Pathophysiology of Meningiomas

Brian Ragel, M.D.1 and Randy L. Jensen, M.D., Ph.D.1,2,3

ABSTRACT

This article provides a brief description of the current knowledge of meningioma

tumorigenesis and biology. Meningioma grade, subtyping, histology, and MIB-1 labeling
index are discussed in relationship to tumor behavior and recurrence prediction. Chromo-
somal abnormalities associated with meningioma development are discussed with an em-

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phasis on chromosome 22 and the neurofibromatosis type 2 gene. The current knowledge
of prognostic features of 1p deletions is outlined. The role of sex hormones in menin-
gioma growth and development is also discussed and summarized. To date, treatment
regimens based on inhibiting hormonally mediated meningioma growth have been disap-
pointing. Research concerning growth factors and peptide hormones that have been im-
plicated in meningioma tumorigenesis is discussed. It is hoped that further understanding
of the biology of meningioma development, growth, and angiogenesis will lead to new
successful treatments for refractory meningiomas.

KEYWORDS: Meningioma tumorigenesis, tumor grading, histology, prognosis

Objectives: Upon completion of this article, the reader should be able to: (1) list the WHO grading for meningiomas; (2) describe the
decisive step in meningioma progression to a higher grade; and (3) summarize current thinking on hormone receptor staining.

T he term meningioma was first coined by Har-
vey Cushing to describe a benign tumor arising from
the central nervous system meninges.1 Meningiomas
account for ~20% of all primary adult intracranial tu-
mors. The vast majority of meningiomas occur in pa-
tients 50 to 60 years of age, with a twofold higher in-
cidence in females.2 Advances in brain imaging and
neurosurgical techniques have allowed safe removal of
the majority of meningiomas. However, the intrinsic bi-
ology of a given meningioma remains the main factor in
determining the overall outcome of the patient with this
lesion.
Meningiomas are slow-growing tumors derived
from specialized meningothelial cells called arachnoid
cap cells (Fig. 1). The meninges have two separate em-
bryologic origins. Neural crest cells give rise to the te-
lencephalic meninges, whereas mesoderm gives rise to
the remaining meninges. Despite the meninges’ dual
embryologic origin, no differences are noted in the clin-
ical behavior or tumor histologic subtype of menin-
giomas as related to tumor location.3 Arachnoid cap
cells show the greatest abundance within arachnoid
villi, but the rest of these cells are present throughout
the cranial spinal arachnoid space, including the
choroid plexus and tela choroidea.4 This explains their
common occurrence in the parasagittal region (25%)
and over the cerebral convexities (20%) and why they
occasionally occur within the ventricles (< 2%). Other

Meningiomas: Contemporary Treatment; Editor in Chief, Winfield S. Fisher III, M.D.; Guest Editor, Gail L. Rosseau, M.D. Seminars in
Neurosurgery, volume 14, number 3, 2003. Address for correspondence and reprint requests: Randy Jensen, M.D., Ph.D., Department of
Neurosurgery, University of Utah, 3B-409 SOM, 30 North 1900 East, Salt Lake City, UT 84132–2303. E-mail: randy.jensen@hsc.utah.edu.
1Department of Neurosurgery, University of Utah, Salt Lake City, Utah; 2Neurosurgical Section, Surgical Service, Department of Veterans

Affairs (VA), Salt Lake City Health Care System, Salt Lake City, Utah; 3Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
1526-8012,p;2003,14,03,169,186,ftx,en;sns00164x.
169
170 SEMINARS IN NEUROSURGERY/VOLUME 14, NUMBER 3 2003
Figure 1 H&E-stained slide of arachnoid villi at 40  magnifi-
cation, showing arachnoid cap cells.
locations include the sphenoid ridge (15%), olfactory
groove (5%), and posterior fossa (10%).5
TUMOR GRADING AND PREDICTION
OF RECURRENCE
Meningiomas are graded as benign (~92% of menin-
giomas), atypical (6%), and atypical or malignant (4%)
(Table 1).6,7 The grading of meningiomas takes into ac-
count both the tumor subtypes known to have a higher
rate of recurrence and specific histologic features sug-
gesting a more aggressive biology.4 There are 13 histo-
logic variants of meningiomas differentiated by their
histologic features on hematoxylin and eosin–stained
sections.4,8 Nine of these variants are considered low-
grade tumors (grade I), whereas the clinical aggressive-
ness of the remaining four warrants a higher grade
(Table 1).4 Classification of an atypical meningioma
(grade II) is made by demonstrating either brain inva-
sion, a mitotic index of 4 per 10 high-powered field
(HPF), or three of the five following features: sheeting
architecture, hypercellularity (> 53 nuclei per HPF),
macronuclei, small cell formation, or micronecrosis with
pseudopalisading. An anaplastic meningioma (grade III)
is diagnosed by having either a mitotic rate of 20 per 10
HPF or histologic features resembling those of sarcoma,
carcinoma, or melanoma.4
Meningioma grading has significance for predic-
tion of aggressive behavior and recurrence after surgical
resection. The 5-year recurrence rate after complete sur-
gical removal for benign tumors is 2 to 3%, compared
Table 1 Pathological Classification of Meningiomas
(World Health Organization Classification 2000)
I Typical:
Meningothelial; fibrous; transitional; psammomatous;
angiomatous; microcystic; secretory; lymphoplasmacyte-
rich; metaplastic
II Atypical:
Choroid; clear cell
III Anaplastic:
Papillary, rhabdoid
Based on WHO Classification 2000.8
with 38 to 50% for atypical and 33 to 78% for anaplastic
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meningiomas.6,9 The median times to recurrence are
3.1–7.5, 2.4–3.3, and 3.5–7.7 years, respectively, for be-
nign, atypical, and malignant meningiomas.6,9
Immunohistochemical staining with the MIB-1
antibody (Ki-67) has been consistently shown to corre-
late with meningioma recurrence.10–12 Ki-67 is a nu-
clear, nonhistone protein expressed during the prolifera-
tion phases of the cell cycle (G1, S, G2, M) and not
expressed in the resting phase (G0). Staining with
MIB-1 gives a labeling index (LI) that allows quantifi-
cation of the number of cells dividing. Ho et al studied
83 meningioma patients with total resections who were
observed for a minimum of 10 years.11 They reported
that 52 tumors had an MIB-1 LI < 10% and none of
these recurred in 10 years. Of the 31 tumors with an LI
>10%, 97% recurred within 10 years. Korshunov et al
retrospectively stained 263 meningioma patients with
the Ki-67 antibody and noted a significantly reduced
recurrence-free survival in patients with an LI of less than
4.4%.13 Variations between MIB-1 LI values center
around differences in tissue processing and the method
of counting stained cells. An absolute value for the
MIB-1 LI is difficult to ascertain because of the vari-
ability in immunohistochemical staining between labo-
ratories. Nakasu et al examined two methods of calcu-
lating the MIB-1 LI (area of highest labeling versus
randomly selected) and concluded that a randomly se-
lected method correlated better with meningioma re-
currence (see Table 4, later in article).10
Other markers that have been reported to corre-
late with higher grade meningiomas include the bcl-2
proto-oncogene, p53, p51, alterations in tumor sup-
pressor genes, Fas-APO1 (CD95) transmembrane pro-
tein, the extracellular matrix protein tenascin, and five
novel meningioma-expressed antigens as described by
Comtesse et al.12,14–19 In the future, these markers may
provide both identification of refractory meningiomas
and “novel” therapeutic targets.

GENETIC ALTERATIONS
Cytogenetically, meningiomas are perhaps the best
studied solid tumor. Giemsa staining, fluorescence in
situ hybridization (FISH), comparative genomic hy-
bridization (CGH), and, most recently, spectral kary-
otyping (SKY ) have shed light on the most common
chromosomal abnormalities associated with menin-
giomas. Familial meningiomas are uncommon and are
usually associated with neurofibromatosis type 2
(NF2).20,21 Most meningiomas are sporadic. Deletions
of chromosome 22 are found in 54 to 78% of menin-
giomas taken from human patients, suggesting that
one or more tumor suppressor genes might reside
there (Fig. 2).22–31 The NF2 gene is also located on
chromosome 22q12.1, and the hallmark of this disease
is bilateral acoustic neuromas as well as an increased
incidence of meningiomas.32–35 In fact, the inactiva-
tion of the NF2 tumor suppressor gene is thought to
be involved in the pathogenesis of a proportion of
meningiomas.36–39
The NF2 gene codes for the schwannomin/mer-
lin protein (Moesin, Ezrin, Radixin-like protein), part
of the band 4.1 families of cytoskeleton-associated pro-
teins. Studies have demonstrated that loss of the merlin
protein results in decreased cell adhesion and tumori-
genesis.40,41 Reduced expression of schwannomin/mer-
lin is demonstrated in sporadic meningiomas.42 Bial-
lelic NF2 inactivation of mouse leptomeningeal cells
Figure 2 Proposed schematic of meningioma tumor progression. Production of vascular epidermal growth factor (VEGF) is associ-
ated with peritumoral edema. Loss of chromosome 1p is a decisive step in meningioma progression to higher World Health Organi-
zation grade. Immunohistochemically, higher grade tumors are associated with a decrease in progesterone receptor staining and an
increase in MIB-1 nuclear staining.
PATHOPHYSIOLOGY OF MENINGIOMAS/RAGEL, JENSEN 171
using Cre-mediated molecular techniques resulted in
the development of meningioma in roughly one third
of mice studied.43 This suggests that merlin loss alone
is not sufficient for meningioma development. Several
researchers have suggested the likelihood of a second
tumor suppressor gene on the q arm of chromosome
22, in close proximity to but distinct from the NF2
gene.23,44–51
Next to chromosome 22 anomalies, deletion of
the short arm of chromosome 1 is the most frequent al-
teration detected by cytogenetic analysis of menin-
giomas.52 Loss of chromosome 1p has been shown to
correlate with meningioma progression, with FISH
studies showing monosomy 1p in 70% of atypical and
almost 100% of anaplastic meningiomas.31,53–55 Clini-
cally, loss of 1p also correlates with tumor recurrence,
which was noted in 4.3% without and 30% with loss of
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1p.56 The gene lost with 1p aberrations is unknown, but
research has suggested alkaline phosphatase (ALPL) as
a possible tumor suppressor.31,56 Its location on chromo-
some 1p (1p34 → 1p36.1) and loss of function have
correlated nicely with higher grade meningiomas.31,56 In
addition to 1q loss, chromosome aberrations associated
with higher grade meningiomas include 6q, 10p, 10q,
14q, and 18q.16,57–60 Mechanisms by which these losses
aid tumor progression are unknown, but several genes
have been suggested. Membrane-associated 4.1 protein
family, DAL-1 (differently expressed in adenocarci-
172 SEMINARS IN NEUROSURGERY/VOLUME 14, NUMBER 3 2003

noma of the lung), located on 18p11.3 is suggested as a
tumor suppressor.61,62
Other chromosome abnormalities that have been
reported include 1;19 chromosomal translocation and
nonrandom loss of chromosomes 1, 6, 7, 14, 18, 19, and
20.32,63–66 Interestingly, the genes for the epidermal
growth factor receptor (EGFr) and insulin-like growth
factor II (IGF-II) (both discussed later as putative
growth factors important in tumor growth) are located
on chromosome 7.67,68 Changes in chromosome num-
ber are found in several meningiomas. Sixty percent
have been found to be hypodiploid, 33% diploid, 4.5%
hyperdiploid, and 2.5% hypotriploid.69 Complex kary-
otypes with hypodiploidy, structural rearrangements
such as ring chromosomes, dicentrics, double minutes,
and association between satellites seem to be associated
with aggressive tumor characteristics.70 Identification of
tors noticed the higher than expected incidence of
breast cancer associated with meningioma and raised
the question of hormonal dependence of menin-
giomas.77,78 A statistical association between “obesity”
and 176 patients with meningiomas has been found.
Conversion of androgens to estrogens in peripheral fat
has been hypothesized to make obese men and women
more likely to develop hormone-related tumors.79
Sex steroid receptors were discovered in menin-
giomas in 1979. In the following years, estrogen, pro-
gesterone, and, later, androgen receptors were found in
some meningiomas studied.80–84 Further studies impli-
cate estrogen binding to low-affinity, nonspecific as well
as high-affinity, specific receptors.85–87 However, the use
of more sensitive techniques revealed that there was ac-
tually little estrogen receptor binding but rather a high
percentage of meningioma cells that had progesterone

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a microsatellite instability phenotype in meningiomas
has also been described.71
SEX HORMONES
Estrogen, Progesterone, Androgen Receptors
In their description of bitemporal visual field defects
and optic atrophy associated with sellar meningiomas,
Cushing and Eisenhardt noted that one of the patients
had worsening visual symptoms during pregnancy, with
improvement upon delivery.72 The association between
pregnancy or menstruation and worsening neurological
symptoms (usually visual) was reaffirmed by several in-
vestigators over the ensuing years.73–76 Other investiga-
and androgen receptors.82,83,86,88–106 Progesterone recep-
tors have been identified from the cytosols of human
arachnoid granulations (from which meningiomas pre-
sumably originate).107 Table 2 contains a summary of all
measurements of estrogen, progesterone, and androgen
receptors in meningiomas by one of four methods: a
dextran-coated charcoal-radioligand assay, enzyme im-
munoassay, nuclear binding assay (measures biological
activity), or northern blot analysis. Discrepancies be-
tween studies may be due to the different sensitivities of
the various methods. Immunocytochemical assay has
higher sensitivity than dextran-coated charcoal but is
less sensitive than the enzyme immunoassay.108 Sum-
mation of these published studies reveals that 475 of
1963 (24%) meningiomas tested were positive for estro-

Table 2 Estrogen, Progesterone, and Androgen Receptors in Meningiomas

Reference Techniques Estrogen (%) Progesterone (%) Androgen (%)

Donnell, 1979 SGM 2/6 (66)*

Poisson, 1980 DCC 13/22 (59) 22/22 (100)
Martuza, 1980 DCC 7/10 (70) 2/3 (66)
Schnegg, 1981 DCC 10/10 (0) 4/10 (40)
Tilzer, 1982 DCC 1/6 (17) 4/6 (63)
Magdelenat, 1982 DCC 30/38(79) 39/40 (93)
Yu, 1982 EIA 4/16 (25) 9/16 (82)
Vaquero, 1983 DCC 0/13 (0) 7/13 (54)
Markwalder, 1983 DCC 0/34 (0) 23/34 (68)
Glick, 1983 DCC 4/21 (19) [frac34] (75)
Blankenstein, 1983 DCC 0/21 (0) 18/20 (90)
Hinton, 1983 DCC 4/11 (36) 6/11 (55)
Cahill, 1984 DCC 4/23 (17) 9/23 (39)
Schwartz, 1984 DCC 8/26 (31) 18/26 (63)
Markwalder, 1984 DCC 0/77 (0) 34/44 (77)
Zava, 1984 DCC 6/10 (60) 0/10 (0)
Moguilewsky, 1984 DCC 8/21 (38) 19/21 (90)
Hayward, 1984 DCC 0/22 (0) 17/22 (81)
Blankenstein, 1984 DCC 7/44 (16) 40/45 (89)
Brentani, 1984 DCC 2/6 (33) 6/6 (100) 6/6 (100)
Table 2 (Continued)
Reference Techniques Estrogen (%) Progesterone (%) Androgen (%)

Poisson, 1984 DCC 87/177 (48) 152/177 (89)

Martuzz, 1985 DCC 8/42 (19) 9/22 (41)
Jay, 1985 DCC 3/3 (100)
Courriere, 1985 DCC 0/12 (0) 10/12 (83)
Maiuri, 1986 DCC 12/14 (86) 6/9 (66)
Ironside, 1986 DCC 0/45 (0) 24/45 (53)
Blaauw, 1986 DCC 0/67 (0) 54/67 (80)
Olson, 1986 DCC 3/3 (100) 3/3 (100)
Lesch, 1986 DCC 8/70 (11) 53/70 (76)
Grunberg, 1987 DCC 1/17 (6) 11/17 (69)
Lesch, 1987 EIA 36/58 (62)
DCC 26/58 (45)
Lesch, 1987 DCC 48/54 (65) 48/54 (89)
Lesch, 1987 DCC 28/70 (40) 53/70 (76) 33/70 (47)
EIA 36/70 (51)

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Olson, 1987 DCC 1/1 (100) 1/1 (100)
Blankenstein, 1987 EIA 2/21 (9) 18/21 (86)
Benzel, 1988 DCC 0/22 (0) 19/22 (86)
Olson, 1988 DCC 8/8 (100)
Press, 1988 EIA 2/4 (50)
Halper, 1989 DCC 1/49 (2) 37/49 (76)
EIA 0/47 (0) 42/47 (89)
NB 14/42 (33) 20/29 (69)
Stojkovic, 1989 DCC 0/6 (0) 4/6 (66) 2/5 (40)
Gibelli, 1989 DCC 2/3 (67)
Lee, 1989 DCC 6/17 14/17
Adams, 1990 DCC 10/50 (20) 49/50 (98)
Piquer, 1991 DCC 1/39 (3) 32/39 (82)
Huisman, 1991 DCC 4/21 (19) 16/21 (76)
Meixensberger, 1992 DCC 3/28 (11) 18/28 (64)
Koehorst, 1992 DCC 0/6 (0) 5/6 (83)
Perrot-App, 1992 EIA 0/36 (0) 27/36 (72)
Piantelli, 1992 DCC 3/11 (27) 7/11 (64)
Brandis, 1993 EIA 0/61 (0) 37/61 (61)
Maxwell, 1993 NoBl 0/9 (0) 8/9 (88) 6/9 (66)
Carroll, 1993 NoBl 21/33 (64)
Matsuda, 1994 EIA 4/13 (31)
Bouillot, 1994 EIA 0/52 (0) 27/52 (53)
Khalid, 1994 EIA 0/34 (0) 34/34 (65)
Carroll, 1995 NoBl 26/39 (69)
Bozzetti, 1995 EIA 0/44 (0) 32/46 (70)
Bozzetti, 1995 DCC 16/99 (16) 88/103 (86)
Nagashima, 1995 EIA 28/39 (72)
Plisknow, 1995 EIA 0/1 (0) 1/1(100)
Blaauw, 1995 DCC 6/21 (29) 17/21 (81)
Blaauw, 1995 EIA 4/22 (18) 18/22 (82)
Khalid, 1995 EIA 10/15 (67)
Black, 1996 NoBl 0/33 (0) 21/33 (64) 22/33 (67)
Hsu, 1997 EIA 6/70 (8.6) 58/70 (83)
Totals Estrogen Progesterone Androgen
495/2054 1408/1812 79/134
(%) (24%) (78%) (59%)
*Above 10 fmol/mg protein considered significant.
DCC, dextran-coated charcoal, radioligand assay; EIA, enzyme immunoassay; NB, nuclear binding assay (measures biological activity); NoBl,
northern blot analysis.
173
174 SEMINARS IN NEUROSURGERY/VOLUME 14, NUMBER 3 2003
gen receptors, 1352 of 1736 (78%) were positive for
progesterone receptors, and 57 of 101 (56%) were posi-
tive for androgen receptors. Progesterone receptors have
been identified on the presumed meningioma cell of
origin: arachnoid granulation/cap cells.107
In Vitro and Vivo Studies
Varied response of meningioma cells in culture to ago-
nists and antagonists to these sex hormone receptors
have been reported. Some reports have shown that an-
drogens and glucocorticoids increase growth whereas
tamoxifen, estrogen, and progestin are without effect on
cell growth.109 Estradiol can increase growth of cells in
culture, and both progestin and tamoxifen can inhibit
the effect of estrogens.110 RU486 (an antiprogesterone)
inhibited growth of meningioma in culture, whereas es-
tradiol, progesterone, and tamoxifen stimulated growth.111
Others observed increased cell growth with estrogen
treatment and no effect with progesterone.112 Medrox-
yprogesterone, an antagonist and competitive binder to
the progesterone receptor, inhibited some in vitro growth
of meningiomas.113 In a human stem cell clonogenic
assay, 2 out of 13 tumors were sensitive to estrogen (both
were estrogen receptor negative) and 5 out of 16 tumors
were sensitive to progesterone (all had progesterone re-
ceptors).114 Progesterone, estrogen, and analogs of these
hormones produced no change in growth or DNA syn-
thesis of meningiomas in culture.115
A meningioma with both estrogen and proges-
terone receptors has been implanted into nude (athymic)
mice and treated with RU486. Slowed tumor growth
was reported, but these data were not statistically signif-
icant ( p < .41).116 In meningiomas positive for EGF re-
ceptors, progesterone increased growth after stimulation
with EGF, and mifepristone (RU486), a progesterone
antagonist, inhibited this effect.102,117,118
Clinical Studies
Six patients with inoperable or recurrent meningiomas
were treated with tamoxifen over 8 to 12 months without
detectable treatment efficacy as evidenced by computed
tomography (CT), scintigraphy, or clinical improve-
ment.119 Of 19 patients with unresectable meningiomas
treated with tamoxifen, one experienced a “partial re-
sponse” and another had a “minor response” as indicated
by magnetic resonance imaging.120 Medroxyprogesterone
acetate (MPA, Depo-Provera) was given preoperatively
and observed to decrease progesterone receptor number
and Ki-67–positive cells when tested after a second resec-
tion in three patients as compared with tissue from the
first operation.121 MPA given to five patients with previ-
ously resected, recurrent meningiomas (four benign, one
anaplastic), which were deemed inoperable, resulted in no
change in size or necrosis of the tumor on CT scans.122
Others have demonstrated no effect on meningioma
growth in nine patients treated with MPA over a 12-
month period.123 Mifepristone (RU486) has been used
clinically in similar situations with modest success.124–127
A Southwest Oncology Group (SWOG) trial using
RU486 for recurrent meningiomas was undertaken, but
currently results are unavailable. There is a case report of a
in situ, de novo meningioma that showed progression on
imaging studies after the placement of a subcutaneous
contraceptive implant containing a progesterone ago-
nist.128 Mifepristone and a new, more potent antiproges-
terone agent, onapristone, have been shown to decrease
meningioma cell growth in culture as well as in a nude
mouse in an in vivo model.129 Gestrinone, a pure proges-
terone antagonist with no antiglucocorticoid activity, has
been used to treat 11 patients with meningiomas that
were unchanged in size radiographically over an average
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follow-up of 38 months.130
Prolactin and Other Female Hormones
Prolactin (PRL) receptors have been demonstrated on
roughly half of tumors studied.131 Meningioma growth
in culture can be stimulated by PRL. Based on these
findings, the relationship of pregnancy and meningioma
growth has been proposed to be related to PRL stimula-
tion instead of progesterone or estrogen.132 In vitro
meningioma growth is stimulated by PRL and human
placental lactogen (hPL) and inhibited by human chori-
onic gonadotropin (hCG), luteinizing hormone (LH),
and follicle-stimulating hormone (FSH). Increasing
levels of the protein hormones PRL and hPL, falling
levels of hCG, and the absence of LH and FSH in the
second and third trimesters of pregnancy may play a
role in the acceleration of meningioma growth in these
stages of pregnancy.133
ONCOGENE EXPRESSION
Enhanced expression of the c-sis and c-myc oncogenes
in human meningiomas has been reported.21,134,135 Rare
Ha-ras and c-mos oncogenes have been shown to have a
higher occurrence in individuals with intracranial tu-
mors, including meningiomas, compared with normal
patients.136,137 Detta et al in 1993 found a greater than
70% occurrence of proto-oncogene messenger RNA
(mRNA) expression for c-myc and c-fos in meningiomas
and proposed that these nuclear transcription regulating
genes are normally under control of tumor suppression
genes, which are lost in meningiomas.138 Tumor sup-
pressor gene TP53 mutation has been considered a reli-
able marker for malignant transformation of menin-
gioma.139 Expression of the ROS1 oncogene for tyrosine
receptor kinase is commonplace in meningiomas and is
thought to play a role in the etiology of these tumors.140
 PATHOPHYSIOLOGY OF MENINGIOMAS/RAGEL, JENSEN 175

GROWTH FACTOR AND PEPTIDE In meningiomas, DNA synthesis after stimulation by

STIMULATION
Epidermal Growth Factor/Transforming
Growth Factor-
The majority of meningiomas studied have receptors
for EGF (Table 3). These receptor appear to be physi-
cally similar to previously described EGF receptors and
functional, exhibiting phosphokinase activity when
stimulated.112,141 No correlation has been demonstrated
between histopathology and the presence of EGF re-
ceptor in meningiomas.141,142 Unlike gliomas, in which
the EGF receptor is overexpressed, meningiomas have
normal expression of the gene encoding this receptor.143
Normal adult human and rat meninges do not exhibit
detectable EGF receptors but neonatal rat meninges do,
suggesting a role in development for EGF.144 These re-
EGF is not blocked by pertussis toxin; therefore, it is not
thought to be G protein mediated, as with other cells.150
A correlation between EGF receptor–positive menin-
giomas and increased phospholipase C (PLC) has been
demonstrated. These data were consistent with the possi-
bility that the EGF receptor tyrosine kinase activity regu-
lates PLC-1 activity in native meningioma tissue.151 In-
terferon- can inhibit the growth stimulation of EGF
and serum.148 The treatment of low-passage meningioma
cells with EGF results in increases in inositol triphosphate
(IP3), which is the intracellular chemical messenger that
causes calcium to be released from internal stores.152 EGF
receptors found on meningiomas are activated and inter-
act with phosphorylated Shc, an SH2 domain–containing
adapter protein that is important in traducing mitogenic
signals from EGF receptors to the nucleus via activation

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ceptors have also been demonstrated on cultured menin- of the Ras signaling pathways.153 Interferon- can inhibit
gioma cells (Westphal, 1986). Transforming growth the growth stimulation of EGF and serum.148
factor- (TGF-) is a potent agonist of the EGFr, and
this protein has been demonstrated in meningiomas
from human patients.145 Recurrent tumors have been Platelet-Derived Growth Factor
shown to have increased TGF- expression over time, Most, if not all, meningiomas appear to express platelet-
even when the tumors remained histologically benign.146 derived growth factor (PDGF) receptors (Table 4).
EGF has been shown to stimulate cell proliferation PDGF has been shown to stimulate proliferation and
and DNA synthesis in human meningioma cul- DNA synthesis in human meningioma cultures.112,154–157
tures.112,115,117,147–149 This effect can be prohibited by pro- This appears to require the mitogen-associated protein
gesterone and counteracted by antiprogesterone agents.117 kinase (MAPK) pathways in these tumors.157 Treat-
ment with PD098059 (a selective inhibitor of MAPK
phosphorylation/activation) on proliferating meningioma
cells stimulated with 10% fetal bovine serum produced
Table 3 Epidermal Growth Factor Receptors 52 to 84% loss of [3H]thymidine incorporation and in-
and Meningiomas hibition of meningioma MAPK phosphorylation even
Reference EGF Receptor after PDGF-BB stimulation.
Exposure of meningiomas to PDGF-BB results
Libermann, 1984 5/5
in significantly increased c-fos protein expression.156
Westphal, 1986 12/12
Meningiomas apparently express a particular subtype of
Weisman, 1987 2/4
receptor; the PDGFr- but not PDGFr- is found on
Shirurba, 1988 6/12
most meningiomas studied.158 PDGF-BB protein but
Grimaux, 1988 26/28
not PDGF-AA stimulates DNA synthesis; however,
Kurihara, 1989 8/8
both protein subtypes seem to be produced in human
Reubi, 1989 23/27
meningiomas.154,156,158,159 Northern blot analysis has
Reifenberger, 1989 13/15
demonstrated c-sis/PDGF-2 proto-oncogene and the
Sanson, 1989 32/32
PDGF receptor gene in meningiomas taken from hu-
Jones, 1990 21/72
Koper, 1990 4/4
Baugnet-Mahieu, 1990 45/48
Table 4 Platelet-Derived Growth Factor Receptors and
Hawkins, 1991 20/21 Meningiomas
Huisman, 1991 17/19
Reference PDGF Receptor
Torp, 1992 15 /15
Chaffanet, 1992 12/12 Maxwell, 1990 9/9
DiCarlo, 1992 17/20 Wang, 1990 3/3
Detta, 1993 18/18 Detta, 1993 18/18
Sanfilipp, 1993 16/16 Figarella-Branger, 1994 45/46
Johnson, 1994 13/19 Black, 1994 19/20
Total 335/410 (82%) Total 94/96 (98%)
176 SEMINARS IN NEUROSURGERY/VOLUME 14, NUMBER 3 2003

mans; whereas only the PDGF receptor gene, but not Table 5 Fibroblast Growth Factor Receptors
proto-oncogene, was found in control meninges.159 and Meningiomas
Studies have shown that PDGF was a component of Reference FGFr FGF
“conditioned media” produced from meningiomas in
Takahasi, 1990 20/22
culture, which could stimulate growth of both menin-
Paulus, 1990 11/11
gioma and neuroblastoma cells in serum-free cell cul-
Ueba, 1994 10/10
ture. This autocrine effect could be blocked by an anti-
Samoto, 1995 16/16
body to PDGF, especially antibodies directed toward
Totals 41/41 (100%) 16/16 (100%)
PDGF-BB.155,160 Suramin is a drug that reduces the bi-
ological activity of extracellular growth factors in a non-
specific but dose-dependent manner. This drug inhibits
growth and DNA synthesis of meningioma cells in cul-
ture. In a similar manner, trapidil, a drug with non- Glick et al first demonstrated that meningiomas
specific antagonistic action against PDGF and EGF in serum-free media showed increased growth in the
receptors, inhibits autocrine cell culture growth of menin- presence of insulin.181 IGF-I increases thymidine incor-
giomas.161,162 poration in primary meningioma cultures in a dose-
The growth of meningiomas in culture and the dependent manner.184,186 Others have found no increase

Downloaded by: University of Pennsylvania Libraries. Copyrighted material.

potent growth stimulation of meningioma cells by EGF
and PDGF are inhibited by calcium channel antago-
nists by a mechanism that appears not to involve the
calcium channel receptor signaling pathways.163–166 Sim-
ilar work was performed in vivo, but the growth inhibi-
tion demonstrated was modest and no long-term “cures”
were found.167 There is evidence that calcium channel
antagonists can potentiate the effects of chemothera-
peutic drugs. Human glioma tumor growth is inhibited
by verapamil alone and more dramatically in combi-
nation with the chemotherapeutic agent 1,3-bis(2-
chloroethyl)-1-nitrosourea (BCNU) both in vitro and
in vivo.168 In fact, the cytotoxicity of many different stan-
dard anticancer agents is augmented by calcium channel
antagonists in several tumor cell types.166,169–173 Cur-
rently, the authors of this chapter are investigating
whether calcium channel antagonists coupled with the
two chemotherapeutic agents most commonly used for
the treatment of meningioma (hydroxyurea and RU486)
might constitute a more effective treatment for growth
inhibition of meningiomas.
Fibroblast Growth Factor
All meningiomas studied to date have been shown to
express fibroblast growth factor (FGF) receptors (Table
5) as well as FGF protein.174–179 Like the other growth
factors mentioned in this article, FGF has been re-
ported to stimulate cell proliferation and DNA synthe-
sis in human meningioma cultures.112
in DNA synthesis in response to insulin. Only one of six
meningiomas showed increased DNA synthesis in re-
sponse to IGF-I when grown in the presence of proges-
terone.117 Suramin, a nonspecific inhibitor of binding of
growth factors to their receptors, can inhibit DNA syn-
thesis and the growth stimulation of IGF-I.161,187
Interest in the role that growth hormone (GH)
and IGF-I play in meningioma tumorigenesis stems first
from observations that patients with acromegaly have a
high incidence of meningiomas (1.5% in one large se-
ries) and second from studies showing involvement of
IGF-R in meningioma growth in cultures.188,189 GH is
produced and secreted from the anterior pituitary and
stimulates the synthesis of IGF-I in the liver, the com-
bined effects of which result in normal growth. In vivo
and in vitro studies have shown that the GH receptor is
ubiquitous in meningiomas and that blockade results in
decreased tumor growth.186,190 Pegvisomant is a geneti-
cally engineered protein designed to be structurally sim-
ilar to the natural human GH. It is capable of binding
to the GH receptor, acting as a competitive antagonist.
Friend found the ubiquitous expression of GH receptor
mRNA in all 14 human meningioma specimens stud-
ied. Blockade of the GH receptor with pegvisomant re-
Table 6 Insulin-Like Growth Factor Receptors and
Meningiomas
Receptors
Reference IGF-I IGF-II

Glick, 1989 9/9

Kurihara, 1989 8/8
Insulin-Like Growth Factor and Human
Lichtor, 1991 2/2
Growth Factor
Unterman, 1991 5/7
IGF-I and IGF-II receptors have been found on menin-
Antoniades, 1992 3/3 3/3
giomas.138,180–185 Seventy-seven percent of meningiomas
Glick, 1992 5/12 6/11
studied have been positive for IGF-I (30 of 39) and
Totals 30/39 (77%) 11/16 (69%)
(69% (11 of 16) positive for IGF-II (Table 6).

duced serum-induced DNA synthesis as measured by
thymidine incorporation by 8 to 33% (mean 20%).186
In studies of xenograft human meningiomas
treated for 8 weeks with pegvisomant, mean tumor vol-
ume of the treated groups was 198.3 ± 18.9 mm3 versus
350.1 ± 23.5 mm3 for the control group ( p < .02).190
The serum IGF-I concentration in the control group
was 319 ± 12.9 µg/L, compared with 257 ± 9.7 µg/L in
the pegvisomant group ( p < .02). The effects noted in
this in vivo tumor model were most likely due to both
the decrease in circulating IGF-I and the direct block-
ade of meningioma tumor GH receptors. Because this
drug is well tolerated by patients in clinical trials for ac-
romegaly, it may be a suitable drug for the treatment of
patients with recurrent or refractory meningiomas in
the future.191,192
Somatostatin
Somatostatin receptors are present on meningiomas in
high density, and the addition of somatostatin in vitro
inhibits meningioma cell proliferation.193–198 Schulz et
al developed a panel of somatostatin receptor subtype-
specific antibodies, which showed high expression of
the sst2A subtype on 40 randomly selected menin-
giomas (29 of 40 meningiomas ss2A positive, 70%). In
contrast, all other somatostatin receptors were noted to
stain weakly and sporadically. Based on these data, a
prospective study of 16 surgically resected meningiomas
was undertaken, and the level of sst2A expression was
determined using Western blot analysis. The somato-
statin sst2A subtype was readily detectable as a broad
band migrating at molecular weight 70,000 in 12 (75%)
of these 16 tumors; 8 tumors (50%) showed particularly
high levels of immunoreactive sst2A receptors. There
was an excellent correlation ( p < .001) between the level
of sst2A protein expression detected in Western blots
and the sst2A-immunoreactive staining seen in tissue
sections. The authors suggested that this immunohisto-
chemical method could prove useful in identifying re-
current meningiomas that may respond to therapy with
sst2-selective agonists.198 Garcia-Luna et al reported on
the clinical use of octreotide, a long-acting somatostatin
agonist, in three patients with unresectable menin-
giomas. Doses used were gradually increased up to
1000, 900, and 1500 µg per 24 hours during 16, 6, and 7
weeks, respectively. Patients had excellent tolerance for
the drug, with abdominal discomfort and diarrhea ob-
served in only one patient. Findings included the sub-
jective improvement of headache in two patients and
objective transient improvement in ocular movements
in one patient. In all cases, CT showed no change in
meningioma size. This report confirms the safety of
octreotide, but the study is too small to draw any mean-
ingful conclusions.193
PATHOPHYSIOLOGY OF MENINGIOMAS/RAGEL, JENSEN 177
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) has been
found within meningiomas taken from human patients;
however, only the receptors for VEGF, termed FLT-1 and
KDR, are found on the intratumoral vasculature.179,199–201
Most meningiomas studied have been positive for VEGF
protein, with 156 of 187 (84%) and two thirds (67%) pos-
itive for VEGFr (Table 7). VEGF has been thought to
play a significant role in the development of central ner-
vous system tumor neovascularity and peritumoral edema,
which is characteristic of several meningiomas.179,199,202 A
correlation between meningioma peritumoral edema and
expression of VEGF mRNA has been demonstrated.202–204
Curiously, the relationship of meningioma grade and
VEGF expression is less clear; some have found a positive
correlation.205,206 whereas others have found no difference
in VEGF expression and meningioma degree of malig-
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nancy.199,200,207–209 Even more confounding is that even in
studies that have shown a correlation between menin-
gioma grade and VEGF expression, it did not always cor-
relate with increased microvascular density, vascularity, or
invasiveness.205 On the other hand, others have shown a
high correlation between VEGF expression and neovas-
cularization in meningioma.179 A correlation between
VEGF content and meningioma malignancy grade and
lack of a correlation with microvessel density suggest that
VEGF could serve functions other than angiogenesis in
meningiomas, such as autocrine stimulation of the tumor
cells.205 This is questionable, however, because we have
shown that VEGF does not stimulate meningioma growth
in culture (R. L. Jensen, unpublished).
In a similar manner, VEGF expression and re-
currence rate of meningiomas have been correlated.210 It
has been suggested that VEGF secreted from tumor
cells might promote the proliferation of microvessels
and feeding pial arteries as well as increase edema (with
resultant adhesion to the surrounding brain tissue),
which would in turn increase recurrence of the tumor.210
This is supported by evidence showing a link between
VEGF expression, arterial tumor supply, and peritu-
moral brain edema.211 Others have suggested that
Table 7 Vascular Endothelial Growth Factor and VEGF
Receptors and Meningiomas
Receptors
Reference VEGF VEGFr
Berkman, 1993 6/7
Hatva, 1995 2/3 2/3
Samoto, 1995 16/16
Takano, 1996 2/2
Provias, 1997 13/17
Jensen, 2003 117/142 ____
156/187 (84.4%) 2/3 (67%)
178 SEMINARS IN NEUROSURGERY/VOLUME 14, NUMBER 3 2003
VEGF expression contributes to peritumoral brain
edema in meningioma only when a cerebral-pial blood
supply exists.212 Control of VEGF expression in menin-
giomas is not well understood.
VEGF expression can be increased by growth
factors such as EGF and PDGF or decreased by dex-
amethasone in meningiomas in culture.213 Hypoxia-
inducible factor-1 (HIF-1) induces the transcription of
VEGF in most cell types studied.139,214,215 We have
demonstrated that HIF-1 expression correlates with
VEGF expression in meningiomas, especially after com-
plete preoperative embolization.216
Endothelins
Endothelin (ET) is a peptide composed of 21 amino acids
with three identified isoforms (ET-1, ET-2, and ET-3).
They exert their effects through two receptor subtypes:
ET-A and ET-B. ET-1 and its receptor ET-A (ET-Ar)
and ET-B (ET-Br) protein expression has been demon-
strated in meningiomas taken from human pa-
tients.150,217–219 This expression seems to be predominately
in the capillaries of meningiomas.220 ETs are angiogenic,
potent vasoconstrictors (ET-Ar) and vasodilators (ET-Br)
and also incite mitogenesis and c-Fos expression.221,222
Thus, ET has been hypothesized to promote angiogenesis
and act as an autocrine-paracrine growth factor in cerebral
tumors, and it has been proposed that the high-affinity
ET-A receptor antagonist PD156707 may be of thera-
peutic value in treating these lesions.222
Transforming Growth Factor-
TGF- receptors are found on meningiomas and the
autocrine expression of this growth factor has been
demonstrated by these tumors.223,224 Cultured human
leptomeningeal and meningioma cells synthesize TGF-
isoforms and secrete them in a latent form in vitro.225,226
TGF- administration to cultured meningiomas results
in a reduction of DNA synthesis.175,225 Defects in the
activation of TGF- might contribute to unregulated
meningioma cell proliferation.227
Dopamine
Dopamine 1 (D1) but not D2 receptors are found in the
majority of meningiomas studied.115,118,131,228,229 Bro-
mocriptine and dopamine decrease the proliferation of
meningioma cells in culture.102,115,118
Cytokines and Interleukins
Interleukin-6 (IL-6) is secreted by meningiomas and is
found to be an inhibitory factor that produces decreased
cell growth. This effect can be modified by other cy-
tokines such as IL-4 and IL-1.230–232 IL-6 has been im-
plicated as an autocrine or paracrine inhibitory factor for
meningioma proliferation, and this inhibition is exerted
by elevated intracellular cyclic adenosine monophosphate
as a result of increased IL-6 secretion.233 Others have
found only elevated IL-10 (without IL-6) gene expres-
sion by polymerase chain reaction analysis.224
Interferon (IFN) , a leukocyte-produced cy-
tokine, is a glycoprotein that is related to TGF- and
tumor necrosis factor. The IFNs work mainly by their
antiangiogenesis effect as well as by direct tumor cell in-
hibition.234,235 Interferon has been reported to have an
effect on meningiomas in vivo and in vitro.148,235–238
Kaba et al reported on six patients with recurrent or ma-
lignant meningiomas treated with IFN--2B. Five of
the six patients had stabilization of disease progression,
with the duration of tumor stabilization ranging from 6
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to 14 months. Muhr et al looked at meningioma metab-
olism in 12 patients treated with INF-.238 This group
observed patients with serial [C]-L-methionine uptake
positron emission tomography (PET) studies and showed
stabilization of disease in nine patients. They concluded
that PET was a useful tool in determining responders to
INF treatment. In both reports, IFN treatment toxici-
ties were tolerable, with patients complaining mostly of
flu-like symptoms and leukopenia.
Miscellaneous Peptides
Receptors for glucocorticoids239–241 that appear to be
functional are as follows242: neurotensin,243,244 transfer-
rin,245 phorbol ester,246 and low-density lipoproteins,247
all of which have been found on meningiomas. Plas-
minogen activator inhibitor-1 levels were found to be
significantly lower in meningiomas than their more ma-
lignant glioma counterparts.248 Complement regulatory
protein RNA expression is altered in malignant menin-
giomas compared with the benign and atypical histo-
pathological counterparts.249 Neural cell adhesion mol-
ecule and epithelial cadherin have been suggested to
play a role in the morphogenesis and histogenesis of
human meningiomas.250 Prostaglandin D synthase has
been suggested as a specific cell marker for cells of men-
ingeal origin and implicated in the tumorigenesis of
meningiomas.251
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