumors lends itself well to targeting by small-molecule inhibitors such as gefinib and erlotinib. However, despite the high frequency of EGFR gene overexpression and gene amplification in glioblastoma multiforme, as well as the presence of EGFR in the brain microenvironment, gefitinib has not been found to provide therapeutic benefit in patients with glioblastoma multiforme (111). It is surprising that no association between EGFR gene amplification and response to EGFR inhibitors has been found. Nevertheless, coexpression of the vIII mutation in EGFR and PTEN was statistically significantly associated with response to EGFR kinase inhibitors (114). However, in a study with erlotinib, no association between vIII mutation status and response to EGFR inhibition was found, although high tumor expression of EGFR coincident with low levels of protein kinase B/Akt phosphorylation were associated with response to erlotinib (115).
The promises of targeted agents have not been fulfilled in glioblastoma multiforme. Given the disappointing results from these clinical trials, it seems clear that novel biomarker-guided clinical trial designs are needed. One such trial design uses a pharmacodynamic marker to monitor the efficacy of a given therapeutic agent. Thus, after a stereotactic biopsy, treatment-naive patients are administered the novel agent during a 1–2 week period prior to surgical tumor removal. Drug levels and status of biomarkers in posttreatment samples relative to pretreatment samples should reveal the degree of penetration of the central nervous system by the drug and help to define the biologic effective dose based on biomarker engagement.
Because glioblastoma multiforme is characterized by extensive neovascularization, it may respond to treatments that disrupt angiogenesis. The monoclonal antibody bevacizumab targets VEGF, the paracrine stimulator of angiogenesis. The combination of antiangiogenic and cytotoxic treatment (i.e., bevacizumab and irinotecan) has been very promising in clinical trials (116) (Table 2) and may provide the rationale for future testing of VEGF-Trap, an angiogenesis inhibitor, and small-molecule inhibitors of VEGFR.
Interaction of glioblastoma multiforme cells with cells present in the normal brain stroma can enhance the invasive process. Chemokines (such as CXCL12) and chemokine receptors (such as CXCR4) are well known agents of pro-invasive inter-cellular communication, they have therefore become the focus of new anti-invasive therapies. The histone deacetylase inhibitors suberoylanilide hydroxamic acid (SAHA) and butyrate have been found to reduce CXCR4 mRNA and protein levels (117) and are therefore further along in clinical development than other agents that interfere with CXCL12–CXCR4 signaling. In preclinical studies, histone deacetylase inhibitors were found to inhibit the migration of leukemia cells and lymphoblasts that were stimulated with CXCL12 (117) and to inhibit in vitro invasion and increase tumor necrosis factor–induced apoptosis by suppressing activation of nuclear factor-kappa B (118).
Successful treatment of invasive brain tumors will depend on blending cocktails of targeted agents that are tailored for an individual patient. A thorough understanding of the interaction between the tumor and its microenvironment will help to define the context of vulnerability, such as the dependence on specific signaling pathways, which may lead to novel antitumor approaches. Clinical testing of such targeted interventions will require careful monitoring of the effects of these agents on both cells in the tumor microenvironment and in the tumor. Advances in imaging modalities will allow for better assessment of the tumor microenvironment's contribution to tumor biology.
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Conclusions |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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Multiple autocrine motility-enhancing signaling systems are likely to be involved in the maintenance of glioblastoma multiforme invasion. The observation that glioblastoma multiforme invasion occurs along specific anatomic features suggests the presence of scaffolding that enables the traction necessary for cell motility. Conversely, invasive glioblastoma multiforme cells receive distinct signals that are generated by the cellular context along which they transit; such proximity of tumor and normal cells enables communication via paracrine signaling systems (Fig. 1), which may support tumor invasion. Most of the autocrine receptor/ligand groups discussed herein have documented roles in central nervous system development, specifically in association with glial and neuronal precursor cell waves of colonization. This similarity suggests that normal cells in the brain express, or have the capacity to express, receptors for tumor-secreted ligands or that brain cells produce ligands that activate receptors on glioma cells (Table 1). The hypothesis that neoplastic cells use signals that influence cell types involved in normal developmental tissue morphogenesis is not new; a hallmark of this hypothesis is the recruitment of macrophages, fibroblasts, and the vasculature to tumor sites. Such phenomena have been observed in several cancers, including breast cancer and melanoma (7). However, until recently it has been difficult to demonstrate communication between invasive tumor cells and the surrounding stroma. The use of gene expression profiling of specific subpopulations of tumor cells has begun to shed light on the differences between invasive tumor cells and the original tumor mass from which they emanated. Gene expression signatures of tumor invasion that have been identified for glioblastoma multiforme invasion (43) and for breast cancer invasion (119) revealed possible interactions between the invasive cells and immune cells. Confirmation of this interaction revealed that macrophages are indeed required elements in tumor invasion (120).
Studies of the influence of the tumor microenvironment on tumor biology are further advanced in the field of breast cancer. Normal myoepithelium has a recognized tumor suppressor role in breast cancer pathogenesis (121). This normal tissue surrounding the neoplasm expresses antiangiogenic factors and protease inhibitors that slow tumor progression (122). On the other hand, breast tumors have an impact on normal breast tissue, even at the molecular level: there are statistically significant differences in gene expression patterns of myoepithelial cells derived from normal breast tissue and of those derived from invasive breast carcinoma (36). These observations suggest that invasive stages of breast carcinoma induce changes in the host tissue that could synergize with the tumor to promote invasion. It is interesting that the majority of differentially expressed genes encode secreted proteins and/or their receptors (36), including CXCR4 and CXCL12, indicating the involvement of paracrine interactions. It is highly likely that glioblastoma multiforme tumor burden may have similar impact on normal cells in the brain parenchyma.
In this review, we have examined select autocrine receptor/ligand groups that are expressed by glioblastoma multiforme and linked to glioblastoma multiforme invasion, and we hypothesize that glioblastoma multiforme motility signals may have paracrine effects on proximal normal cells in the brain. Glioblastoma multiforme re-engages pre-established ontogenetic motility signals that drive central nervous system migration events that involve every cell type present in the brain parenchyma. The expression and function of paracrine receptor–ligand pairs in the context of glioblastoma multiforme and its microenvironment suggest that glioblastoma multiforme autocrine motility signals may elicit responses from the brain parenchyma that support or even facilitate invasion.
The interaction of neoplastic cells with the peritumoral stroma can also result in the disruption of tissue homeostasis. For example, tumor burden frequently results in the recruitment of leukocytes to the tumor site (through cytokines and chemokines), which leads to an inflammatory reaction [reviewed in (123)]. Even though this process reflects the natural course of wound healing, these inflammatory responses are not self-limiting, and thus it has been proposed that tumors resemble wounds that do not heal (124). Reinstating tissue homeostasis by inhibiting tumor–stroma communication (such as by inhibiting proinflammatory or proinvasive signals) may be one way to slow tumor progression. Inhibiting the activity of chemokine colony-stimulating factor 1, which attracts inflammatory cells to the tumor site, has been shown to reduce invasion and metastasis in breast cancer (125). Similar inhibition of the autocrine motility loops of glioblastoma multiforme could also interrupt their collateral paracrine pro-invasion signaling effects. There are two potential benefits to targeting autocrine motility stimulation: one is to arrest tumor-driven motility, the other is to impede tumor motility that is supported and even sustained by the peritumoral stroma. A better understanding of the influence of tumors on their microenvironment could lead to therapies that target the more genetically stable normal cells that surround the glioma rather than the genetically unstable tumor cells themselves, which invariably develop resistance to therapy. Making the host tissue more resistant to the aberrant signaling of invasive tumor cells may be an avenue of tumor management that could produce palliative adjuvant therapy slowing tumor recurrence.
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Funding |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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National Institutes of Health (R01NS42262-4 to M. E. B.).
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NOTES |
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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We would like to thank David Hoelzinger, MD, for creating the illustration for the figure and Mitsutoshi Nakada, MD, PhD, for critical evaluation of the manuscript.
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TopAbstractAutocrine signals in glioma...Paracrine interactions between...Axonal guidance molecules may...Therapeutic targeting of...ConclusionsFundingReferencesNotes |
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Manuscript received April 10, 2007; revised August 13, 2007; accepted September 4, 2007.
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