. . . those left behind. Reflections on Invasive, Nonresectable Glioma Cells
Michael E. Berens, PhD
Sherri Treasurywala, PhD
Division of Neurology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center
Glioma invasion remains a lethal, evasive pathological process for which intervention strategies elude application. The invasive behavior of glioma cells is reviewed, specifically focusing on the cell-associated receptors likely to engage this locomotion. Our own studies and the literature suggest a link between growth and cell motility, forwarding a paradigm of the dichotomy between proliferation and migration. We propose that activation of glioma cell migration will suppress tumor growth. Furthermore, the propensity of glial tumors to invade could be exploited for therapeutic advantage by adoption of what we refer to as “out-of-my-head” therapy.
Key Words : gliomas
Gliomas are one of the most lethal solid tumors in humans. Last year the American Cancer Society(1) attributed an estimated 17,600 new cases of brain tumors and more than 13,200 deaths to this disease. Prognosis for patients is bleak, with median survival times ranging from 6 months to 5 years, depending on the grade of the tumor (see The Therapy of Primary Brain Tumors in this issue). Surgical excision of brain tumors is limited by accessibility (i. e., the risk of possible neurological damage)49 and the resectability of the tumor.65 Current standard treatments include a combination of surgery and radiation. Normal brain tissue is not spared by radiation protocols, and use of this modality is therefore limited by its toxicity to normal tissue. Ultimately, treatments fail due to the resistance of tumor cells.
Treatments for malignant brain tumors have also included single agent chemotherapy with nitrosoureas [1,3-bis-(2-chlorethyl)-1-nitrosourea (BCNU) or lomustine (CCNU)] and combination chemotherapy with other agents. These aggressive measures, however, fail locally in more than 95% of the cases.36 Therapeutic targeting of brain tumors is complicated by permeability constraints imposed by the blood-brain barrier, and almost all therapies for brain cancer are thwarted by tumor recurrence in normal brain tissue. Thus, current treatment modalities directed at proliferating tumor cells show limited success in arresting the progression of this disease. All glial neoplasms recur after therapy, usually within 2 to 3 cm of the site of the primary tumor.9 Unlike most other solid tumors, gliomas almost never establish systemic metastasis.8, 68 Locally invasive glioma cells investing into the brain parenchyma become the seeds of destruction for patients. The development of management strategies for a local disease like glioma has a high likelihood of ushering in profound improvements in the clinical outcomes of patients. Thus, sober reflection on the biology of local brain invasion and possible means to exploit this behavior is crucial in developing new treatments for this disease.
How the Tumor Got This Way
The molecular genetic changes described in glial tumors are elaborated in Genetics of Adult Malignant Gliomas in this issue. Mounting evidence provides strong impetus to conclude that as specific genetic aberrations accumulate (which may be the loss of tumor suppressor genes and the emergence of mutated oncogenes), the tumor cell’s behavior descends into more malignant grades.7,11,78These molecular genetic studies derive their information from resected tumor lesions. Even at their rim, these specimens are typical of a bulky, crowded, tumor mass.
The degree of heterogeneity between different gliomas of the same grade and within an individual glioma sample is remarkable.6,12Absent from surveys on the molecular changes in gliomas, however, are the genotypes of the invasive glioma cells, which become the subject of study only when regrown as a solid recurrent tumor. Morphologically, however, there is clear evidence that the invasive cells giving rise to recurrences are likely to be the small anaplastic glioma cells beyond the peritumoral rim.20
Glioma invasion is a dynamic process that affects multiple features of glioma cells. During any given period, such as at the time of biopsy, the invasive and proliferative behaviors of glioma cells are regionally and temporally variable. It may not be surprising that single-look biopsy analysis fails to demonstrate an association between proliferation and invasion.67 Despite very low proliferating indices of distantly invasive glioma cells14 or even an inability to identify glioma cells morphologically more than 4 cm from the rim of frank tumor, it is, nonetheless, possible to harvest clonogenic glioma cells at such distances.69 The clonogenic potential of these most invasive glioma cells, referred to as “guerrilla cells” by Pilkington,59 is the ultimate cause of tumor recurrence. How invasive glioma cells survive in the setting of invasion, evading immune detection,80 thwarting cytotoxic therapies,72,83 and deferring commitment to proliferation,22 remains largely unknown. Recently, however, the biology of glial cell invasion, both developmentally and in diseased states, has advanced, allowing a paradigm of the functional constraints on migrating glial cells to be assembled.
Invasion of Normal Astrocytes
Developmentally, glioblasts emerge in the subventricular zone of the brain as O-2A progenitor cells (type 2 astrocytes) or as type 1 astrocytes.44 The centripetal spread of radial glia into the cortex is accompanied by the elaboration of directional matrix fibers composed of laminin, tenascin, and vitronectin as well as proteoglycans on which the movement of subsequent progeny glial cells is facilitated.10,17,45,60,84
The motility of glial cells during development is a manifestation of contact with their matrix as well as dynamic cell-to-cell interactions mediated through specific receptors. The gap junction protein on astrocytes, connexin43, shows a pronounced role in glial cell behavior, including communication pathways51 and cell proliferation.48,52 Knockout mice lacking an ability to express connexin43develop viable offspring, but their brains show architectural aberrations consistent with abnormal astrocyte migration.58Phosphorylation states of connexin proteins may regulate cell-to-cell communication;30 oncogene transfection of glial cells leads to reduced phosphorylation of connexins.29
The neural cell adhesion molecule (NCAM), which binds to NCAM on adjacent cells, promotes astrocyte migration.79 During the course of development, the level of NCAM on astrocytes diminishes profoundly70 with consequences for both the motility of astrocytes and the ability to support neurite outgrowth.53,71
Like many growth factors, soluble factors are actually potent activators of astrocyte migration. Transforming growth factor b, basic fibroblast growth factor, epidermal growth factor, and transforming growth factor a each promote astrocyte migration.18 The earliest glial cells, the radial glia, maintain their migratory immature state under the influence of soluble factors elaborated by the embryonic brain.32 Mature astrocytes adopt radial glia morphology when exposed to these same factors.
Although the term glia refers to an early anatomical description of these cells as a sort of brain “glue,” adult astrocytes retain their ability to migrate. After trauma, stroke, or other disease conditions characterized by necrotic brain cells, astrocytes migrate and proliferate to form scar tissue. When propagated in cell culture, nontransformed astrocytes isolated from normal brain adopt successful migratory behavior and some limited ability to self-renew.43 In the setting of brain tumors, gliotic scarring is common. When appropriately activated, such cellular remodeling of the brain by normal astrocytes indicates that invasion is a normal and regulated behavior of astrocytes.74
Studies of transplanting brain tissue or brain cell cultures into developing or adult brain also highlight the propensity of astrocytes toward motility. The migration of such implanted astrocytes is invariably most pronounced in white matter tracts.56,61 Young, developmentally immature brains sustain extensive infiltration by transplanted astrocytes,2,85 consistent with a loss of plasticity in the mature brain. In a complementary manner, if immature glial cells are induced to differentiate in vitro, their invasive potential as an intracranial transplant is also diminished.27 These findings indicate that a reduced migratory potential accompanies the differentiation of astrocytes and that the fully mature brain is a structure somewhat resistant to cell percolation. The hormonal induction of specific integrin matrix receptors can re-engage the migratory behavior of mature astrocytes on specific substrates,19 pointing to an ability to recall developmental programs by fully differentiated cells.
Malignant Glioma: A Moving Story
Because of their nonmetastatic nature,68 gliomas are an ideal cancer in which to develop local therapies. The natural patterns of glioma dissemination indicate that white matter is the preferred route for glioma cell invasion.5,25 Given the improved understanding of the biology of cellular interactions with the immediate environment, a paradigm of how cell-substrate interactions influence much of cell behavior is emerging.
Glioma Invasion Biology
Interactions between glioma cells and their cellular and extracellular matrix (ECM) environments are mediated by adhesion molecules, a family of cell-surface receptors. The expression of adhesion molecules is organ specific, which might account for the preferential seeding of tumors in certain organs. Unlike most neoplasms that metastasize to distant organs via the lymphatic and vascular systems, it might also explain why malignant gliomas almost never seed outside the brain. Adhesion molecules are classified according to their functional behavior, which is derived from their amino acid sequence and receptor ligand(s). The four major categories of cell adhesion molecules are integrins, cadherins, selectins, and the immunoglobulin superfamily.
Integrins are transmembrane glycoproteins that act as receptors for specific amino acid sequences found in ECM proteins or for membrane-bound counter-receptors on other cells. Because the ECM is ubiquitous throughout tissues, integrins both establish the texture of solid tissue and mediate much of the motility behavior of normal and transformed cells. Tumor cell lines show alterations in the expression and/or function of integrins.37 For example, integrins a3b1 and a3b3 are overexpressed in glioma cell lines while a2b1 and a6b4 are down-regulated in carcinomas of the breast.13 Integrin expression may be related to tumor progression. avb3 is not present in normal skin melanocytes but is strongly expressed in melanomas.34
About 20% of the total volume of the central nervous system is comprised of extracellular space, which is largely filled by the complex macromolecules constituting the ECM.54 Molecules in the matrix, which include fibronectin, collagens, and proteoglycans, among others, influence a number of cellular functions including adhesion, migration, proliferation, and differentiation. The migration of glioma cells depends on ligands in the matrix.23 Laminin and collagen type IV are permissive substrates for astrocytoma migration while fibronectin and vitronectin are almost nonpermissive.3
The interactions among glioma cells, their ECM, and the expression of integrins have been analyzed extensively and all correlate with the migratory abilities of the cells. Individual cells can vary their adhesive properties by selective expression of integrins. Cells also can modulate the binding properties of integrins. Normal astrocytes express integrin subunits a2, a3, a6, b1, and b4 while subunits a4, a5, av, b2, and b3 are consistently absent. In contrast, neoplastic astrocytes show increased expression and/or neoexpression of these subunits.57
Ohnishi et al.55 demonstrated that the migration of glioma cells can be stimulated by fibronectin. The degree of expression of the a5 integrin subunit correlates well with the strength of glioma cell adhesion to fibronectin. Studies using primary tumor cells have shown that the intensity of glioma cell adhesion to fibronectin correlates negatively with the degree of tumor invasion.82
Laminin is a strong promoter of glioma cell migration out of multicellular spheroids.26 Blocking the a3b1 integrin receptor significantly reduces migration on laminin.76 Antibody-blocking studies with rat C6 glioma cells suggest that migration and invasion are mediated by b1 integrin laminin receptors.50
Deryugina et al.15 have found that only a subset of integrin receptors involved in cell adhesion is required to mediate migration, and these integrins are ligand specific. For example, glioma cell migration on fibronectin critically depended on av integrins, while tenascin-mediated cell migration depended on b1 integrins.
The matrix glycoprotein tenascin can provoke an anti-migratory response in glioma cells, and this phenotype is mediated by an av-containing integrin.21 The migratory phenotype of glioma cells may be directly influenced by manipulating the expression of the av gene as demonstrated by both antibody-blocking studies and antisense strategies.75 Yamamoto et al.81 showed that inappropriate sialylation of integrin a3b1 can change focal adhesion as well as adhesion-mediated signal transduction and block glioma cell invasion in vitro. Such novel approaches for arresting the local invasion of brain tumors by selectively activating anti-migratory integrins and potentially blocking migration-enhancing integrins may have a profound impact on future therapeutic strategies.
Cadherins are calcium-dependent, homotypic adhesion receptors. They play an important role in the determination of tissue organization. Decreased cadherin expression in epithelial tumors is associated with a more malignant and highly invasive phenotype.38
Selectins are proteins that bind specifically to carbohydrates on the cell surface and mediate heterotypic cell interactions via calcium-dependent recognition of sialyated glycans. Although ligands for the currently known selectins have not yet been completely identified, it appears that signals transmitted by selectins can regulate gene expression in some types of cells.41 These receptors have demonstrated significance in lymphocyte homing and immune regulation but do not appear to play a role in brain development or glial cell biology.
The immunoglobulin superfamily includes a diverse array of cell adhesion receptors including NCAM and ICAM-1 (the intercellular adhesion molecule-1). The expression of ICAM-1 is enhanced in glioblastoma cells in vitro by cytokines. This example serves to demonstrate the effect of the immune system on cell-surface molecules. The tumor suppressor gene DCC (deleted in colon cancer) encodes a protein with significant homology to members of the immunoglobulin superfamily. DCC induces differentiation and controls cell proliferation.28 The loss of DCC expression and glioma progression are correlated. The expression of DCC in malignant gliomas is reduced, whereas low-grade astrocytomas are predominantly DCC-positive.62,66 These findings imply that DCC may play a role in glioma progression.
In addition to their influence in various aspects of cellular structure and function, cell adhesion receptors regulate cell growth and differentiation by initiating intracellular biochemical signaling cascades via signal transduction pathways. Integrins are capable of transmitting biochemical signals from the ECM to the cell interior.35 Integrin-mediated signals overlap considerably with those induced by cytokine and growth factor receptors, most notably the pathway for receptor tyrosine kinase signal transduction.33 Cadherin-initiated signaling events also impinge on the receptor tyrosine kinase pathway as well as on the G-protein pathway.63
Compared to the numerous studies with integrins and cadherins, there is a relative paucity of information on the role of selectins and the immunoglobulin superfamily as signal transducers. However, novel aspects of signal transduction involving cell adhesion molecules most likely impinge on known signaling pathways. The morbidity and mortality rates associated with cancer as a disease are primarily consequences of the abnormal spread of cancer cells. Modulation of adhesion molecule expression in gliomas may afford the possibility of altering cell-cell interactions and cell-ECM interactions, which may be avenues of manipulating local invasion in these neoplasms.
Going and Growing
There is a long-standing recognition of the dichotomy between differentiation and proliferation of normal and tumor cells. Astrocytoma cells follow this mutually exclusive bifurcation in that induced differentiation leads to suppressed growth.64 Treatment of glioma cells with phorbol ester (an agent typically associated with the induction of differentiation) leads to suppressed growth but increased migration and enhanced invasion.77 Antifolate chemotherapeutic agents also suppress growth, but the suppression of migration became evident only after an order of magnitude higher drug concentration,73 consistent with a disparate response by the cells to growth and migration effects from the same treatment. Remarkably, specific receptor-mediated responses to transforming growth factor b1 by human glioma cells demonstrate growth inhibition and migration stimulation.47 ECM proteins that activate glioma cell motility suppress proliferation.4,24,39,46 Results using fluids from tumor cysts demonstrate that autocrine factors generated in the tumor bed lead to proliferative and migratory responses with markedly dissimilar response profiles;24 subsequent work has identified scatter factor as a potent component of such fluids.40 Interleukin-10, however, had identical dose-optima for both growth and migration stimulation.31 A growing body of evidence, using treatments ranging from growth factors, cytotoxic chemotherapeutic agents, and ECM proteins, begins to drive a recognition of the remarkable discrimination by glioma cells for a commitment to cell division or cell locomotion and the mutually exclusive basis of these options at any one time.
“Out-of-My-Head” Therapy for Malignant, Invasive Gliomas
Heightened commitment to migration of glioma cells is accompanied by a diminution of proliferation. One significant implication of the dichotomy between migration and proliferation is that therapies designed to arrest or retard the invasion of glioma cells are likely to accelerate proliferation. We propose that this would be an unwelcomed and unfavorable outcome to anti-invasive therapies.
In the context of the inverse link between proliferative and motile behaviors of glioma cells, we posit consideration of therapies that promote glioma cell migration and invasion (so-called “taxis therapies”). Various ECM proteins activate glioma cell motility.23,42 ECM proteins engage specific receptors on the cell surface, and such receptor occupancy triggers specific signal transduction reactions within the cell. Conceivably, such a signaling cascade would include the controlled prolongation of various phases of cell cycle or even proliferation arrest in its repertoire. In addition to insoluble matrix molecules that engage the motility machinery of the cell, soluble factors function as motility-activation agents.4,16 The roster of such compounds includes epidermal growth factor, platelet-derived growth factor, scatter factor or hepatic growth factor, and insulin-like growth factor. Although many of these factors are typically considered to be agents that stimulate cell proliferation, at appropriate concentrations these compounds provoke motility responses in cells.
Certain combinations of both soluble and insoluble agents that engage the migratory response of glioma cells could be harnessed for what we term out-of-my-head therapy. In this approach after the initial surgical resection of a primary glioma, bioengineered cannulae would be implanted in the resection cavity. The luminal surface of the cannulae would be modified to present a substrate that activates glioma cell motility to wandering glioma cells. The further a cell moved up the cannulae, the higher the ligand density would become to activate the cell’s outward motion. Simultaneously, a solution containing chemotactic concentrations of a specific factor or a cocktail of factors that attract the glioma cells would be pumped into the resection cavity through the cannulae. As glioma cells chemotactically re-invaded the primary tumor bed, they would encounter the cannulae, which would induce their egress out of the head. Strategies that activate glioma cell motility also suppress proliferation. Out-of-my-head therapy would suppress tumor growth by recruiting the migration response of the tumor cells.
Supported by NS-27030, NS-34437, and Phi Beta Psi Sorority.
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