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Short Communications |
From the Extracellular Matrix Section *
and the Flow
Cytometry Unit,
Laboratory of Pathology,
Division of Clinical Sciences National Cancer Institute, National
Institutes of Health, Bethesda, Maryland
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Matrix metalloproteinases (MMPs) mediate remodeling of the extracellular matrix that is requisite in normal tissue development. Altered MMP activity results in a disruption of extracellular matrix organization that is observed in many developmental abnormalities and disease-related phenotypes.6-8 The endogenous tissue inhibitors of metalloproteinases (TIMPs) negatively regulate MMP activity associated with a variety of pathological conditions. Reduction or elimination of TIMP gene expression results in enhanced extracellular matrix proteolysis concomitant with progression of many disease states, including tumor progression.9,10 In contrast, overexpression of TIMPs results in inhibition of tumor cell invasion, tumor growth, metastasis, and angiogenesis.11-15 Recent transgenic animal models have demonstrated that modulation of TIMP-1 activity in host hepatic tissues can block neoplastic proliferation in the SV40 T-antigen-induced model of hepatocellular carcinoma.16 TIMP-1 expression in this model inhibits the MMP-dependent processing of insulin-like growth factor binding protein-3, that in turn results in a decrease in the release of insulin-like growth factor II. Other studies have demonstrated that decreased hepatic expression of TIMP-1 can increase host susceptibility to liver metastasis from subcutaneous T cell lymphoma.17 The results of such studies indicate that TIMPs can indirectly suppress tumor growth in vivo through inhibition of MMP activity.16,17
However, recent data demonstrate a direct positive correlation between TIMP expression and tumor progression in breast,18 colorectal,19 lung,20 and gastric21 cancer patients. Although frequently dismissed as a nonspecific host response to the invasive activity of these tumors, several laboratories have demonstrated direct effects of TIMPs on cell growth in vitro.11,22,23 In human B-cell lymphoma patients TIMP-1 expression directly correlates with the histological grade, ie, high-grade lymphomas have a statistically significant increase in TIMP-1 transcripts compared with low-grade lymphoma tissues as determined by semiquantitative polymerase chain reaction.24 TIMP-1 expression also correlates with the latency1,25 of EBV infection in BL cells. Advanced latency (II/III) EBV-positive BL cells express TIMP-1, whereas EBV-negative cells and cells with EBV latency I do not.26 The aggressive clinical behavior of the EBV-positive BL cells is correlated with altered expression of cell differentiation and activation markers, enhanced resistance to apoptosis, as well as induction of autocrine B-cell growth factors such as interleukin-10. All of these BL tumor markers correlate with TIMP-1 expression in clinical samples.22,24,26 Furthermore, TIMP-1 expression in an EBV-negative BL cell line results in altered expression of cell differentiation markers, as well as resistance to programmed cell death.22,26 These findings suggest that enhanced TIMP-1 expression may be causally related to the aggressive phenotypic changes in human B cell tumors associated with EBV infection. These phenotypic changes associated with increased TIMP-1 expression are consistent with the clinically aggressive behavior of BL tumors in human lymphoma patients. However, these in vitro results are in contrast to the reduced tumorigenicity of human EBV-positive BL cells in the nude mouse model observed by many investigators.3,5 To resolve these divergent effects of TIMP-1 on the growth of EBV-positive (II/III) BL cells, we examined the effect of TIMP-1 expression on the in vivo growth of EBV-negative BL tumors. Our findings are the first in vivo demonstration of divergent effects of TIMP-1 on the same tumor; an early TIMP-1 tumor growth-promoting effect that is followed by a subsequent and dominant anti-angiogenic effect of TIMP-1 resulting in tumor regression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BL cell lines were a gift from Dr. Ian Magrath (Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD). The generation of overexpressing TIMP-1 clones (JD38TIMP-1) and vector control clones (JD38LXSN) by retroviral transduction of the parental JD38 BL cells has been previously described.22 Cell cultures were grown in RPMI 1640 (Life Technologies, Inc., Gaithersburg, MD) supplemented with 10% fetal bovine serum, antibiotics, and L-glutamine. Serum was removed from cultures by washing with phosphate-buffered saline (PBS) before injection into mice.
Mice
Six- to eight-week-old, female, athymic nu/nu mice (National Cancer Institute) were used. Exponential growing cells (0.5 to 0.8 x 107 cells in 0.3 ml of PBS per mouse) were injected subcutaneously into the right posterior lateral thoracic wall. Tumor growth was assessed by two-dimensional caliper measurements and recorded as cm2 every third day for 30 days. These data are presented as tumor area (mean ± SE). Statistical differences between groups were determined using analysis of variance methods.
Histology and Immunostaining
Tumors were removed frozen or fixed in 10% neutral-buffered formalin solution and embedded in paraffin. Tissue sections were stained with hematoxylin and eosin. Immunohistochemistry of tumor sections was performed using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA) for the staining of murine antigens and the M.O.M. kit (Vector Laboratories) for the staining of human antigens in murine tissue. Murine bone marrow cells were stained with appropriate antibody combinations (Becton Dickinson, San Jose, CA) for identifying cell subsets and analyzed by flow cytometry using a FACScan and Cell Quest analysis software (Becton Dickinson).
Functional TIMP-1 Assay
Supernatants from control JD38-LXSN cells and two independent clones of JD38-TIMP-1 cells were tested for TIMP-1 inhibition of gelatin digestion using reverse zymography as previously reported.27
Endothelial Cell Migration Assay
Human microvascular endothelial cells–lung (Clonetics, San Diego, CA) were labeled with 5 µmol/L of calcein-AM (Molecular Probes, Eugene, OR) in serum-free media for 2 hours at 37°C and constant rocking. After washing, cells were resuspended in tissue culture media supplemented with 0.1% bovine serum albumin. Fifty thousand cells were added to each well of a Falcon HTS Fluoroblok (3-µm pore) insert. Endothelial basal media (EBM; 200 µl) containing 10% fetal bovine serum, 50 ng/ml bFGF (Collaborative Biomedical Products, Franklin Lakes, NJ) was used as a chemoattractant in the lower wells of both positive controls and cells treated with 15 µl of JD38-LXSN and JD38-TIMP-1 supernatants or 50 nmol/L of rTIMP-1. EBM/0.1% bovine serum albumin was added to the bottom of negative control wells. After 4 hours of incubation at 37°C, the fluorescence of the cells that had migrated through the insert was measured on a plate reader (Perkin Elmer, Emeryville, CA) at 485/530 nm and compared with the fluorescence standard curve of calcein-AM-labeled human microvascular endothelial cells–lung cells at 10, 100, 1,000, 10,000, and 100,000 cells/well.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. EBV latency
II/III (AG876 and PA682) cell lines expressed TIMP-1 and developed
central tumor necrosis before regression. In contrast, EBV-negative
tumors (JD38) or tumors with EBV latency I (ST482) failed to express
TIMP-1, develop necrosis, or undergo regression. In addition, all EBV
latency II/III, TIMP-1-positive BL tumors had shorter lag period before
tumors were first detectable with an average time of 4.8 ± 1.3
days compared with 13 ± 5 days for TIMP-1-negative cell lines
(P < 0.01). These results indicate that EBV
II/III BL tumors grow faster when compared with either EBV I or
EBV-negative, TIMP-1-negative BL tumors. These representative results
suggest a strong association between TIMP-1 expression, rapid tumor
growth, and subsequent tumor necrosis.
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shows TIMP-1 inhibition of
gelatinolytic activity by two independent JD38-TIMP-1 cell clones
(clones 24 and 20) compared with the TIMP-1-positive control cell line
(HT-1080). In contrast, the JD38-LXSN control cells were negative for
TIMP-1 expression. However, a low expression of TIMP-2 is produced by
control cells that is absent in the cells with up-regulated TIMP-1. We
previously reported that JD38 untransfected cells are negative for
TIMP-1 expression.22
Figure 1B
demonstrates TIMP-1
expression in vivo by JD38-TIMP-1 tumors grown
subcutaneously in athymic nude mice, and lack of TIMP-1 in JD-38-LXSN
tumors. Immunohistochemistry using an antibody against human TIMP-1 was
used. In contrast to control JD38-LXSN tumors, intense TIMP-1 staining
was detected in the stroma of JD38-TIMP-1 tumors (compare Figure 1B
,
top panels). Control cells do not express TIMP-1 in vivo
whereas TIMP-1 is readily detected in the cytoplasm and on the surface
of JD38-TIMP-1 cells (compare Figure 1B
, bottom panels). However, in
JD38-LXSN tumors, TIMP-1 was limited to perivascular staining
consistent with basement membrane localization (Figure 1B
, bottom).
These findings clearly demonstrate that JD38-TIMP-1 cells produce
functional TIMP-1 in vitro and TIMP-1 localization can be
demonstrated in tumor cells and stroma.
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shows the growth kinetics of mice
inoculated subcutaneously with JD38-LXSN control and JD38-TIMP-1 (clone
24) cells. The JD38-TIMP-1 cells formed readily measurable tumors at 7
days after inoculation, whereas control cells required more than 10
days for measurable tumor formation. The growth kinetics of both
JD38-TIMP-1 clones in vivo was essentially identical and
similar to that of EBV III, TIMP-1+ BL cells listed in Table 1
. Similar
growth patterns for EBV-positive BL tumors have been reported by
others.4
These results indicate that JD38-TIMP-1 tumors
show faster initial growth compared with control JD38-LXSN tumors.
However, JD38-TIMP-1 tumors show signs of central necrosis before
reaching 0.4 cm2. These tumors continued to grow
through days 10 to 14 after injection and reached an average size of
0.6 cm2
before a decrease in tumor volume was
detected, as shown in Figure 2B
. In contrast, TIMP-1-negative,
JD38-LXSN tumors grew progressively without evidence of necrosis or
regression. Four weeks after inoculation, JD38-LXSN tumors reached an
average size of 1.4 cm2
and the mice became
moribund. In contrast, JD38-TIMP-1 tumors showed a marked decrease in
volume and evidence of scar formation can be observed at the
inoculation site (Figure 2B
, bottom). These mice show no evidence of
disease. The growth data reach statistical significance
(P < 0.01) by day 7 and demonstrate a bimodal
effect of TIMP-1 on the kinetics of tumor growth—an initial phase of
rapid or enhanced tumor growth followed by necrosis and tumor
regression. In summary, TIMP-1 in the absence of EBV induces initial
rapid growth in vivo followed by tumor necrosis and
regression similar to that shown by EBV-positive, TIMP-1-positive, BL
cell tumors (Table 1)
. This effect seems specific for TIMP-1 and is not
observed with the TIMP-2 expressing JD38-LXSN cells.
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shows the histology
at the onset of necrosis of JD38-TIMP-1 tumors (day 10) as well as the
histology of control JD38-LXSN tumors at the same time point. Results
demonstrate that JD38-TIMP-1 tumor regression starts with the formation
of central necrosis (Figure 2C
, top). Areas of tumor lacking necrosis
were seen at the periphery and these areas were found to consist of
viable, actively proliferative (pRb-positive) tumor cells (Figure 2C
,
middle and bottom). Moreover, few blood vessels were seen in residual
areas of viable JD38-TIMP-1 tumor cells. When compared to JD38-TIMP-1
tumors, the histology of control JD38-LXSN tumors demonstrates lack
of necrosis as well as an intense neovascularization throughout the
tumor mass (Figure 2C
, middle left, arrows). There is also a moderate
mononuclear inflammatory cell infiltrate that is confined to the
periphery of the centrally necrotic JD38-TIMP-1 tumor mass (Figure 2C
,
middle right, arrow). In contrast, a minimal mononuclear inflammatory
cell infiltrate is associated with JD38-LXSN tumors (data not shown).
These mononuclear inflammatory infiltrates were also observed by others
using similar model systems.3,5
They seem to be a reaction
to the central necrosis in the EBV-positive BL tumors and may mediate
resolution of the tumor necrosis.
JD38-TIMP-1 tumors were also analyzed after regression when scar tissue
had begun to form and were compared with control tumors of the same
age. Examination of tissue excised from the inoculation site in mice 24
days after inoculation with JD38-TIMP-1 tumor cells demonstrated the
presence of few residual tumor cells as identified by immunostaining
with antibodies against human B-cell markers (data not shown). This
small, residual, poorly organized, tumor cell mass was observed in all
JD38-TIMP-1 tumors after regression of the bulk of the tumor mass. In
contrast, at the same time point (24 days), control JD38-LXSN tumors
have continued growth and formed highly vascularized tumors.
Proliferation of residual JD38-TIMP-1 cells after tumor regression was
confirmed by immunohistochemistry using an antibody against
phosphorylated retinoblastoma protein (pRb). The positive
nuclear-staining indicates that residual JD38-TIMP-1 cells in the scar
tissue are actively proliferating (Figure 2C
, bottom right). Likewise,
control JD38-LXSN sections show viable proliferating tumor cells.
Interestingly, these control sections also demonstrate nuclear staining
of endothelial cells, indicative of active vascular proliferation of
the newly established blood vessels (Figure 2C
, bottom left, arrows).
These findings also support the conclusion that TIMP-1 does not
suppress proliferation of BL cells, either directly or indirectly, but
does alter the host response of tumor-induced angiogenesis. The lack of
tumor-induced angiogenesis limits tumor size in the JD38-TIMP-1, but
does not alter the proliferation of the small residual foci of
JD38-TIMP-1 tumor cells that may remain resistant to induction of
apoptosis secondary to the effects of TIMP-1.
To determine the role of TIMP-1 in preventing vascularization of BL,
tumor sections were analyzed for angiogenesis at day 10 before the
onset of necrosis in the JD38-LXSN tumors. Assessment of the angiogenic
responses in tumors at later time points was difficult because of the
presence of necrosis that interfered with the anti-CD31 antibody
staining. Tumor sections were analyzed for the presence of blood
vessels by immunohistochemistry using an antibody against the murine
endothelial cell antigen CD31. Figure 3A
shows CD31 staining in JD38-LXSN and JD38-TIMP-1 tumors before
necrosis. In contrast to control JD38-LXSN tumors, JD38-TIMP-1 tumors
demonstrate a decreased frequency of vascular staining by CD31. The
insert shows at higher magnification, the absence of blood vessel
staining in the central areas of JD38-TIMP-1 tumors before the onset of
tumor necrosis. Quantification of tumor angiogenesis was performed by
CD31+ vessel counts. These results demonstrate that JD38-TIMP-1 tumors
have statistically significantly fewer blood vessels (>50% decrease)
compared to the JD38-LXSN control tumors (Figure 3B)
. These findings
suggest that up-regulation of TIMP-1 expression in EBV latency II/III
BL tumors, inhibits angiogenesis required for sustained tumor growth.
The initial rapid growth and subsequent lack of angiogenic response can
account for the onset of central necrosis in the TIMP-1-positive BL
tumors.
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shows inhibition of human microvascular endothelial-cell migration by
the supernatant from JD38-TIMP-1 tumor cells. The migration of human
microvascular endothelial cells was suppressed by 60% compared with
untreated culture media. Conditioned media from TIMP-2 expressing
JD38-LXSN cell cultures did not inhibit endothelial cell migration. The
percentage of inhibition by the supernatant of JD38-TIMP-1 cells is
comparable to the inhibition observed in cells treated with 50 nmol/L
of human rTIMP-1 (Figure 3C)
. In previous reports the differential
effects of TIMPs on endothelial cell behavior are noted. TIMP-1
has been shown to selectively inhibit endothelial cell migration
in vitro, whereas TIMP-2 specifically inhibits endothelial
cell proliferation without altering
migration.12,28-30
Taken together, these data indicate
that inhibition of vascularization in vivo by TIMP-1 can be
mediated, at least in part, by preventing migration of endothelial
cells into the tumor mass.
These data demonstrate down modulation of the host angiogenic response
by TIMP-1-expressing BL tumors. The differences in the reported effects
of TIMPs on hematological cells,31,32
as well as the
observed difference in mononuclear cell infiltrates surrounding the
JD38-TIMP-1 tumors, prompted us to analyze possible effects of TIMP-1
at distant sites such as the bone marrow. Therefore, bone marrow from
mice bearing control JD38-LXSN and JD38-TIMP-1 tumors were removed and
analyzed by flow cytometry using a panel of antibodies against various
bone-marrow cell populations. Figure 3D
shows the results of this
analysis of bone marrow cells obtained 7 days after tumor inoculation.
The upper panels depict bone marrow cells according to their size
(forward scatter) and their cytoplasm granularity (side scatter). The
gated cell population indicates granulocytes and large leukocytes. The
arrow indicates an observed decrease in this bone marrow cell
population in the mice inoculated with JD38-TIMP-1 BL cells as compared
with bone marrow from mice inoculated with JD38-LXSN cells. Bone marrow
from mice with JD38-TIMP-1 tumors show both a significant lower
percentage of Gr-3-1-positive granulocytic (17.8%) cells and a higher
number of NK1.1-positive NK (45.4%) cells, compared with mice bearing
JD38-LXSN tumors (Figure 3
, bottom). This data suggests that in the
JD38-LXSN animals an angiogenic stimulus could be driving bone marrow
progenitors toward granulocyte differentiation. This observation is
consistent with reports suggesting a role for inflammatory cell types
in the angiogenesis process.33-35
Concurrent with the
production of angiogenesis effector genes, the expression of genes
associated with granulocyte chemotaxis has also been reported in
vascularized tumors.36
Alternatively, TIMP-1 may function,
directly or indirectly, to modulate the tumor effects on the bone
marrow cell populations. It has recently been demonstrated that TIMP-1
expression in BL cells is responsible for up-regulation of
interleukin-10 expression.24
Resolution of the mechanism
of the effects of TIMP-1 expressing BL on bone marrow will require
further investigation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The tumor-host environment changes induced by TIMP-1 may also encompass modulation of host inflammatory cells and their functions, in addition to altered endothelial cell migration. Effects such as those observed in the bone marrow of athymic mice with JD38-TIMP-1 tumors are in agreement with the previous reports on the pro-angiogenic function of granulocytes, as mentioned previously. The increase in NK cells in the bone marrow of JD38-TIMP-1 tumor-bearing mice is also consistent with the report on TIMP-1 regulation of B cell factors, such as interleukin-10, that are known to stimulate NK cell production and recruitment.24 However, examination of tumor tissues suggests that the mononuclear infiltrate at the periphery of JD38-TIMP-1 tumors is a response to tumor necrosis and not a primary mechanism of tumor destruction. Although, our histological analysis of the tumor tissues showed no evidence of an NK-mediated cytotoxic response against the JD38-TIMP-1 tumors, further investigation of this effect is warranted.
We have shown that in EBV-negative JD38 cells, up-regulation of TIMP-1 expression results in similar in vivo growth characteristics as those seen in TIMP-1-positive BL cells with an EBV latency II/III phase of infection. Our study is the first in vivo demonstration of a biphasic effect of TIMP-1 on tumor cell growth. There is an initial growth-promoting effect consistent with the previously reported in vitro growth-promoting40 and anti-apoptotic effects of TIMP-1.22,23 However, our data demonstrate that this initial effect is overcome by the ongoing suppression of the host angiogenic response. This anti-angiogenic function eventually becomes dominant during continued tumor growth and results in tumor necrosis and regression. Recent results from one of our laboratories have demonstrated that EBV infection of B cells results in up-regulation of TIMP-1 expression (M Stetler-Stevenson et al, manuscript in preparation). The present model may be a valuable tool for studies on viral mechanism controlling TIMP-1 expression and further implications for the growth and angiogenesis not only of B cell lymphomas, but also in other EBV-associated pathologies.42,43 In summary, our findings clearly demonstrate that TIMPs have multiple, divergent effects on tumor growth that can be detected in vivo. Further understanding of the role of TIMPs in tumor progression may provide new therapeutic targets for disrupting tumor growth and/or prognostic markers in B cell lymphoma.
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Acknowledgements |
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Footnotes |
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Present address of Theresa A. Bennett: University of New Mexico, Albuquerque, New Mexico.
Accepted for publication December 18, 2000.
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