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Tumor Biology |
Department of Molecular Genetics, Nagoya City University Medical School, Nagoya 467-8601 [K-i. K., T. M., T. K., T. O.], and Department of Surgery, 2nd Teaching Hospital, Fujita Health University Medical School, Nagoya 454-8509 [K-i. K., T. M., S. M.], Japan
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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B, a transcriptional activator of
E-selectin gene expression. Because two other histamine type 2 receptor
antagonists, famotidine and ranitidine, did not show any similar
effect, these actions of cimetidine probably do not occur via
blocking of the histamine receptor. These observations support the idea
that cancer metastasis can be blocked by cimetidine administration
through blocking the adhesion of tumor cells to the endothelium when an
interaction between E-selectin and sialyl-Lewis antigens plays a role. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we have attempted to examine the action of cimetidine by
investigating its effect on the cancer cell adhesion to endothelial
cells, one of the critical steps of cancer invasion and metastasis. We
have also applied an in vivo metastasis model to confirm the
effect of cimetidine. We demonstrated previously (16)
that
the induction of E-selectin in HUVECs by IL-1ß induced the adhesion
of cancer cells expressing the E-selectin ligand sialyl Lewis antigens
(17, 18)
to HUVECs and that inhibitors of NF-B
activation including pentoxifylline, aspirin, and
N-acetyl-L-cysteine could block the
cancer cell adhesion by inhibiting the IL-1ß-mediated induction of
E-selectin. Here we attempted to examine the effect of
cimetidine by applying a similar approach, and we found that cimetidine
blocked cancer cell adhesion to HUVECs. We also demonstrated that
cimetidine can prevent liver metastasis in a nude mouse model in which
tumor cell line HT-29 was injected intrasplenically.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cytotoxicity of Compounds.
To evaluate the cytotoxicity of each compound,
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays
were performed by incubating HUVECs or HT-29 cells with various
concentrations of each compound according to the method described
previously (20)
.
Reagents.
Recombinant IL-1ß was a gift from Otsuka Pharmaceutical Co.
(Tokushima, Japan). Immunostaining and flow cytometry (FACScan) of
E-selectin were carried out using a peptide-specific mouse monoclonal
antibody to human E-selectin as a primary antibody (R&D Systems,
Minneapolis, MN) as reported previously (16, 21) . For
ELISA, mouse monoclonal antibodies to human E-selectin (CD62E;
PharMingen, San Diego, CA) and human ICAM-1 (CD54; Becton Dickinson,
San Jose, CA) were used. The secondary antibodies used for
immunostaining and ELISA were FITC-conjugated rabbit antimouse IgG or
rhodamine-conjugated goat antirabbit IgG (Cappel, Durham, NC) and
horseradish peroxidase-conjugated sheep antimouse IgG antibody
(Amersham Pharmacia Biotech, Buckinghamshire, United Kingdom),
respectively. For the immunostaining of NF-B, the peptide-specific
rabbit antibody to human p65 was used as a primary antibody
(22)
. Commercial antibodies to p65 and p50 (Santa Cruz
Biotechnology, Santa Cruz, CA) were also used for this study. For
blocking of the HT-29 cell adhesion to HUVECs, antibodies to E-selectin
(CD62E) and to sialyl LewisX (CD15s; PharMingen)
were used. Pentoxifylline and aspirin were purchased from Sigma
Chemical Co. (St. Louis, MO). Cimetidine, famotidine, and ranitidine
were kindly provided by Smith Kline Beecham Japan (Tokyo, Japan),
Yamanouchi (Tokyo, Japan), and Sankyo (Tokyo, Japan), respectively.
Aspirin was dissolved in 99% ethanol. H2R blockers and pentoxifylline
were dissolved in PBS.
Monolayer Cell Adhesion Assay.
HUVECs were stimulated with 10 ng/ml IL-1ß for 0–4 h in a
10-cm2 plate. HT-29 cells (1 x 105 cells/200 µl/well) were added onto a
semiconfluent monolayer culture of HUVECs, incubated for 20 min at
37°C with rotation at 120 rpm, and washed extensively to exclude
nonspecific cell attachment. The number of attached cells was counted
directly under a microscope as reported previously (16)
.
For antibody-mediated blocking of cell adhesion, the IL-1ß-stimulated
HUVECs were incubated with antibody to either E-selectin (CD62E) or
ICAM-1 (CD54; final dilution of 1:400 for both antibodies) for
3 h at 37°C in humidified CO2 incubator,
and then HT-29 cells were added. In the case of sialyl
LewisX, the antibody (CD15s) was incubated with
HT-29 for 1 h and added to the IL-1ß-stimulated HUVECs.
Northern Blot Analysis.
Poly(A) RNA was purified from HUVECs treated with various
concentrations of cimetidine in the absence or presence of IL-1ß
using a commercial mRNA isolation kit (Boehringer Mannheim, Mannheim,
Germany). Two µg of poly(A) RNA were loaded onto each lane. The
electrophoresis and blotting to Hybond-N membrane filter (Amersham
Pharmacia Biotech) were performed as recommended by the supplier.
Hybridization was carried out with a specific cDNA probe for E-selectin
that did not hybridize with other selectin genes. A cDNA probe for
glyceraldehyde-3-phosphate dehydrogenase was used as an internal
control. Radiolabeling was carried out using a commercial kit (Random
Primer Labeling Kit; Stratagene, La Jolla, CA).
Immunostaining, Flow Cytometry, Immunoblotting, and Confocal
Laser Microscopy.
Immunostaining was performed as reported previously (16, 21)
. Briefly, semiconfluent HUVECs on Lab-Tek tissue culture
chamber slides (Nunc, Inc., Naperville, IL) were fixed with acetone for
10 min at -20°C and washed three times with PBS. They were
subsequently incubated with the primary antibody for 1 h at
37°C. After washing three times with PBS containing 0.05% Triton
X-100, they were incubated with the secondary antibody for 20
min at 37°C. Slides were mounted with buffered glycerol for
fluorescence (BX50; Olympus Co., Tokyo, Japan) or confocal laser
microscopic examination (MRC-600UV; Bio-Rad, Hercules, CA). Primary and
secondary antibodies were diluted 1:100 in PBS containing 3% BSA. For
analysis of cell surface E-selectin expression, unfixed cells were
stained with the same anti-E-selectin antibody and FITC-conjugated
rabbit antimouse IgG, and cytofluorometric examination was carried out
as described previously (Ref. 21
; FACScan; Becton
Dickinson). For immunoblotting, total cell extracts prepared from HUVEC
cultures were analyzed with the mouse monoclonal anti-E-selectin
antibody according to the method reported previously (21)
.
ELISA.
An ELISA method was developed, according to the work of Wellicome
et al. (23)
, to quantitatively measure the
amount of cell adhesion molecules, including E-selectin and ICAM-1,
expressed on the cell surface of HUVEC cultures. Basically, the ELISA
was performed at room temperature with three washes of 0.1% BSA in PBS
between each step. HUVECs were incubated for 1 h with the primary
antibody, antihuman E-selectin monoclonal antibody (CD62E) or antihuman
ICAM-1 monoclonal antibody (CD54). After washing, the secondary
antibody, horseradish peroxidase-conjugated sheep antimouse IgG
antibody, was added and incubated with HUVECs for 30 min. The enzyme
substrate O-phenylenediamine (1 mg/ml) and 0.03% hydrogen
peroxide in citrate-phosphate buffer (pH 5.0) were then added. Color
development was stopped with 2 N sulfuric acid,
and the absorbance of each well was read at 450 nm in a Titertek ELISA
plate reader (SLT Lab Instruments, Salzburg, Austria). Test and control
samples were examined in triplicates for each experiment. The degree of
specific antibody binding was calculated by subtracting the mean
negative control value (without the primary antibody), and the results
were expressed as the fold activation of surface E-selectin expression
(mean ± SD). In each experiment, HUVECs at the fourth
or the fifth passage were used to minimize the interassay variation.
Although HUVEC cultures from three unrelated donors were tested,
there was no significant difference in the level of E-selectin or
ICAM-1 expression. Within each experiment, cells from a single donor
were used.
Nude Mouse Model of Liver Metastasis.
All of the experimental procedures were performed with the approval of
the Animal Experimentation Committee of Nagoya City University
Medical School. Specific pathogen-free athymic BALB/c female mice of
3–4 weeks of age were kept under sterile conditions in a laminar flow
room in cages with filter bonnets and fed a sterilized mouse diet and
water. To induce hepatic metastasis of tumor cells, HT-29 was injected
intrasplenically. The mice were anesthetized by i.p. administration of
pentobarbital (12 µg/g body weight), and a small left subcostal
incision was made to expose the spleen. HT-29 cells (1 x 106 or 1 x 107 cells in different experiments) in 100 µl
of PBS were injected beneath the splenic capsule using a 27-gauge
needle. To examine the effect of H2R antagonists, the mice were treated
with 200, 50, or 10 mg/kg/day cimetidine or saline (control) i.p. for
10 consecutive days, that is, for 5 days before HT-29 injection and for
5 days after HT-29 injection. Subsequently, H2R antagonists or saline
(control) was administered every other day for an additional 9 weeks
and 2 days (a total of 10 weeks after HT-29 cell implantation).
Quantification of Hepatic Metastasis in Nude Mice.
Ten weeks after HT-29 cell injection, animals were sacrificed, and the
status of liver metastasis was evaluated quantitatively. The livers
were excised and cut into 2–3-mm-thick slices that were then fixed in
ice-cold acetone for subsequent H&E staining. The area of tumor nodules
was measured with the aid of a video image processor (VIP-21C; Olympus
Co.), and it was expressed as a percentage of occupancy in the liver
according to the method of Hirose et al. (24)
.
Statistical Analysis.
Differences between the results of experimental treatments were
evaluated by means of the two-tailed Student’s t test.
Fisher’s exact probability test was used to assess the difference in
the incidence of metastatic liver lesions. StatView-J 4.0.2 computer
software was applied for these analyses.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, the adhesion of HT-29 cells to HUVECs was strongly induced
on stimulation with IL-1ß (10 ng/ml). The maximum induction of cell
adhesion by IL-1ß was obtained after 4 h of stimulation. Using
this model, we investigated the effects of various H2R antagonists at a
range of noncytotoxic concentrations [from
10-4 to
10-8
M (9, 13)
; also confirmed by
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in
this study]. Cultured HUVECs were pretreated with cimetidine or other
H2R antagonists 2 h before the addition of IL-1ß. After 4 h
of IL-1ß stimulation, HT-29 cells were added, and the cell adhesion
assay was performed. As shown in Fig. 1
, pretreatment of HUVECs with
pentoxifylline blocked the adhesion with HT-29 cells, as reported
previously (16)
. Similarly, this adhesion of HT-29 cells
to HUVECs was inhibited by cimetidine in a dose-dependent manner.
However, other H2R antagonists, famotidine and ranitidine, had no
inhibitory effect.
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, we incubated HUVECs that had been stimulated with IL-1ß with the
antibody to E-selectin or ICAM-1, and the monolayer cell adhesion assay
was carried out. When HUVECs were preincubated with the antibody to
E-selectin, the IL-1ß-induced HT-29 adhesion to HUVECs was
abolished (Fig. 2, A and B)
. Similarly, when
HT-29 cells were preincubated with the antibody to sialyl
LewisX, the HT-29 adhesion to HUVECs was also
blocked. In contrast, preincubation of HT-29 cells with anti-ICAM-1
antibody did not significantly reduce cell adhesion. There was no
significant effect of antibodies to E-selectin or sialyl
LewisX antigens on the basal level of HT-29
adhesion to HUVECs (without IL-1ß stimulation; data not shown). These
findings were consistent with previous observations by others
(18, 25, 26)
and indicate that both E-selectin and sialyl
LewisX are primarily involved in our experimental
cell adhesion assay system using HT-29 cells and HUVECs.
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B Activation.
). Poly(A) RNA purified from HUVEC cultures treated with
various concentrations of cimetidine in the absence or presence of
IL-1ß was hybridized with the E-selectin cDNA probe. As shown in Fig. 3A
, IL-1ß could induce E-selectin gene expression.
However, even at the highest concentration, cimetidine could not
significantly reduce the E-selectin mRNA level. We also examined the
effect of cimetidine on the IL-1ß-induced nuclear translocation of
NF-B (Fig. 3B
). In contrast to aspirin, which effectively
blocked the nuclear translocation of NF-B as reported previously
(16, 21) , cimetidine or other H2R antagonists did not
block the nuclear translocation of NF-B elicited by IL-1ß (Fig. 3A
).
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). Maximum induction of E-selectin by IL-1ß (10 ng/ml) was obtained
after 4 h of treatment (Fig. 4A
), which coincided with
the HT-29 adhesion to HUVECs. Interestingly, a significant suppression
of E-selectin induction was observed on pretreatment of HUVECs with
cimetidine in a dose-dependent manner at noncytotoxic concentrations
(from 10-8 to
10-4
M), which again correlated with the effect of
cimetidine on the adhesion of HT-29 cells to HUVECs (Fig. 1)
. It was
noted by confocal microscopic examination that there was no significant
change in the intracellular localization of E-selectin (Fig. 4A
). Neither famotidine nor ranitidine showed any inhibitory
effect on E-selectin levels. There was no change in the expression
level of sialyl Lewis antigens on the HT-29 cell surface by cimetidine
(data not shown). There was no significant effect of cimetidine on the
ICAM-1 level in HUVECs in either the presence or absence of IL-1ß
(data not shown). In spite of our repeated attempts to identify the
change of E-selectin protein levels by Western blotting using a number
of commercially available antibodies, we were not able to detect the
monospecific band corresponding to E-selectin, a failure we believe to
be due to the low affinity of the antibodies in solution or the
presence of interacting proteins that interfered in the antibody
reaction.
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, the E-selectin level on HUVECs was augmented by
6.0 ± 0.36-fold on stimulation with IL-1ß. When
HUVECs were pretreated with cimetidine 2 h before IL-1ß
stimulation, the extent of E-selectin induction decreased to
4.9 ± 0.35-, 1.9 ± 0.06-, and
1.1 ± 0.12-fold at cimetidine concentrations of
10-8,
10-6, and
10-4
M, respectively (P < 0.01). The cell surface ICAM-1 expression was also augmented by
6.37 ± 0.43-fold on IL-1ß treatment (Fig. 5B
). However, ICAM-1 expression was not significantly
inhibited by cimetidine pretreatment. Neither famotidine nor ranitidine
showed any inhibitory effect (Fig. 5, C and D)
.
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, cimetidine prevented the incidence of liver metastasis in a
dose-dependent manner. At the highest dose of cimetidine (daily doses
of 200 mg/kg), liver metastasis was completely inhibited when
1 x 106 HT-29 cells were injected
intrasplenically (none of the nine mice had detectable liver
metastasis; Table 1
, experiment 1), whereas there was no notable
difference in the size of the primary tumor in the spleen (data not
shown). Famotidine or ranitidine at doses equivalent to that of
cimetidine had no inhibitory effect on liver metastasis (data
not shown). A repeated experiment using a greater number of HT-29 cells
(1 x 107) for inoculation
demonstrated similar effects of cimetidine on the prevention of
liver metastasis (Table 1
, experiment 2). Furthermore, the
extent of liver metastasis (the percentage of occupancy of the
metastatic nodules in the liver slices) was significantly diminished in
the cimetidine-treated animals (Table 2
).
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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E-selectin is considered to play a primary role in initiating the adhesion of cancer cells to vascular endothelial cells through its interaction with its specific ligand sialyl Lewis antigens (16–18, 25–28) . In a previous study (16) , we reported that adhesion of tumor cell line QG90 to HUVECs was dependent on E-selectin expression on the cell surface of HUVECs and was induced by IL-1ß. Similar results were reported with HT-29 cells by Dejana et al. (26) . In these studies, IL-1ß was used to activate E-selectin on HUVECs to mimic the local inflammatory response in the metastasized region (29, 30) , and some tumor cells were reported to produce IL-1ß (31, 32) . In fact, expression of E-selectin in endothelium adjacent to the metastatic tumor lesion was reported by others (33, 34) . It is also known that E-selectin is induced on ischemia-reperfusion injury (35) , which may be associated with tumor embolism during metastasis. Thus, it is likely that E-selectin is induced by such mechanisms in our nude mice model.
We found that the effect of cimetidine did not appear to be at the
level of E-selectin gene expression because the E-selectin protein
level was reduced without significantly reducing its mRNA level. The
failure of cimetidine to block NF-B nuclear translocation also
supported this possibility. Previous studies have indicated a variety
of unexpected actions of cimetidine. For example, cimetidine was
reported to have direct growth-inhibitory effects on certain cancer
cell lines (1, 14)
and direct stimulatory effects on
lymphocyte function (10–12)
. It was also reported that
histamine was released into the blood stream during the operation,
presumably from tumor cells (36)
or the adjacent mast
cells (37)
, and that histamine interfered with the host
immune system (10, 11, 38)
. It was then suggested that
histamine might promote the growth of tumor cells (12, 14, 39)
. However, we did not observe any cytotoxic or cytostatic
effects of cimetidine on HT-29. In addition, we found that other H2R
antagonists did not have the same effect as cimetidine in our
experimental systems, indicating that this action of cimetidine is
probably not mediated via the H2R. In addition, although some reports
have indicated that cimetidine may have antioxidant activity
(40–42)
, and antioxidants have been shown to block
E-selectin gene expression by blocking the activation cascade of
NF-B (16)
, cimetidine did not block IL-1ß-induced
NF-B activation (Fig. 3B
).
The action of cimetidine on E-selectin expression does not appear to
involve the transcription step. Therefore, the experimental
observations obtained in this study suggest that cimetidine may block
E-selectin expression at a step after transcription. In this regard, it
may be worth noting that other regulatory molecules such as p38 MAPK,
in addition to NF-B, were also involved in IL-1ß signaling
(43, 44)
. Because it has been implicated that E-selectin
expression requires p38 MAPK (43)
, and p38 MAPK activates
the expression of a number of genes at the level of posttranscription
(44–46)
, the issue of whether cimetidine but not other
H2R antagonists might interfere with such signaling mediators should be
explored.
Our observations support the previous clinical findings that cimetidine increased the survival of cancer patients. It is likely that cimetidine may block cancer cell adhesion to endothelial cells and thus prevent metastasis. In fact, we found in our recent randomized clinical study that cimetidine treatment significantly reduced cancer metastasis and recurrence, thus resulting in the prolonged survival of patients with colorectal cancer whose tumors had high levels of sialyl Lewis antigens.4 There were no effects when the tumor had no sialyl Lewis antigens or low levels of sialyl Lewis antigens. Additional analyses on the actions of cimetidine are needed to identify a novel therapeutic target against cancer aggression.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by grants-in-aids for
Scientific Research from the Ministry of Education, Science, Sports and
Culture, the Ministry of Health and Human Welfare, Japan and the
Japanese Health Sciences Foundation. 
2 To whom requests for reprints should be
addressed, at Department of Molecular Genetics, Nagoya City University
Medical School, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601,
Japan. Phone: 81-52-853-8204; Fax: 81-52-859-1235; E-mail: tokamoto{at}med.nagoya-cu.ac.jp
3 The abbreviations used are: H2R, histamine type
2 receptor; NF-B, nuclear factor B; HUVEC, human umbilical vein
endothelial cell; ICAM, intercellular adhesion molecule; IL-1,
interleukin 1; poly(A) RNA, polyadenylated RNA; MAPK, mitogen-activated
protein kinase.
4 S. Matsumoto, K. Kobayashi, S. Umemoto,
K. Suzuki, and T. Okamoto. Effects of cimetidine on survival after
curative operation of colorectal cancer: cimetidine increases survival
of colorectal cancer patients with high levels of sialyl Lewis-X and
sialyl Lewis-A epitope expression on tumor cells, manuscript in
preparation.
Received 12/14/99. Accepted 5/16/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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  P. Auguste, L. Fallavollita, N. Wang, J. Burnier, A. Bikfalvi, and P. Brodt The Host Inflammatory Response Promotes Liver Metastasis by Increasing Tumor Cell Arrest and Extravasation Am. J. Pathol., May 1, 2007; 170(5): 1781 - 1792. [Abstract] [Full Text] [PDF]
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A.-M. Khatib, L. Fallavollita, E. V. Wancewicz, B. P. Monia, and P. Brodt Inhibition of Hepatic Endothelial E-Selectin Expression by C-raf Antisense Oligonucleotides Blocks Colorectal Carcinoma Liver Metastasis Cancer Res., October 1, 2002; 62(19): 5393 - 5398. [Abstract] [Full Text] [PDF]
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