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923
Specific Matrix Metalloproteinase Profiles in the
Cerebrospinal Fluid Correlated with the Presence of
Malignant Astrocytomas, Brain Metastases, and
Carcinomatous Meningitis
Marc H. Friedberg, M.D., Ph.D.1
Michael J. Glantz, M.D.3
Mark S. Klempner, M.D.2
Bernard F. Cole, Ph.D.4
George Perides, Ph.D.2
BACKGROUND. Detection in tumor tissue of specific matrix metalloproteinases
1
Department of Medicine, Tupper Research Institute, New England Medical Center, Boston,
Massachusetts.
2
Department of Neurosurgery, Tupper Research Institute, New England Medical Center,
Boston, Massachusetts.
3
Department of Medicine, University of Massachusetts, Amherst, Massachusetts.
4
Center for Statistical Sciences, Brown University, Providence, Rhode Island.
Submitted in abstract form to the Society for Neuroscience and the Society for Neuro-Oncology.
(MMPs), particularly gelatinases A and B, correlates with the grade and aggressiveness of primary and metastatic brain tumors. The ability to detect these enzymes
in the cerebrospinal fluid (CSF) would be a minimally invasive method of evaluating brain tumors.
METHODS. CSF from 66 patients with white blood cell counts of °5 mL were analyzed for the presence of gelatinolytic activity by zymography. Twenty-nine patients
had malignant astrocytomas, 10 had brain metastases from systemic malignancies,
4 had systemic cancer not involving the central nervous system, 4 had nonmalignant neurologic diseases, and 19 were healthy controls. Fifteen CSF samples had
positive cytologies. The zymographic results were retrospectively correlated with
clinical information and CSF cytologic data.
RESULTS. CSF from all patients with malignant astrocytomas or brain metastases
contained precursor gelatinase A (pMMP2) and precursor gelatinase B (pMMP9),
whereas control CSF contained only pMMP2. All patients with positive CSF cytologies had activated MMP2. A similar correlation was observed between the presence
of activated MMP9 and positive CSF cytology.
CONCLUSIONS. The precursor and activated forms of gelatinases A and B can be
detected in the CSF of patients with primary and metastatic brain tumors. The
distribution of gelatinase activity in CSF distinguishes patients with malignant
gliomas or brain metastases from those without brain tumors, and distinguishes
patients with meningeal carcinomatosis from those without CSF spread of tumor,
regardless of their brain tumor status. Analysis of MMPs in the CSF may be a
sensitive technique for diagnosing CNS tumors and provide an early indication of
tumor recurrence. This technique may also provide longitudinal information that
would be useful in evaluating ongoing treatment and predicting tumor behavior.
Cancer 1998;82:923–30. q 1998 American Cancer Society.
Supported by National Institutes of Health Grant
NO1 AI 65308 and a grant from the Anna and
Ida Reiss Memorial Fund.
KEYWORDS: matrix metalloproteinases, brain tumor, cerebrospinal fluid, carcinomatous meningitis.
The authors thank Linda Tanner for technical
support.
D
Address for reprints: George Perides, Ph.D.,
New England Medical Center #41, 750 Washington St., Boston, MA 02111.
Received June 26, 1997; revision received September 18, 1997; accepted September 18, 1997.
espite decades of intensive investigation, the prognosis of patients
with malignant gliomas and brain metastases remains poor.1 – 3
The ability of gliomas to infiltrate normal brain parenchyma and
disseminate widely along cerebrospinal fluid (CSF ) and white matter
pathways are key factors accounting for the resistance of these tumors
to currently available therapies.4 – 7 Similarly, the development of brain
metastases from a systemic cancer remains an ominous and in almost
all cases a rapidly fatal event.
q 1998 American Cancer Society
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W: Cancer
924
CANCER March 1, 1998 / Volume 82 / Number 5
Compelling in vitro and in vivo evidence supports
the concept that invasion, angiogenesis, and successful metastasis to the brain, as well as the spread of
tumor into the CSF depend on the ability of tumor cells
to degrade and migrate through the brain extracellular
matrix (ECM).8 – 13 The ECM of the mature brain, and
in particular its most abundant proteins, versican and
glial hyaluronate binding protein (GHAP), are not permissive to neuronal migration, axonal growth, or cell
attachment.13 – 17 Primary brain tumors and systemic
cancers secrete matrix metalloproteinases (MMPs),
which can digest the versican and GHAP portion of
the ECM.14,15,18,19 Metastatic potential, tumor growth,
and invasiveness have been correlated with MMP expression and with degradation of ECM in melanoma
and in breast, bladder, ovarian, colon, small cell lung,
prostate, and brain cancers.20 – 24 A subset of MMPs,
the gelatinases, have been correlated quantitatively
with the aggressiveness of primary and metastatic
brain tumors and with the ability of gliomas to migrate
along myelinated tracts in the central nervous system
(CNS). Thus, the greater the gelatinolytic activity
within the tumor specimen, the more malignant the
behavior of that tumor.24 – 26
Until now, the application of MMP analysis to oncology has been limited to the measurement of MMP
levels in tumor tissue specimens.25 – 27 In this report,
we describe characteristic MMP profiles in CSF from
patients with primary and metastatic brain tumors and
meningeal carcinomatosis. We also describe the potential utility of this less invasive procedure for diagnosing CNS cancer, detecting recurrence, monitoring
response to treatment, and predicting tumor behavior.
MATERIALS AND METHODS
CSF Specimens
Sixty-six CSF samples from patients with biopsyproven primary or metastatic brain tumors, cytologyproven meningeal carcinomatosis, nonmalignant nervous system disorders (‘‘controls’’), systemic cancer
without CNS involvement, and healthy individuals
(CSF from spinal anesthesia) were obtained from a
CSF archive (Tables 1, 2). Inform consent was obtained
from all patients for the collection of CSF. No patients
had ventriculoperitoneal shunts, and two control patients had normal-pressure hydrocephalus. All CSF
specimens were placed in polyethylene tubes and
stored in a freezer at 070 7C within 15 minutes of
sample acquisition, until they were withdrawn for
MMP analysis. Cell count data was available for all
CSF specimens. Specimens with a white blood cell
(WBC) count of ú5/mm3 were excluded from the study
to avoid false elevations of MMP levels secondary to
an increased WBC count.28 In addition, large-volume,
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TABLE 1
Patient Characterization
Patient group
GBM/AA
Brain metastases
Systemic tumors only
Nonmalignant
neurologic disease
Healthy controls
Total
Positive CSF
cytology
Negative
CSF cytology
Total
10
5
0
19
5
4
29
10
4
0
0
15
4
19
51
4
19
66
CSF: cerebrospinal fluid; GBM: glioblastoma multiforme; AA: anaplastic astrocytoma; Brain metastases:
lung, breast, and melanoma; Systemic tumors only: lymphoproliferative cancer without CNS involvement; Healthy controls: asymptomatic and radiographically normal patients; Nonmalignant neurologic
disease: isolated cranial nerve VI palsy (1 patient), normal pressure hydrocephalus (2 patients), and
dementia (1 patient).
optimally handled CSF aliquots were examined cytologically for malignant cells at the time the CSF was
obtained.29
SDS-PAGE Zymography
CSF samples were subjected to zymography as described previously.18,30 Briefly, electrophoresis in 0.5%
gelatin was performed at 4 7C on 16 mL of CSF supplemented with 4 mL of 51 sodium dodecyl sulfate sample
buffer without b-mercaptoethanol. After 1 hour of incubation at room temperature in 2.5% Triton 1-100,
the gels were incubated for an additional 40 hours at
37 7C in 20 mM Tris acetate, pH 7.5. Gels were then
stained for 1 hour with Coomassie brilliant blue R-250
and then destained in 10% acetic acid 5% methanol
overnight. Stained gels were photographed with an
MP-4 Polaroid system. An internal control was included in all zymograms, which contained gelatinase
A and B in both precursor and activated forms.
MMP Analysis
The presence of activated and latent MMP2 and MMP9
and the 130 kDa and 250 kDa gelatinases were identified by three independent observers based on the presence or absence of the gelatinolytic activity. All three
scorers were blinded to diagnosis and other patient
characteristics.
Immunoblot
Immunoblot analysis was performed after protein
transfer according to the method of Towbin et al.31
on polyvinyldifluoride membranes as described previously.14 We have shown that a monoclonal antibody
raised against gelatinase A recognizes isolated gelatinase and the 72 kDa gelatinase on immunoblot
W: Cancer
CSF Matrix Metalloproteinases in CNS Cancer/Friedberg et al.
925
TABLE 2
Gelatinolytic Activity in Patients with CNS Cancer
Patient
no.
Age/
gender
DX
CSF cyt
PMMP2
MMP2
PMMP9
MMP9
130kDa
250kDa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
42/M
61/F
67/F
25/F
33/F
61/F
30/F
64/F
27/M
41/M
73/M
58/F
79/M
58/F
48/F
76/M
64/F
59/F
71/M
54/M
75/F
56/F
60/F
23/M
79/F
55/M
57/M
34/M
30/F
30/F
23/M
48/F
34/M
32/M
43/M
65/F
41/F
73/F
86/F
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
AA
AA
Mel
SCLC
SCLC
SCLC
Breast
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
GBM
AA
AA
AA
AA
AA
AA
SCLC
Breast
Breast
Breast
Breast
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Pos
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
Neg
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
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/
/
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/
/
CNS: central nervous system; DX: histologic diagnosis; GBM: glioblastoma multiforme; AA: anaplastic astrocytoma; SCLC: small cell lung carcinoma; Breast: breast carcinoma; Mel: melanoma; Pos: positive; Neg:
negative; CSF cyt: cerebrospinal fluid cytology.
analysis.30 To determine whether the 92 kDa gelatinase found in the CSF was gelatinase B (MMP9), we
employed immunoblot analysis on CSF proteins and
human recombinant gelatinase B. A monoclonal antibody raised against human gelatinase B recognized
the 92 kDa gelatinase, showing that this was gelatinase B.
Sources of Materials
Monoclonal antibodies raised against gelatinase A
(MMP2) and gelatinase B (MMP9) were purchased from
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Oncogene Science (Uniondale, NY). Gelatin was obtained from Bio-Rad (Hercules, CA). Biotin-conjugated
goat antimouse antibody and avidin-conjugated alkaline phosphatase were purchased from Vector (Burlingame, CA). Polyvinyldifluoride membranes were obtained from Millipore (Bedford, MA). Gelatinase A was
isolated from mouse 3T3 fibroblasts.18 Human recombinant gelatinase A and gelatinase B were purchased
from Biogenesis (Sandown, NH). All other chemicals
were of analytic grade and were purchased from Sigma
Chemicals (St. Louis, MO).
W: Cancer
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CANCER March 1, 1998 / Volume 82 / Number 5
FIGURE 1.
Twenty-five mL of CSF were
subjected to zymography, as described in
the ‘‘Materials and Methods’’ section. The
samples were from a healthy individual
(Lane 1), a patient with headache and negative workup (Lane 2), two patients with
lymphoproliferative disorders without central nervous system involvement (Lanes 3
and 4), a patient with normal pressure hydrocephalus (Lane 5), one with anaplastic
astrocytoma with negative cytology (Lane
6), one with glioblastoma multiforme and
negative cytology (Lane 7), one with anaplastic astrocytoma and positive cytology
(Lane 8), one with glioblastoma multiforme and positive cytology (Lane 9), and
one with leptomeningeal carcinomatosis
(Lane 10). Arrowheads point to activated
gelatinases.
MMP Identification
The electrophoretic mobilities reported by different
laboratories for the various gelatinases vary somewhat.18,25,28,32 – 34 Based on immunologic results and activation patterns from our and others’ laboratories,
we concluded that the gelatinase reported to have an
electrophoretic mobility at 72 kDa was pro-MMP 2
(pMMP2); at 64 kDa, activated MMP2; at 92 or 100
kDa, pro-MMP 9 (pMMP9); and at 84 kDa, activated
MMP9. The two additional gelatinolytic bands with
electrophoretic mobilities of 130 kDa and 250 kDa will
be referred to as the 130 kDa and 250 kDa gelatinases.
The 130 kDa band may be a complex of gelatinase B
and TIMP135 – 37 or a dimer of the active 68 kDa form
of gelatinase B.38 The 250 kDa gelatinase is also believed to be a derivative of gelatinase B.39
Statistical Analysis
Fisher’s exact test was used to compare patient groups
in terms of gelatinase activity rates. All P values were
two-sided.
RESULTS
Zymography gels illustrating the MMP profiles of CSF
samples from patients with primary and metastatic
brain tumors, meningeal carcinomatosis, and nonmalignant neurologic disorders are reproduced in Figure
1. There was complete concordance between all three
observers who evaluated all the gels for the presence
of gelatinase activity. The results of all 66 assays, along
with clinical information on individual patients, are
given in Tables 2 and 3.
Pro-MMP2 was detected by zymography in all pa-
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tients, those with cancer and those without. ProMMP9 was found in the CSF of all patients with brain
tumors, whether primary (29/29) or metastatic (10/
10), and in none of the control patients not bearing
brain tumors (4 with systemic cancer, 4 with neurologic disease, and 19 healthy controls) (0/27). In a different study, we described the MMP levels in the CSF
of 131 patients with Alzheimer’s disease, multiple sclerosis, lymphoproliferative disorders without CNS
involvement, inflammatory diseases, strokes, metabolic encephalopathies, and normal neurologic controls (patients with neurologic complaints but normal
CSF and imaging data).30 The CSF of 103 patients had
WBC counts of õ5/mL, and only 6 contained proMMP9 gelatinase. These results indicated a significant
increase in gelatinase activity (pro-MMP9) for patients
with primary and metastatic brain tumors as compared with controls not bearing brain tumors (P õ
0.0001 in both cases). A similar, though less striking,
pattern was observed with the 250 kDa gelatinase activity: 18 of 29 patients with malignant astrocytomas
and 7 of 10 patients with brain metastases had detectable activity in their CSF, whereas none of the 27 patients without brain tumors had such activity.
In contrast, activated MMP2 was found only in
patients with meningeal carcinomatosis and in one
patient with anaplastic astrocytoma and negative CSF
cytology. This patient (No. 33) had compelling magnetic resonance imaging (MRI) scan evidence of leptomeningeal tumor spread. Similarly, activated MMP9
was present in 10 of 15 patients with positive CSF
cytologies, no patients with nonmalignant disorders,
and only 1 patient (No. 19) without a positive cytology.
W: Cancer
CSF Matrix Metalloproteinases in CNS Cancer/Friedberg et al.
927
TABLE 3
Gelatinase Profiles of CSF Samples from All Patients
Primary or metastatic brain tumors
Control patients
MMP activity
CSF cytology
positive
(n Å 15)
CSF cytology
negative
(n Å 24)
Nonmalignant
neurologic disease
(n Å 4)
Systemic tumors without
CNS metastasis
(n Å 4)
Healthy controls
(n Å 19)
pMMP2
MMP2
pMMP9
MMP9
130 kDa
250 kDa
100%
100%
100%
67%
100%
100%
100%
4%
100%
4%
88%
42%
100%
0%
0%
0%
50%
0%
100%
0%
0%
0%
25%
0%
100%
0%
0%
0%
11%
0%
CSF: cerebrospinal fluid; CNS: central nervous system; pMMP2: precursor gelatinase A; MMP2: activated gelatinase A; pMMP9: precursor gelatinase B; MMP9: activated gelatinase B; 130 kDa: 130 kDa gelatinase;
250 kDa: 250 kDa gelatinase.
This patient (No. 19) also had a head MRI scan that
was strongly suggestive of CSF tumor dissemination.
DISCUSSION
The ability of primary brain tumors to infiltrate normal
brain parenchyma and the ability of systemic cancers
to metastasize to the brain remain unanswered challenges despite advances in other areas of oncology.
Under normal circumstances, versican and GHAP, the
most plentiful components of the brain’s ECM, inhibit
tumor cell attachment, cell growth, and cell migration.13,16,17 This barrier is overcome during the course
of glial scar formation.40
MMPs belong to a growing family of zinc- and
calcium-dependent endopeptidases with varying substrate specificities.42 – 44 The activity of MMPs is meticulously controlled and depends on the balanced action
of transcriptional regulators, activators, and inhibitors
and certain other normal cellular processes (e.g., ovulation, implantation, and bone remodeling) by the
carefully orchestrated synthesis, activation, and inhibition of MMPs.41 MMPs are secreted in latent form
and can subsequently be activated by plasmin and
other serine proteinases and metalloproteinases. Conversely, endogenous proteins known as tissue inhibitors of metalloproteinases (TIMP 1, 2, and 3) can inactivate MMPs by forming high-affinity complexes with
them. The expression of MMPs is transcriptionally regulated by cytokines (e.g., interleukin-1 and tumor necrosis factor-a), growth factors, glycocorticoids, matrix
interactions, and tumor transformation.42 – 44 In cases
of primary and metastatic brain tumors, however,
MMPs are overproduced and activated.24,45 The increased MMP levels in primary brain tumors and brain
metastases appear to promote the digestion of brain
ECM and facilitate tumor metastasis and invasion.10,20
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A similar correlation between increased MMP levels
and increased malignant behavior has been described
for numerous systemic cancers, including prostate adenocarcinoma, melanoma osteosarcoma, nonsmall
cell lung carcinoma, and carcinomas of the colon,
bladder, ovary, and breast.21 – 23,46 – 52
In the current study, we have shown that MMP
profiles can be reliably detected from microliter volumes of CSF. In addition, we found that specific MMP
profiles correlate with specific clinical situations. Thus,
although pro-MMP2 is present in the CSF of all patients assayed, pro-MMP9 is present only in patients
with primary or metastatic brain tumors. A similar correlation is observed between the presence of 250 kDa
activity and brain tumors. In contrast, activated MMP2
seems to be a marker for meningeal carcinomatosis.
The presence of activated MMP9 activity in the CSF
also correlates with the presence of malignant cells.
These CSF findings parallel results obtained with brain
tumor tissue: normal brain demonstrates only pMMP2
activity, whereas brain tumors express both pMMP2
and pMMP9 activity.19,25,27
There are several caveats associated with our results. WBCs secrete MMPs, and increased numbers of
WBCs in the CSF are associated with increased levels
of pMMP9.28,53 To avoid this potentially confounding
situation, we excluded all CSF samples with WBC
counts above 5/mL. We also analyzed other substances
in the CSF that may have contributed to increased
MMP levels. No correlation was found between protein or glucose and MMP levels. Repeated freezing and
thawing can lead to the appearance of activated forms
of MMPs and eventually diminished activity. Therefore, the handling of CSF specimens is critical. This
potential problem was eliminated by using CSF samples that had been frozen only once prior to zymogra-
W: Cancer
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CANCER March 1, 1998 / Volume 82 / Number 5
phy. Finally, despite negative CSF cytologies, one patient demonstrated MMP2 activity and another MMP9
activity in their CSFs. For both patients, MRI scans of
the head provided compelling evidence of meningeal
spread of tumor, and both were considered clinically
to have carcinomatous meningitis. Negative CSF cytologies in the face of characteristic MRI scans are widely
recognized, and, in the appropriate clinical setting,
such MRI scans constitute strong supportive evidence
of meningeal carcinomatosis.54,55
Our results suggest that the defining characteristics of malignancy in both primary brain tumors (invasiveness) and brain metastasis (the ability to metastasize successfully) depend on the ability of these tumors
to produce increased amounts of activated MMPs. We
have shown that these MMPs can be detected in the
CSF, and that specific MMP patterns correlate with
the presence of brain tumors and the presence of meningeal carcinomatosis. CSF is easily obtained by relatively noninvasive means, and recent experience has
shown that lumbar punctures can be performed safely
in patients with supratentorial brain tumors.2,6,56 Patients with tumors that preclude lumbar puncture usually have surgical resection, and CSF can be obtained
at the same time. CSF analysis for MMP content may
contribute to the diagnosis of primary brain tumors
and brain metastases. More importantly, this approach may provide early evidence of tumor recurrence or malignant change and an early indication
of response to therapy; for these purposes, currently
available neuroradiographic techniques are often inadequate or cumbersome.57 – 60 Finally, for diseases in
which median survival is short but in which an appreciable minority of patients with malignant gliomas,61
brain metastases,2 and meningeal carcinomatosis62
enjoy remarkably long survivals, MMP analysis of CSF
specimens may facilitate prognostication and may
even determine a target for therapy.63 – 65 Longitudinal
studies are underway to determine whether the MMP
profiles of patients with intracranial tumors can be
diagnostic of tumor recurrence and/or response to
treatment. Additional investigations are currently underway to explore these possibilities, and we suggest
that analysis of MMPs in the CSF may represent an
important diagnostic and monitoring advance for patients with CNS cancer.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
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