Mitogens as motogens

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Journal of Neuro-Oncology 35: 249–257, 1997.  1997 Kluwer Academic Publishers. Printed in the Netherlands.

Mitogens as motogens Michael R. Chicoine and Daniel L. Silbergeld Washington University School of Medicine, Department of Neurological Surgery, St. Louis, MO 63110-1093, USA

Key words: brain tumor, cell culture, cell locomotion, glioma, cytokines, mitogens Summary Numerous in vivo methodologies have documented the invasive behavior of glioma cells through normal brain parenchyma. Glioma cell locomotion has also been assessed with a number of in vitro assays including the Boyden chamber and other chemotaxis assays, colloidal gold cell tracking, analysis of migration of cells tumor cells from spheroids, confrontation cultures of glioma cells with aggregates of non-neoplastic tissue, time-lapse video microscopy, electron microscopic examination of the cytomorphologic correlates of cell motility, the radial dish assay, and quantitative enzyme immunoassay of proteins associated with invasion (e.g. laminin). Several of these techniques have been specifically modified to assess the effects of cytokines on glioma cell motility in vitro. Cytokines studied utilizing these methods include: epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), the bb dimer of platelet-derived growth factor (PDGFbb), nerve growth factor (NGF), interleukin 2 (IL-2), transforming growth factors alpha and beta 1 (TGFα and TGFstraat1), and tumor necrosis factor alpha (TNFα). This review summarizes the investigational methods used to evaluate random and directional glioma cell motility and invasion in vivo and in vitro. The roles of specific mitogens as motogens, as evaluated with these methods are then presented.

Introduction Malignant astrocytomas are the most common primary supratentorial cerebral neoplasms in adults, are diffusely infiltrative and rapidly fatal [1–12]. It is the motile invading cells from these tumors, which cannot be surgically extirpated, that are responsible for tumor recurrence following radical resection [13], and also these cells that, by unknown mechanisms, can lead to progressive neurologic dysfunction without evidence of mass effects or recurrence of bulk disease [14]. Although most current treatments are aimed at tumor control within the region of bulk disease, and/or the area of brain adjacent to the tumor, it is now clear that malignant brain tumors extend microscopically through much of the neural axis at the time of diagnosis [2, 15]. Cytokines are polypeptides that regulate mitosis

[16, 17], differentiation [16], angiogenesis [18], locomotion [16, 19], and a variety of other cell functions. Cytokinies exert these effects by highly specific binding to membrane receptors which convey signals via tyrosine kinases and possibly other second messenger systems (such as cAMP-dependent kinase and protein kinase C) [17]. The proliferation of virtually all cell types is under the receptor-mediated control of one or more cytokines [20]. Neoplastic cells may downregulate or lose dependence on exogenous cytokines as a result of upregulated endogenous cytokine production, altered expression of membrane receptors, and/or alterations of secondary messenger systems [20, 21]. Aberrations of normal cytokine-mediated cell proliferation have been extensively described for gliomas [22–25]. For example, amplification of the EGF receptor (EGFR) has been inversely correlated with length of sur-

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250 vival for patients with malignant gliomas [26]. Further evidence for the role of cytokines in neoplastic glia lies in the relation between proto-oncogenes and cytokines. For example, proto-oncogenes c-sis and c-erbB code for the B chain of PDGF, and the EGF-R, respectively [17, 20, 27]. It has been documented that alterations of the expression of cytokines and their receptors are most apparent in the more malignant gliomas [24, 26, 28–30]. This review summarizes the methodologies developed to assess glioma cell motility and invasion, and how specific cytokines affect this movement.

In vivo assays of glioma cell invasion Rapid and extensive invasion of tumor cells throughout the central nervous system has been demonstrated in rats implanted with C6 cells prelabeled by various methods including phagocytosed fluorophores (e.g. fast blue), membrane-bound markers (e.g. phaseolis leukoagglutinin), and transfected DNA vectors (e.g. the p3′ss DNA vector) [31– 33]. Labeled C6 cells distant from the bulk tumor at the site of injection were predominantly found along the white matter tracts and lining the CSF pathways, rather than in corticla or subcortical gray matter. Tumors were found only at the site of implantation, while invading cells remained single. The reasons for this remain conjectural. It is possible that invading motile cells undergo division and then daughter cells migrate away from one another. Alternatively, it is possible that mitosis and motility are mutually exclusive processes. Similar invasive properties have been demonstrated with numerous other rat glioma implantation models [34, 35]. Investigations utilizing human glioma cell lines implanted as xenografts in the brains of immunodeficient nude mice have also demonstrated infiltrating tumors, but in these models the success of transplantation is less consistent, and tumor histology ften changes significantly compared to the original lesion [36]. The results of these studies approximate the widespread invasion of the central nervous system that occurs in patients bearing malignant glial neoplasms [37], and in a similar fasion lead to neurologic dysfunction and eventual death often without tumor mass effect [14]. Al-

though rodent models provide a means to investigate in vivo brain tumor cell motility and invasion, they do not permit real-time observation, or accurate quantification of cell migration, or assessment of the factors that modulate this movement.

In vitro assays of glioma cell invasion and motility Boyden chamber and other chemotaxis assays The original Boyden chemotaxis chamber [38] and subsequent modifications assess cellular movement from one chamber to another through a porous membrane of known constituents (e.g. fibronectin, matrigrel, or other basement membrane substrates). This technique was originally developed to assess leukocyte chemotaxis, but has been adapted to evaluate glial and glioma cell movements as well [39–42]. The substance to be tested is added to culture medium, and is placed in the lower chamber, while the cells are plated on the upper chamber side of the membrane. Cells that migrate to the lower chamber, through the pores, to the chemoattractant side of the membrane are counted, and compared to controls. Colloidal gold cell tracking Random glioma cell movement in 2 dimensions has been evaluated by plating of cells on colloidal gold deposits. During movement, ‘phagokinetic’ tracks are left in the path traversed by the cells. Evaluation of these tracks can determine the pattern of cellular migration, and how it is affected by cytokines or other factors [19]. Migration of tumor cells from spheroids Spheroids are generated by culturing cells in multiwell dishes coated with agar, thus creating 3 dimensional aggregates of cells [43]. Migration is assessed by quantification of the egress of glioma cells from isolated spheroids plated on a plastic suface [43, 44]. The rate of migration from the spheroid is a measure of the directional movement from a region of high cell density to a region of low cell density. Cellular migration increases as the cells move from the spheroid because the inhibitory effect of cell-to-cell contacts is lessened [44].

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251 Confrontation cultures Invasion is evaluated by determination of the extent to which glioma cells in a spheroid penetrate into a co-culture aggregate of non-neoplastic cells [45–48]. Evaluations of numerous rat glioma cell lines have revealed that the growth and invasion demonstrated by glioma cells in this three-dimensional culture system mimic the growth and invasion demonstrated by thes cells after intracranial implantations in rats [34, 35, 49]. Therefore, this methodology closely approximates glioma cell invasion in vivo. Three-dimensional nature of the cocultured spheroids permits extensive cell-to-cell interactions, cell projections, and elaboration of extracellular matrix [43, 45, 46]. The target tissues assessed for invasion by co-cultured glioma cell spheroids inclucde rat brain aggregates, fetal human brain aggregates, rat optic nerve, and chicken heart fragments [45]. Time-lapse video microscopy Random glioma cell movements in 2-dimensions can be evaluated over extended periods using time-lapse video microscopy [16, 32]. A heated stage with atmosphere control (humidified 5% CO2 environment) prolongs cell survival for upto 3 to 4 days). This technique enables visualization of the circuitous path followed by the motile glioma cells, and permits observation of the cytomorphological changes occurring during movement. Additionally, cellular velocities can be precisely determined. Investigations have revealed that using this technique cells from malignant gliomas have higher in vitro velocities than cells from low grade gliomas or non-neoplastic glia, thus demonstrating the correlation between the clinical and in vitro behaviors of glioma cells [32]. Electron microscopy of morphologic features of cell motility Scanning electron microscopy enables three-dimensional examination of cellular membranes, and the morphological changes undergone by these membranes during movement [19, 50]. Ruffled cellular membranes and pseudopod projections are morphologic features of motile cells, and the extent to which cytokines induce these features can be readily assessed with scanning electron microscopy.

Modified radial dish assay This technique entails plating human brain tumor cells in the center of a Petri dish, and counting the cells as they migrate in 2 dimensional space from a central region of high cell density (as in bulky tumor) to a peripheral region of lower cell density (as in surrounding brain) [5, 32, 52]. The chemoattractant effects of cytokines can be assessed with this technique by placing the cytokine of interest in agar at the periphery of the dish on one side, and agar alone at the periphery of the opposite side of the dish as a control. Motility is then quantified by daily assessment of cell density at predetermined distances from the periphery of the center cells, and cellular velocities can be estimated. Investigations have revealed that cells from malignant human glial neoplasms migrated farther in this assay than cells from lower grade human glial neoplasms or non-neoplatic human glia, and therefore results from this methodology demonstrate the correlation between the clinical and in vitro behavior of the glioma cells tested [51]. Assessment of laminin production Utilizing a modified Boyden chamber assay laminin has been demonstrated to be a strong chemoattractant and a substrate for attachment for invasive glioma cells in culture [53]. Assessment of laminin production in vitro using a quantitative enzyme immunoassay is, therefore, considered to be a potential assay of the invasive potential of glioma cells because of the potential importance that laminin has for the attachment phase of invasion [54]. This method begins to address the biochemical and mechanical process by which growth factors increawe the motile and invasive properties properties of glioma cells.

Summary of the effect of cytokines on glioma motility EGF EGF is of particular interest in light of the amplified expression of its receptor, EGF-R in glioma cells [26, 29, 55, 56], especially in more malignant tumors [23, 24, 28]. The mitogenic properties of EGF en-

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252 hance tumor mass formation [19], while the locomotion-promoting effects, likely promote brain invasion. As summarized in Table 1, EGF promoted migration, invasion, ruffling of cellular membranes, and laminin production in most of the cell lines tested [19, 43, 46, 52, 53, 57]. Additionally, antibodies against the EGF receptor (anti-EGF-R) prevented EGF stimulated invasion [46]. Interestingly, Bressler et al. demonstrated no effect of EGF on migra-

tion of non-neoplastic rat astrocytes in a modified Boyden chamber [41]. Perhaps it is the amplified expression of EGF receptors on transformed astrocytes (i.e. glioma cells) that leads to their enhanced motility and invasion in rresponse to EGF. TNF The monocyte derived TNFs (α and β) demonstrate in vivo cytotoxicity against various tumors, antiviral

Table 1. Summary of the effects of mitogens on motility and invasion of glia and glioma cells in vitro Mitogen

Investigation

Cell type

Assay

Motility change

EGF

Westermark [19] Engelbraaten [57] Lund-Johansen [45] Lund-Johansen [46]

human glioma human glioma human glioma human glioma

A, F B, C B, C B, C

Pedersen [43]

human glioma

B, C

Chicoiine [52] Koochekpour [54] Bressler [41] Engelbraaten [57] Lund-Johansen [45] Pedersen [43] Chicoine [52] Bressler [41] Koochekpour [54] Engelbraaten [57] Chicoine [52] Bressler [41] Engelbraaten [57]

human glioma human glioma rat astrocytes human glioma human glioma human glioma human glioma rat astrocyte human glioma human glioma human glioma rat astrocyte human glioma

E H G B, C B, C B, C E G H B, C E G B, C

Lund-Johansen [45] Pedersen [43] Mellstrom [50]

human glioma human glioma human glia

B, C B, C D, F

Noble [16]

O2A cell

D

Chicoine [52] Bressler [41] Chicoine [52]

human glioma rat astrocyte human glioma

E G E

Pedersen [43] Nakano [40] Koochekpour [54] Merzak [42] Pedersen [43]

human glioma human glioma human glioma human glioma human glioma

B, C G H G B, C

↑ random migration, ↑ ruffling leading edges ↑ migration (5 of 8 cell lines), ↑ invasion (7 of 8 cell lines) ↑ migration and invasion ↑ migration (3 of 3 cell lines), – blocked by EGF-R antibody (3 of 3 cell lines), ↑ invasion (1 of 2 cell lines), EGF-R antibody ↓ invasion (2 of 2 cell lines) ↑ migration (5 of 5 cell lines), and ↑ invasion (2 of 5 cell lines) chemoattractant effect ↑ production of laminin no effect ↑ directional motility (3 of 8); ↑ iinvasion (2 of 8) ↑ migration, no effect on invasion ↑ migration (4 of 5 cell lines), no effect on invasion chemodeterrant effect no effect ↑ production of laminin ↑ migration (1 of 5 cell lines), no effect on invasion chemodeterrant effect no effect on invasion PDGFbb – ↑ migration (1 of 3 cell lines), had no effect on invasion PDGF(aa&bb) – no effect on migration or invasion PDGFbb – ↑ migration, and invasion ↑ ruffling & pseudopod formation (dimer subtype not specified) PDGF(aa&bb) – ↑ random motility – blocked by antibody to PDGF PDGFbb had chemodeterrant effect chemoattractant (dimer subtype not specified) initial chemodeterrant effect followed by chemoattractant effect ↑ migration (3 of 5 cell lines), no effect of invasion ↑ invasion ↑ production of laminin ↑ migration (3 of 3) and invasion (2 of 3) no effect on migration or invasion

bFGF

NGF

PDGF

TNFα TGFα TGFβ1

IL-2

↓ – decreased, ↑ increased; O2A cells – rat neuroglial progenitor cells; A – colloidal gold cell tracking; B – migration from spheroid; C – glioma/brain spheroid confrontation culture; D – time lapse video microscopy; E – modified radial dish assay; F – electron microscopy; G – modification of Boyden chamber; H – assessment of laminin production.

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253 activity, immune response modulation, stimulation of angiogenesis, and enhancement of epithelial tumor cell migration [58]. TNF (subtype not specified) was also shown to promote release of PDGF from endothelial cells [59]. In the modified radial dish assay, TNFα decreased migration over the first 24–48 hours, but than increased directional locomotion over the remainder of the seven day test period (Table 1). The reasons for this bimodal effect were not readily apparent, but possible explanations can be derived from previous studies. Exposure to a cytokine may modulate cellular production of other cytokines or their receptors. For example, Helseth et al. found that beta transforming growth factor (TGFβ) downregulated EGF-R expression in glioblastoma cells during the initial 6 hours following cell exposure, but during the subsequent 24 hours, TGFβ upregulated EGF-R expression [60]. TNFα might inhibit glioma cell motility while at the same time amplifying production of other cytokines of their receptors (e.g. EGF, EGF-R), which would subsequently enhance glioma cell motility. Alternatively, different TNFα receptors could be mediating the two different glioma motility responses to TNFα. Temporal changes may exist in local TNFα concentration in the modified radial dish assay because of TNFα degradation and/or further elution of TNFα from the agar, might lead to preferential stimulation of different TNFα receptors at different times. PDGF PDGF, discovered in megakaryocytes, appears to be the most powerful in vitro mitogen for gliomas [61], as well as for other cell types of mesenchymal origin [62]. PDGF is a dimer of two polypeptides linked by two disulfide bonds, and has three forms: aa, ab and bb [63]. In addition to its mitogenic properties, PDGF mediates inflammatory responses and wound repair [62], both of which play a role in the central nervous system response to neoplastic insult and to the surgical interventions that are commonly employed for gliomas. The negative effect of PDGFbb upon glioma locomotion demonstrated with the modified radial dish assay was in counterdistinction to the results of other investigators that showed PDGF (bb and ab) elaboration by type 1 astrocytes promoted motility in the type 2 astrocyte

(O-2A) progenitor cells utilizing time lapse video microscopy [16] (see Table 1). The apparent conflicting results may lie in the biologic differences between the progenitor cells (O-2A), and neoplastic glioma cells. Other investigators have found no effect of PDGF (aa or bb) on human glioma cell motility and invasion [44, 57]. bFGF Like EGF and PDGF, bFGF has a pronounced mitogenic effect upon gliomas as well as glia of fetal or neonatal origin [61]. bFGF also promotes angiogenesis, indicating a possible role in modulation of the neovascularity that accompanies glial neoplasms [18]. In studies using co-cultures of human glioma spheroids and aggregates of fetal brain, investigators showed that bFGF had a positive effect on the invasion of 2 of 8 gliomas, and the directinal migration of 3 of 8 gliomas [57] (Table 1). Further investigations with spheroid co-culture invasion experiments confirmed these restuls [44]. However, Pedersen et al. demonstrated no influence upon glioma invasion by bFGF [43]. The modified radial dish assay demonstrated a deterrent effect of bFGF upon cell motility. Given the variable responses among different gliomas by other investigators, results may be specific to the cell line tested. NGF NGF has well characterized roles in development, maintenance, and regeneration of the mammalian nervous system [64]. NGF also has reverse transforming properties which cause neurogenic tumor cells to resume normal patterns of cellular differentiation in vitro [64, 65], and inhibits glioma growth [66]. NGF receptors exist in two forms, high and low affinity, the latter having been shown to be upregulated in C6 rat glioma cells by the neurotrophins it binds (NGF, brain derived growth factor, and neurotrophin-3) [67]. The modified radial dish assay demonstrated that NGF has a chemo-deterrent effect on glioma cells [52]. In confrontation cultures NGF did not effect invasion, and in assays of spheroids, migration was increased in only 1 of 5 glioblastoma cell lines [57] (Table 1). In investigations utilizing a modified Boyden chamber, NGF had no effect upon invasion [41].

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254 TGFα The amino acid sequence of TGFα has significant homology with EGF, and has demonstrated as a stimulator of soft agar colony formation [20]. Growth factor-toxin fusion proteins using TGFα have demonstrated substantial cytotoxic effects in vitro and in vivo against malignant human glioma cells [68]. Utilizing human glioma cells in spheroid cultures, TGFα has been shown to stimulate migration, but had no effect invasion [43]. TGFβ1 Recent investigations utilizing a modified chemotaxis chamber indicate that TGFβ1 increased the invasiveness of 4 of 5 human glioma cell lines [40] (Table 1). Unpublished data from our laboratory utilizing the modified radial dish assay demonstrated an initial chemoattractant effect during the first 24 hours followed by a chemodeterrant effect over the remainder of the week long test period. Other investigators have demonstrated that TGFβ1 is a strong stimulator of invasion and migration in a modified Boyden chemotaxis chamber [42]. Additionally, TGFβ1 has been demonstrated to promote glioma cells to produce laminin which can independently function as a chemoattractant and substrate for attachment of malignant glioma cells [54]. IL-2 IL-2 is produced by CD4 ppositive T helper cells and drives the cell-mediated immune response [69]. Considerable interest in the ability of IL-2 to enhance cellular immunity has lead to clinical trials of intrathecal and intratumoral injection of IL-2 for patients with brain tumor, but there has been only limited success with this therapy [70, 71]. Studies of human glioma cells in spheroid cultures, have demonstrated no effect of IL-2 on mogration or invasion [43] (Table 1).

Discussion Three coordinated events are involved in glioma invasion into normal brain: separation of cells from the bulk tumor, hydrolysis of extracellular matrix components coupled with cell-cell interactions with

normal brain cells (glia and neurons), and locomotion through the matrix. The invasion of glioma cells into areas of the brain remote from the bulk tumor prevents complete surgical removal of these lesions [32]. Brain tumor cells are exceedingly motile both in vivo and in vitro models. Because these motile cells do not appear to enter mitosis [32, 33], cell cycle specific drugs, standard radiotherapy, and therapies that focus on the resection cavity or residual tumor are of limited therapeutic value. Furthermore, these invading cells are protected by the normal blood-brain-barrier rather than the blood-tumor-barrier, making them difficult targets for many chemotherapeutic agents. Current standards for assessing treatment efficacy are: time to tumor progression (TTP), disease-free interval (DFI) and length of survival (LOS). Both TTP and DFI rely on growth of the bulk tuor as visualized with imaging studies. These measures do not take into account the status of the invading cells which appear to play an important role in the evolution of this disease process and hence the LOS [14]. The studies discussed evaluated the effects different cytokines, IL-2, EGF, bFGF, PDGFbb, TNFα, TGFα and β, and NGF, upon a number of different rodent and human glial and glioma cell lines, using varied methodologies. The results of these studies [17, 41, 43, 44, 46, 52, 54, 57] indicate that EGF is consistently the most potent mitogen of the mitogens evaluated. EGF is of particular interest in light of the amplified expression of its receptor, EGF-R [26, 29, 55, 56] in glioma cells, especially in more malignant tumors [23, 24, 28]. The mitogenic properties of EGF enhance tumor mass formation [19], while the locomotion-promoting effects, likely promote brain invasion. TGFβ, which initially downregulates EGF-R expression in glioblastoma cells, but later upregulates EGF-R expression [60], showed a similar biphasic effect on cell motility (initial chemorepulsion followed by chemoattraction). In limited investigations TGFα has demonstrated stimulation of migration, but not invasion. PDGF appears to be one of the most powerful in vitro mitogen for gliomas [61], and in many investigations enhanced migration, and to a lesser extent, invasion. bFGF has also been shown to have a pronounced mitogenic effect upon gliomas [61], as

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255 well as an angiogenic effect [18], but the effect upon motility and invasion has been less consistent. NGF has reverse transforming properties which may induce neurogenic tumors to resume normal patterns of cellular differentiation in vitro [64, 65], and inhibits glioma growth [66], but has demonstrated only limited effects upon motility and invasion. TNFα has an initial repellent effect upon glioma movement followed by a chemoattractant effect in one assay. IL-2, an important cytokine in the regulation of cellular immunity, has not yet been shown to affect glioma cell motility of invasion. The studies discussed cannot necessarily be generalized to other gliomas or glioma cell lines, as the presence of the cytokine receptors varies among different glial tumors [23], among different clonal cell populations from the same tumor [71], and possibly among different passage (i.e. early vs. late) of the same cell line. This may explain, in part, the variation in results when using different methodologies. EGF increased migration and invasion more consistently than the other cytokines, and did so in all the different assays assessed. This consistent effect of EGF may relate to the fact that the EGF receptor gene is amplified in upto 40% of malignant gliomas, and, in fact, EGF receptor expression level has been correlated with quantitative measures of invasiveness [44]. Except for EGF, the effects of the cytokines upon glioma cell migration and invasion varied from one assay to another. This variation may have occurred because of the different cell lines tested with each assay, or possibly that each of the different assays test different components of the 3 step process of invasion. Glioma cells in spheroid experiments, for example, may be more subject to the effects of the extracellular matrix and cell-tocell interactions than in the modified radial dish in which cellular motility is relatively independent of these factors. Although, caution must used when extrapolating the results of these in vitro studies to the clinical situation, continued advances in the understanding of the locomotion of glioma cells, and the mechanisms by which cytokines modulate this locomotion, may enable the development of treatments which specifically target he invasive nature of malignant gliomas.

Acknowledgement This work was supported in part by NS67493 from the National Institutes of Health (MRC) and The McDonnell Center for Cellular and Molecular Biology Award A 26275D (DLS) and KO8 NS01730 from the national Institutes of Health (DLS).

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