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Departments of Surgery [M. J. W., A. M. C.] and Medicine [A. J. D.], The New York Presbyterian Hospital and Weill Cornell Medical College and Strang Cancer Prevention Center, New York, New York 10021; and Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts 02115 [M. M. B.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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0.65 (95% confidence interval,
0.4–1.05; Ref. 4
). Fruits and vegetables contain a number
of constituents associated with colorectal cancer prevention
(4)
, such as antioxidant vitamins and numerous
micronutrients, including the plant phenolics (5)
. Fruits
and vegetables also contain dietary fiber. The beneficial constituents
that prevent colon cancer in plant foods are probably the vitamins and
micronutrients and not the fiber, as recent epidemiological data failed
to show an association of fiber consumption and reduced colon cancer
risk (6
, 7)
. The fact that a diet high in fruits and
vegetables is associated with a lower risk of both adenomas and cancer
suggests that the responsible agents act early in the adenoma-carcinoma
sequence. This observation does not exclude the possibility that these
agents have additional tumor-inhibitory activities late in
carcinogenesis. A number of studies in both cell culture and animal cancer models support a role for plant phenolics in colorectal cancer prevention. Plant phenolics are divided into three categories based on their chemical structure: the simple phenols and phenolic acids, hydroxycinnamic acid derivatives, and flavonoids (8) . These agents inhibit carcinogenesis in the initiation, promotion, and progression stages. For example, plant phenolics prevent tumor initiation because they reduce levels of carcinogen-DNA adducts in chemically treated cells and they suppress the metabolic activation of carcinogens by inhibiting phase I monooxygenases (8) . Examples of inhibitory effects on promotion by plant phenolics include studies showing that they scavenge free radicals, induce the transcription of phase II detoxifying enzymes, and reduce the expression of ornithine decarboxylase (9, 10, 11) . Finally, plant phenolics inhibit cell proliferation and induce cell death or differentiation in tumor cells, suggesting that they may antagonize later phases of carcinogenesis (8 , 12, 13, 14) .
Flavonoids constitute the most important single group of dietary
phenolics and include catechins, proanthocyanins,
anthocyanidins, flavones, and flavonols and their glycosides.
These compounds are abundant in plant foods, and a typical fruit
serving of 200 g contains 50–500 mg of mixed flavonoids.
Catechins are a class of flavonoids with potent antioxidant and cancer
chemopreventive properties. These compounds are found in a variety of
plants and are present in particularly high amounts in tea leaves,
where they may constitute up to 30% of dry leaf weight
(6)
. High levels of monomeric (+)-catechin (Fig. 1)
are found in the skins and seeds of fruit such as apples and grapes
(15)
. Red wines and chocolate also are significant sources
of (+)-catechin (16
, 17)
. In the case of red wine, the
plant phenols, including (+)-catechin, are extracted from the skins of
grapes and concentrated during fermentation.
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One of the most important activities of (+)-catechin may be the modulation of epithelial cell migration (28) . (+)-Catechin binds to laminin, an ECM3 protein, and interferes with cell adhesion, cell spreading, and protease binding. Pretreatment of a laminin substrate with (+)-catechin led to decreased adhesion and spreading of virus-transformed fetal mouse cells (28) . The catechins present in tea, such as epigallocatechin-3-gallate, block tumor cell invasion by inhibiting urokinase and tumor angiogenesis, unfortunately at levels far greater than those achievable by drinking tea (29) . Recently, however, epigallocatechin-3-gallate was found to suppress the activity of the matrix metalloproteinases MMP-2 and MMP-9 in HT1080 fibrosarcoma cells with IC50s of 20 and 50 µM, respectively (30) . This effect, observed at levels achievable in humans through ingestion of moderate amounts of green tea, was associated with inhibition of invasion through Matrigel (30) . Thus, these findings suggest that catechins may prevent cancers by modulating early changes in stromal interactions with initiated cells and, possibly, late changes associated with tumor cell invasion.
Very few data exist on the ability of flavan-3-ols such as (+)-catechin to inhibit carcinogenesis in vivo. Although the epicatechins found in tea extracts did not inhibit carcinogen-induced colon tumors in rats (31) , tumor formation was delayed in mice fed a diet containing red wine solids (32) . Previous studies showed that adenoma formation in Min/+ mice is inhibited by NSAIDs such as sulindac, piroxicam, and aspirin (33, 34, 35, 36) , and the hydroxycinnamic acid derivatives, CAPE and curcumin (37) . This effect may be associated with inhibition of integrin-mediated signaling from the ECM as evidenced by a reduction of the tyrosine phosphorylation state of FAK in vitro (38) . Administration of the flavonoid, quercetin, or its more readily absorbed glycoside, rutin, did not alter tumor formation in the Min/+ mouse, even when administered at a level of 2% by weight in a standard diet (37) . These mixed results suggest that individual compounds of this category may have tissue-specific and/or tumor-specific chemopreventive activities.
Here, we report that treatment of Min/+ mice with diets containing (+)-catechin inhibited intestinal tumor formation with efficacy only moderately lower than that produced by sulindac (36 , 37) . We also found that in vitro exposure of human colon carcinoma cells to (+)-catechin inhibited the tyrosine phosphorylation of FAK and induced changes that alter actin localization and the invasive phenotype. Finally, we found that the relative levels of FAK phosphorylated at Tyr397 (FAK-p-Y397) were increased in macroscopically normal enterocytes and adenomas from untreated Min/+ mice when compared with enterocytes from wild-type littermates, and that these defects were corrected in the (+)-catechin-treated Min/+ animals. Our results suggest that (+)-catechin may be a safe, alternative to NSAIDs for the prevention of colorectal adenomas and cancer.
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MATERIALS AND METHODS |
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) was from
Upstate Biotechnology (Lake Placid, NY). Anti-ß-actin (clone AC-40;
mouse IgG2a) was from Sigma (St. Louis, MO). IPs
were performed using the Boehringer Mannheim Protein A kit (Roche
Molecular Biochemicals, Indianapolis, IN). Biotinylated antimouse and
antirabbit antibodies and Vectashield mounting solution were from
Vector Laboratories, Inc. (Burlingame, CA). Streptavidin-horseradish
peroxidase was obtained from PharMingen. The micro BCA protein assay
reagent kit was purchased from Pierce (Rockford, IL). IB analyses used
Optitran nitrocellulose membranes (Schleicher & Schuell, Keene, NH).
Electrotransfer of proteins used the electroblot buffers of Owl
Separation Systems (Woburn, MA). Matrigel invasion chambers were
purchased from Becton Dickinson Labware (Bedford, MA), and hematoxylin
2 was obtained from Richard-Allan Scientific (Kalamazoo, MI). Western
blotting used the ECL detection reagents of Amersham Pharmacia Biotech
(Piscataway, NJ).
Animal Treatments and Tissue Harvesting.
Five-week-old female Min/+ mice and their wild-type littermates were
obtained from The Jackson Laboratory (Bar Harbor, ME). After arrival,
the littermates were evenly distributed among the treatment groups, and
treatment with study diets was started immediately thereafter.
Wild-type C57BL/6J and untreated Min/+ control groups were fed AIN-76A
chow and given tap water to drink ad libitum. Treatment
groups were fed AIN-76A pelleted with either 0.1% or 1.0%
(+)-catechin (Research Diets, New Brunswick, NJ). The animals were
routinely checked for signs of anemia or bowel obstruction and weighed
weekly to assure similar growth and food intake among groups.
At 110 days of age, all mice were again weighed, rendered moribund by CO2 inhalation, and euthanized by cervical dislocation. The intestine of each animal was removed from stomach to distal rectum. Each intestine was opened along its entire length, flushed with cold PBS, and examined under a direct bright light and by transillumination. The intestinal tumors were then counted by an individual blinded to the animal’s genetic or treatment status. Several tumors from all regions of the small intestine (duodenum, jejunum, and ileum) were excised from each animal, as well as segments of tumor-free duodenum, small bowel, and colon. These tissues were snap frozen and stored separately in liquid nitrogen. Enterocyte samples for immunoblotting were obtained by mechanical dissociation, using the edge of a glass microscope slide (39) , and washed twice in cold PBS prior to storage at -70°C. Tissues used for enterocyte collections were macroscopically free of tumors. However, the possibility of some microadenoma contamination cannot be excluded in the case of samples obtained from Min/+ mice. Enterocytes prepared in this manner also contain lamina propria and associated fibroblasts. This method, however, is best suited for studying stromal-epithelial cell interactions (40) . For consistency, all enterocyte samples were collected from 4-cm segments of the proximal small intestines.
Cell Culture and Treatment Conditions.
The sources for human colon carcinoma cell lines DLD-1 and HT-29 and
rodent NIH3T3 cells were as described (38)
. Cultures were
maintained in DMEM:F-12 medium supplemented with 10% FBS and cultured
at 37°C in a humidified 5% CO2 incubator.
Cells in log-phase growth (70% confluent) were treated with
(+)-catechin in fresh medium containing 0.1% FBS. Unless otherwise
indicated, the treatment time was 24 h. Growth curves were
prepared by plating 105 cells and allowing them
to attach and expand for 48 h prior to treatment with (+)-catechin
(125 µM). Cells were washed and trypsinized, and the
number of viable, attached cells was counted using a hemocytometer at
timed intervals.
IB Analysis and IP.
Procedures and buffers for cell lysis, protein determination, IP, and
IB analysis were exactly as described previously (38)
. All
IP and IB experiments were repeated separately at least twice. Samples
from two mice of the same treatment group were pooled to prepare the
protein extracts.
Fluorescent Histochemistry.
DLD-1 and HT-29 colon cancer cells (5 x 103
) were seeded into 4-well Lab-Tek chamber
slides (Nunc, Inc., Naperville, IL) and incubated for 48 h prior
to treatments. The medium was aspirated and replaced with DMEM:F-12
containing 0.1% FBS with or without (+)-catechin (125
µM) or genistein (100 µM). Treated cultures
were incubated an additional 24 h and then fixed in 4%
PBS-buffered formaldehyde for 20 min. After repeated washings in PBS,
slides were placed in 50 mM NH4Cl for
15 min and in 0.2% Triton X-100 for 10 min. Blocking was for 30 min in
PBS containing 3% BSA. Rhodamine-conjugated phalloidin in PBS
containing 1% BSA was applied, and the slides were placed in a
humidified chamber at room temperature for 1 h. After additional
washing, slides were mounted with coverslips, and imaging was performed
using the Zeiss LSM510 confocal microscope of the Core Imaging Facility
at the Weill Medical College of Cornell University.
Invasion Assay.
The invasion assay was performed as detailed previously
(38)
. Briefly, HT-29 cells were subjected to the standard
treatment conditions (see above), and then trypsinized. The number of
viable cells was determined by trypan blue exclusion and counted as
above. Cells (5 x 104) in
low-serum medium were placed on a Matrigel-coated polycarbonate filter
in each well of the invasion assay plates (8-mm wells; 8-µm pores).
Conditioned medium from NIH3T3 cells, supplemented with 10% calf
serum, was placed in the bottom chambers as a chemoattractant. Plates
were incubated at 37°C for 24 h. Cells that migrated to the
bottom compartment were stained with hematoxylin. A blinded viewer
counted the number of cells present in four fields per chamber, using a
light microscope, and the experiment was repeated separately.
Statistical analysis of the data from this assay was computed by
Student’s t test.
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RESULTS |
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, the treated groups had a significantly lower tumor number, with a mean
of 6.4 ± 3.7 adenomas in the 0.1% (+)-catechin group,
and 7.6 ± 4.0 in the 1.0% (+)-catechin group,
corresponding to reductions of 75 and 71%, respectively. The overall
distribution of tumors throughout the intestinal tract was unchanged by
(+)-catechin administration because uniform decreases in tumor number
at all locations were observed in the treated mice (Table 1)
.
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, treatment with (+)-catechin inhibited the growth of both cell lines by
>50% compared with untreated control cultures. However, this dose of
(+)-catechin was not significantly cytotoxic because >90% of cells
excluded trypan blue at the conclusion of each treatment interval up to
72 h, and the total number of cells in the treated groups
increased relative to the starting point.
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. This structure is characteristic of adherent cells with intact
cell-ECM contacts. Treatment with 125 µM (+)-catechin in
low-serum medium produced a reorganization of the actin cytoskeleton.
Characteristics of the response to drug treatment included retraction
and loss of the stress fibers, the circumferential accumulation of
actin at the cell periphery, and punctate actin staining.
Reorganization of the actin cytoskeleton was more clearly illustrated
in DLD-1 cells, but the increased peripheral staining of treated HT-29
cells suggested that a similar response was induced in them as well.
Control cells were also cultured with genistein, a specific inhibitor
of protein tyrosine kinases that blocks the tyrosine phosphorylation of
FAK and the assembly of focal adhesions and actin stress fibers in
epithelial cells (38
, 43)
. Exposure to 100
µM genistein under the same treatment conditions also
affected the actin cytoskeleton of these cell lines.
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To examine the effect of (+)-catechin on the invasive cancer phenotype,
HT-29 cells were seeded into Boyden chambers and allowed to attach for
48 h. These cells were exposed to 50 or 125 µM
(+)-catechin under standard treatment conditions. The invasive activity
of HT-29 was assessed by counting the number of cells that migrated
through the Matrigel-coated polycarbonate filters. The results in Fig. 5
show a dose-dependent inhibition of tumor cell migration after
treatment with (+)-catechin, with a 90% reduction in cell invasion at
the highest drug dose. This inhibition of invasion was not attributable
to toxicity, as indicated by the results shown above in Fig. 3
.
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The activation of FAK downstream signaling depends on the
phosphorylation of Tyr397. When this residue is
phosphorylated, a SH2 domain is created that allows the binding of
c-Src and the further tyrosine phosphorylation of other secondary FAK
residues (54
, 55) . Tyr397 is the
primary site of FAK autophosphorylation in vitro and the
main phosphorylation target in response to integrin activation
(56)
. To investigate the effect of (+)-catechin on focal
adhesion-associated signaling, we examined the steady-state levels of
FAK expression and relative levels of FAK tyrosine phosphorylation
after treatment of HT-29 and DLD-1 cells. This experiment assessed
overall levels of tyrosine phosphorylation by IP of total cell lysates
using an antiphosphotyrosine antibody followed by Western blot analysis
for FAK. As shown in Fig. 6
, treatment of colorectal cancer cells with (+)-catechin decreased the
levels of overall tyrosine-phosphorylated FAK (Fig. 6
, left
panel), although steady-state FAK expression remained unchanged
(Fig. 6
, right panel). The sensitivity of DLD-1 to
(+)-catechin appears to be greater than that of HT-29 cells because
levels of overall tyrosine-phosphorylated FAK were reduced by 25
µM (+)-catechin in the former, whereas this
effect was observed only at a (+)-catechin concentration of 125
µM in the latter. Similar results were
obtained when these cells were treated with the tyrosine kinase
inhibitor, genistein (100 µM). Again, DLD-1
cells showed a marked reduction of overall levels of
tyrosine-phosphorylated FAK expression, and HT-29 cells showed relative
insensitivity. These differences in sensitivity are consistent with the
fact that DLD-1 cells have a more differentiated phenotype and yielded
more pronounced cytoskeletal changes when treated with these compounds
(Fig. 4)
.
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, there was no difference in relative levels of FAK protein
between normal-appearing mucosa from Min/+ mice and that of their
wild-type C57BL/6J littermates. However, FAK protein is frankly
overexpressed in the adenomas isolated from Min/+ in comparison to
normal-appearing intestinal mucosa from this animal. In examining the
relative level of FAK-p-Y397, noted above to initiate FAK downstream
signaling, we found that this form of the kinase was elevated in
normal-appearing Min/+ enterocytes, as well as in Min/+ adenomas (Fig. 7B)
. Treatment with (+)-catechin reduced the overall
expression of FAK protein in the residual adenomas of treated Min/+
mice (Fig. 7A
, extreme right-hand lane), and also
lowered the expression of FAK-p-Y397 in the macroscopically normal
mucosa of Min/+ mice (Fig. 7B
, middle lanes).
Moreover, expression of FAK-p-Y397 in the adenomas was also inhibited
in treated Min/+ mice (Fig. 7B
, extreme right-hand
lane). Taken together, these changes in the relative expression
and activation of FAK appear to be very early events in
Apc-mediated tumorigenesis in vivo. Furthermore,
these results suggest that inhibition of the expression and
phosphorylation of FAK is associated with the chemopreventive activity
of (+)-catechin.
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DISCUSSION |
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. This finding is significant because, unlike sulindac and curcumin,
which exhibit toxicity at chemopreventive doses, and CAPE, which is not
yet readily available by synthetic means, (+)-catechin is nontoxic and
widely available.
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and 5)
,
suggesting that this compound may also prolong tumor latency or inhibit
progression to an invasive phenotype.
It is possible that Min/+ enterocytes are selected phenotypically
in vivo for increased integrin-mediated ECM adhesion
signaling. A consequence of this selection would be the outgrowth of
cells with improved migration and survival. Fig. 7
shows that FAK
protein expression is the same in Min/+ and wild-type enterocytes but
increased in tumors. It also shows that the phosphorylation of FAK
Tyr397 is increased in apparently normal Min/+
enterocytes compared with the wild-type cells. Therefore, the altered
phosphorylation status of FAK is likely to represent an early event
resulting from the Apc+/- genotype, and
the up-regulation of FAK protein levels in the tumors constitutes a
later change resulting from the conversion to
Apc-/-. The results shown in Fig. 7
also
suggest that the alterations in integrin-mediated survival signaling
are not restricted to the replicative cells of the intestinal crypts.
There is a >10-fold difference in the number of cells per crypt
(250) versus those per villus (3500; Ref.
60
). Hence, the alterations in expression of FAK-p-Y397
demonstrated by Western blotting most likely reflect the phenotype of
the more numerous postmitotic cells of the villi. It will be
instructive for future studies to investigate the expression and
distribution of proteins relevant to FAK-mediated signal transduction
(e.g., proteins of the phosphoinositide-3-OH kinase-PKB
pathway) in Min/+ versus C57BL/6J enterocytes and to compare
these results with those from Min/+ tumors.
The compound studied here, (+)-catechin, is a flavonoid constituent of
fruits and vegetables. The total plant-derived phenol content of an
average adult Western diet is 0.17%, or 1.0 g per day of the usual
dietary intake (8)
. This amount varies greatly depending
on the type and proportion of fruits and vegetables ingested. The most
common biologically active flavonoids are quercetin and its glycoside,
rutin. Although both of these compounds inhibit neoplasia in
carcinogen-induced skin and colon cancer models (61, 62, 63)
,
recent work showed that addition of quercetin and rutin to the diet at
levels as high as 2.0% failed to inhibit tumor formation in Min/+ mice
(37)
. This may be attributable to poor bioavailability of
these compounds because they are rapidly conjugated for elimination
in vivo (8)
.
When human subjects ingest (+)-catechin, the compound is readily
absorbed. Maximum plasma concentrations are reached in 1 h, and the
half-life of elimination is 3 h. (+)-Catechin undergoes extensive
metabolism to sulfates, glucuronides, and O-methylated
catechin conjugates, and these active derivatives persist in tissues
and may undergo reabsorption in the intestine after enterohepatic
circulation (64, 65, 66, 67)
. Certain plant foods and beverages
are good dietary sources of (+)-catechin. For example, the
concentration of (+)-catechin and related phenols in red wine is at
least 1.0 ± 0.01 g/liter (67
, 68)
. This
high level occurs because the fermentation process used in the
production of red wine allows optimal extraction of catechin and other
polyphenols from the fruit. In a common genus of wine and table grapes,
Vitis vinifera, for example, the levels of (+)-catechin are
14–560 mg/kg in the seeds and 14–42 mg/kg in the skins
(15)
, both of which are exposed to the solvent, alcohol,
during fermentation. Recent work showed that dietary supplementation
with a 1% grape seed extract reduced tumor formation in Min/+ mice by
44% (41)
. Our data suggest that this result may have been
attributable to the high (+)-catechin content of the grape seed
extract. Epidemiological studies of colorectal cancer provide
conflicting data concerning the relationship between wine intake and
cancer (69)
. Most case-control and cohort studies suggest
that high alcohol intake increases cancer risk; however, when the type
of alcohol was examined, the significant elevations of risk were found
more often for beer, with less risk for spirits and the least risk for
wine (70
, 71)
. No study has examined the effect in humans
of modest red wine intake alone on colon cancer risk.
By nutrient density estimation, a 0.1% catechin diet, such as shown
here to be effective in the Min/+ mouse, can be achieved in humans by
an average consumption of 560 mg/day. This amount is contained in
500 ml of red wine or a lesser volume of wine if foods containing
(+)-catechin are also regularly consumed (e.g., grapes,
apples, and chocolate; Ref. 70
). Our failure to see a dose
response together with the considerable efficacy of the (+)-catechin
diets suggests that the actual concentration required for tumor
prevention may be <0.1%, making it feasible for dietary modification
alone to achieve tumor prevention. Even if regular dietary ingestion of
this compound is not possible, the (+)-catechin concentration of 0.1%
used in this study corresponds to a human dose of only 8 mg/kg/day, and
(+)-catechin has been administered safely to humans in oral doses of
8–80 mg/kg (71)
.
In summary, these studies add (+)-catenin, a naturally occurring and minimally toxic compound, to a growing list of agents that suppress Apc-associated intestinal tumor formation. Because of its wide bioavailability, this agent may prove effective against a variety of human epithelial tumors. Further study is needed to understand the effects of this agent upon all stages of the adenoma-carcinoma sequence.
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FOOTNOTES |
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1 Supported by National Cancer Institute Grant
NCI-IR29CA74162-01 and the California Raisin Marketing Board (to
M. M. B. and A. J. D.), and by NIH Surgical Oncology Training Grant
525435 (to M. J. W.) and the Irving Weinstein Foundation (to
A. M. C.). 
2 To whom requests for reprints should be
addressed, at Department of Surgery, Brigham and Women’s Hospital, 75
Francis Street, Boston, MA 02115. Phone: (617) 732-8910; Fax:
(617) 582-6177; E-mail: mbertagnolli{at}partners.org
3 The abbreviations used are: ECM, extracellular
matrix; NSAID, nonsteroidal anti-inflammatory drug; CAPE, caffeic acid
phenethyl ester; FAK, focal adhesion kinase; DMEM:F-12, DMEM:Ham’s
F-12; FBS, fetal bovine serum; IP, immunoprecipitation; IB, immunoblot;
APC, adenomatous polyposis coli.
Received 5/16/00. Accepted 10/31/00.
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