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Carcinogenesis |
Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020 [Y-P. L., Y-R. L., M-T. H., C. S. Y., A. H. C.]; University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901 [Y. L., W. J. S.]; and The Cancer Institute of New Jersey, New Brunswick, New Jersey 08901 [Y. L., W. J. S., M-T. H., C. S. Y., A. H. C.]
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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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In an earlier cancer chemoprevention study, we exposed SKH-1 mice to UVB (30 mJ/cm2) twice a week for 22 weeks, and then UVB irradiation was stopped. The mice were tumor-free, but they had hyperplasia and a high risk of developing skin tumors during the next several months in the absence of additional treatment with UVB ("high-risk mice;" Ref. 8 ). This is a useful animal model that may be comparable with humans previously exposed to moderate/high levels of sunlight who have a high risk of developing skin cancers later in life even in the absence of continued heavy sunlight exposure.
We found that p.o. administration of green tea or black tea to these high-risk mice inhibited the formation and size of malignant and nonmalignant tumors (8) . The decaffeinated teas were inactive or less effective inhibitors of tumor formation than the regular teas, and adding caffeine back to the decaffeinated teas restored biological activity (8) . Administration of caffeine alone also had a strong inhibitory effect on tumorigenesis in high-risk mice. In the present report, we describe the results of additional studies with tissues from the same mice used in our earlier cancer chemoprevention study. The additional studies indicate a strong relationship between the inhibitory effects of p.o. administered tea, decaffeinated tea plus caffeine, or caffeine alone on skin carcinogenesis and their effects to decrease the size of the parametrial fat pad and to decrease the thickness of the dermal fat layer both away from and directly under tumors. These effects on fat disposition were not observed with the decaffeinated teas.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Purified water was prepared by reverse osmosis and used for the preparation of all tea infusions and caffeine solutions. Solutions of caffeine (0.44 mg/ml water; 0.044% solutions) or solutions of lyophilized tea solids (6 mg/ml water; 0.6% solutions) were prepared every 2 days and were used as the sole source of drinking fluid. In these studies, the concentrations of tea solids and caffeine were about 50% higher than normally consumed by humans. The concentration of caffeine (0.44 mg/ml) was the same as that in the 0.6% green tea and black tea solutions.
Treatment of the Mice.
Female SKH-1 hairless mice (6–7 weeks of age) were obtained from the Charles River Breeding Laboratories (Kingston, NY) and fed Purina Laboratory Chow 5001 diet (Ralston-Purina, St. Louis, MO) ad libitum. The mice were treated with UVB (30 mJ/cm2) twice a week for 22 weeks, as described earlier (8, 9, 10)
. For these studies, UV lamps (FS72T12-UVB-HO) that emit UVB (280–320 nm; 75–80% of total energy) and UVA (320–375 nm; 20–25% of total energy) were obtained from the Voltare Co. (Fairfield, CT). When one animal developed a small skin nodule, UVB treatment was stopped and the mouse was discarded. The remaining treated mice without tumors and with a high risk for the development of tumors in the absence of continued UVB exposure were then given various teas or caffeine solutions as their sole source of drinking fluid in the absence of additional UVB treatment. In these studies, the mice were given tea solutions or caffeine that were 25%, 50%, and 75% of full strength (2 days at each concentration), and then full strength solutions were given until the animals were killed after 23 weeks of treatment with the teas or caffeine. None of the treatments had an effect on the food intake or body weight of the mice.
Tumor Size, Parametrial Fat Pad Size, and Histopathology Studies.
For studies on tumor size, parametrial fat pad size and histopathology studies, the animals were killed, the size of the parametrial fat pads was estimated, and dorsal skins were removed and stapled flat to a plastic sheet before they were placed in 10% buffered formalin phosphate at 4°C for 18–24 h for histological examination. Tumor diameter was determined for each mass by measuring the three-dimensional size (height, length, and width) of each mass before making histological sections and by using the average of the three measurements as the diameter. The formalin-treated skin samples were dehydrated in ascending concentrations (80%, 95%, and 100%) of ethanol, cleared in xylene, and embedded in Paraplast. Four-µm serial sections were made for regular H&E-phloxine staining. The tumors were characterized by histological criteria, and the thickness of the dermal fat layer was determined directly under tumors and in nontumor areas of the skin (>0.5 cm away from tumors) using a light microscope with an ocular micrometer and x100 magnification.
Statistical Methods.
Student’s t test was used for simple comparisons of two groups. The ANOVA models with Dunnett’s adjustments (11
, 12) were used for the comparisons of multiple treatment groups with the common control (water) group. The Fisher’s exact test was used for the comparison of the number of mice with tumors in the different groups.
The random coefficient (hierarchical linear) model was used to study the treatment effect on the relationship between the thickness of the dermal fat layer under tumors and the tumor diameter (13 , 14) , where the response variable was the logarithm of thickness of the dermal fat layer under tumors and the covariate was the tumor diameter. The mixed (repeated measurement) models (15 , 16) were also used to study the relationship between tumor diameter and the thickness of dermal fat layer under tumors. The linear regression models and the Pearson correlation coefficients (17) were also used to study the relation between variables.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and 2
). Administration of the decaffeinated teas had little or no effect on any of these parameters, and adding caffeine (equivalent to the amount in the regular teas) to the decaffeinated teas restored their inhibitory effects (Table 2)
. Administration of caffeine alone (0.44 mg/ml) decreased the number of tumors/mouse by 61%, the size of the parametrial fat pads by 56%, the thickness of the dermal fat layer away from tumors by 40%, and the thickness of the dermal fat layer directly under tumors by 49% (Table 2)
. A representative illustration of the effect of p.o. administered green tea on the thickness of the dermal fat layer away from tumors and under tumors is shown in Fig. 1
. Although only the regular teas, caffeine, or the decaffeinated teas plus caffeine decreased tumor multiplicity in high-risk mice, tumor size (per tumor) was decreased by the administration of the regular teas, the decaffeinated teas, and caffeine (Table 1)
. The number of mice with tumors was decreased significantly (P < 0.05) in mice treated with green tea, caffeine, decaffeinated green tea plus caffeine, or decaffeinated black tea plus caffeine (Table 1)
.
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is that the dermal fat layer is much thinner under tumors than away from tumors in all experimental groups. For instance, in high-risk mice given only water as their drinking fluid for 23 weeks, the thickness of the dermal fat layer away from tumors was 162 µm, but it was only 60 µm directly under tumors (Table 2)
. In high-risk mice given 0.6% green tea for 23 weeks, the thickness of the dermal fat layer away from tumors was 100 µm, but it was only 28 µm directly under tumors (Table 2)
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Relationship between the Thickness of the Dermal Fat Layer away from Tumors and Tumor Multiplicity.
The 179 mice with skin nodules (Table 1)
were analyzed histologically for tumors; 152 of these mice had a total of 689 tumors, and 29 mice had no tumors. The relationship between the thickness of the dermal fat layer away from tumors (possible surrogate for total body fat levels) in individual mice and the number of tumors/mouse in all 179 mice is shown in Table 3
. Fourteen mice with a very thin dermal fat layer (
50 µm) away from tumors had an average of only 1.6 ± 0.7 tumors/mouse, whereas seven mice with a thick dermal fat layer (>250 µm) away from tumors had 7.4 ± 1.8 tumors/mouse. Regression analysis was performed with data from all 179 mice to assess the relationship between the thickness of the dermal fat layer away from tumors for each mouse and the number of tumors/mouse. There was a highly significant positive linear association between the number of tumors/mouse and the thickness of the dermal fat layer away from the tumors (P = 0.0001). The regression equation was: tumors/mouse = 0.83 + 0.025 x (thickness of the dermal fat layer away from tumors in µm).
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. For mice ingesting only noncaffeinated beverages, there was still a highly significant positive linear association between the number of tumors/mouse and the dermal fat thickness away from tumors (P = 0.009). The regression equation was: tumors/mouse = 2.84 + 0.02 x (thickness of the dermal fat layer away from tumors in µm).
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Effects of Caffeinated Beverages on the Thickness of the Dermal Fat Layer under Tumors of Different Sizes.
For the 152 tumor-bearing mice ingesting noncaffeinated or caffeinated beverages, the thickness of the dermal fat layer under the 689 tumors described in Table 1
was related to tumor size, and it can be seen that larger tumors had a smaller dermal fat layer under the tumors than did smaller tumors (Table 5
; P < 0.0001). For tumors 0.5 mm diameter, the thickness of the dermal fat layer directly under these tumors was 58 ± 3 µm (202 tumors), and for tumors >3 mm, the thickness of the dermal fat layer under the tumors was 24 ± 5 µm (50 tumors). Analysis of the data using the random coefficient model showed that there was a significant negative linear association between tumor size and the log thickness of the dermal fat layer directly under tumors (P = 0.0001).
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The results indicate that p.o. administration of caffeinated beverages decreased the thickness of the dermal fat layer under tumors, and this effect was greatly magnified with large tumors. The administration of caffeinated beverages decreased the thickness of the dermal fat layer directly under the tumors by 36% for small tumors (0.5 mm diameter), by 57% for 0.5–1-mm tumors, by 70% for 1–2-mm tumors, by 90% for 2–3-mm tumors, and by 97% for tumors >3 mm (Table 5)
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Effect of Administration of Green Tea, Black Tea, and Caffeine on the Weight of the Parametrial Fat Pads and the Thickness of the Dermal Fat Layer in Normal Non-UVB-treated Mice.
p.o. administration of green tea, black tea, decaffeinated green tea plus caffeine, decaffeinated black tea plus caffeine, or caffeine alone to normal non-UVB-treated SKH-1 mice for 4 or 8 weeks decreased the weight of the parametrial fat pads and the thickness of the dermal fat layer, but the decaffeinated teas had little or no effect (Table 6)
. None of the treatments had an effect on body weight (Table 6)
. There was a strong positive correlation between the weight of the parametrial fat pads and the thickness of the dermal fat layer (P < 0.0001; Table 6
, experiments 5 and 6). Administration of caffeine or green tea for only 2 weeks decreased the weight of the parametrial fat pads and the thickness of the dermal fat layer (Table 6
, experiments 1–3). Oral administration of EGCG (2 mg/ml) for 2 or 4 weeks had little or no effect on the weight of the parametrial fat pad (Table 6
, experiments 3 and 4) or the thickness of the dermal fat layer (Table 6
, experiment 4). The concentration of EGCG used was equivalent to the concentration of total catechins in 0.6% green tea.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These effects on tumor multiplicity and fat disposition were not observed in animals treated with the decaffeinated teas, thereby pointing out the importance of caffeine for the effects of the regular caffeinated teas on carcinogenesis and in lowering tissue fat levels. The importance of caffeine as a major component of tea that is responsible for the inhibition of UV-induced carcinogenesis was pointed out in our earlier studies (8
, 10)
. The effects of caffeinated teas or caffeine to decrease the size of the parametrial fat pads and to decrease the thickness of the dermal fat layer were also observed in normal non-UVB-treated mice (Table 6)
. The mechanism of the effects of caffeinated teas or caffeine to decrease tumor multiplicity is not known but could result from effects of these agents on cell proliferation, apoptosis, angiogenesis, and/or the immune system. Tea-induced changes in these parameters could be mediated by changes in body fat levels.
Although caffeine is the major component of p.o. administered tea that inhibits skin carcinogenesis in UVB-pretreated, high-risk mice (8)
or in mice treated concurrently with tea and UVB in a complete carcinogenesis model (10)
, noncaffeine components of tea are strong inhibitors of UVB-induced carcinogenesis in 7,12-dimethylbenz[a]-anthracene-pretreated mice, and they also decrease tumor size in UVB-pretreated high risk mice (8
, 9)
. Additional studies have indicated inhibitory effects of decaffeinated teas or EGCG on the formation of several chemically induced cancers (18
, 19)
. The relationship between the effects of the various teas and caffeine on carcinogenesis and body fat was evaluated in more detail by examining the relationship between tumors/mouse and dermal fat thickness away from tumors (as a surrogate for body fat levels) in individual mice. We observed a highly significant direct correlation between the thickness of the dermal fat layer (measured in areas away from tumors) and the number of tumors/mouse (Table 3
; P = 0.0001). The relationship between tumor size/mouse and dermal fat thickness (away from tumors), however, was much less robust (Table 3
; P = 0.034). These results suggest that tumor multiplicity and tumor size may be regulated differently. The use of dermal fat thickness as a surrogate for body fat is supported by a positive correlation between the thickness of the dermal fat layer and the weight of the parametrial fat pads in individual mice (Table 6
, experiments 5, and 6).
Although several dietary modifications are known to inhibit carcinogenesis, and some may decrease body fat levels in rodents [e.g., calorie restriction (20, 21, 23) , low-fat diets (23) , and CLA administration (24 , 25) ], this is the first study to show a close relationship between the effect of a cancer chemopreventive agent to inhibit carcinogenesis and to lower tissue fat levels. The results of the present study suggest that the inhibitory effect of p.o. administration of tea or caffeine on carcinogenesis in high-risk mice may be related—at least in part—to their effects on tissue levels of fat. The linkage between tea-induced decreases in tissue fat levels and decreases in tumor multiplicity is much stronger than the linkage between tea-induced decreases in tissue fat levels and tumor size. These results suggest that changes in dermal fat levels may be more important for modulating tumor formation (multiplicity) than for modulating tumor growth (size).
The thickness of the dermal fat layer directly under tumors was less than that away from tumors (Table 2)
suggesting that dermal fat under tumors may be used by the tumors as a source of energy. This concept is also in accord with finding less dermal fat under large tumors than under small tumors (Table 5)
. Administration of caffeinated beverages decreased the thickness of the dermal fat layer under both small and large tumors, but the effect of caffeinated beverages on fat was greatly magnified under large tumors (Table 5)
. Administration of caffeinated beverages decreased the thickness of the dermal fat layer by 36% under small tumors (0.5 mm diameter) and by 97% under large tumors (>3 mm diameter; Table 5
). It will be of interest to determine whether tumors secrete substances that synergize with caffeine to decrease dermal fat thickness under tumors.
It should be noted that the inhibitory effects of the regular caffeinated teas and caffeine on tumorigenesis and body fat levels (as measured by changes in the size of the parametrial fat pads and dermal fat thickness) occurred in the absence of effects on body weight (Tables 1
, 6
, and 7
) or food consumption (Table 7)
. These results suggest that administration of the regular caffeinated teas or caffeine decreased the proportion of body fat without changing overall energy intake or utilization. Although additional studies are needed to determine the effects of tea and caffeine on total body fat and protein levels, our results indicate that p.o. administration of the caffeinated teas or caffeine increased lipolysis or decreased the absorption or synthesis of fat without changing body weight.
Other investigators have also demonstrated the effects of tea administration on lipid disposition. Kimura et al. (26) reported that administration of green tea, black tea, or oolong tea inhibited elevations in serum and liver lipids (total cholesterol and triglycerides) that occurred in rats fed peroxidized oil for 1 week. Additional studies showed a hypolipidemic effect of green tea (lowered serum total cholesterol, triglycerides, and low-density lipoprotein-cholesterol) along with a lowered body weight in rats treated with green tea (27) . In another study, administration of oolong tea prevented the obesity and fatty livers that were induced by a high fat diet (28) . An antilipidemic constituent of tea was identified as caffeine, which was shown to stimulate norepinepherine-induced lipolysis in fat cells (28) . A very recent study by Dulloo et al. (29) indicated that oral administration of a green tea extract rich in catechin polyphenols and caffeine during breakfast, lunch, and dinner stimulated 24-h energy expenditure and fat oxidation in humans, but administration of an equivalent amount of caffeine alone was reported to have little or no effect. The amounts of catechin polyphenols administered with each meal were comparable with the amounts commonly ingested by tea drinkers. In other studies, administration of caffeine together with sympathetic stimulation (cold stress or exercise) or with sympathomimetic drugs such as ephedrine stimulated thermogenesis (30 , 31) . Dulloo et al. (29) suggested that caffeine and the tea catechins may have a synergistic stimulatory effect in enhancing energy expenditure and fat oxidation because of an inhibitory effect of tea polyphenols on catechol O-methyltransferase activity (32) , which would be expected to elevate endogenous norepinepherine levels, and because of an inhibitory effect of caffeine on phosphodiesterase activity, which would be expected to elevate the levels of cyclic AMP and potentiate the action of catecholamines on thermogenesis. The studies and concepts by Dulloo are interesting, and they require confirmation. In a preliminary study in SKH-1 mice, p.o. administration of EGCG (2 mg/ml) together with a low concentration of caffeine (0.011%) as the drinking fluid for 4 weeks did not enhance the fat-lowering effect of caffeine itself (data not presented).
Baumann and Rusch (33)
—more than 60 years ago—were the first to demonstrate a stimulatory effect of high levels of dietary fat on UV-induced skin carcinogenesis. Subsequently, Black et al. (34, 35, 36, 37)
confirmed the stimulatory effect of high levels of dietary fat on UV-induced skin carcinogenesis, and they reported that unsaturated fat stimulated carcinogenesis to a greater extent than saturated fat. These investigators also reported that dietary antioxidants inhibited UV-induced carcinogenesis but only when high levels of lipids were administered (35
, 36)
. The stimulatory effect of a high fat diet on UV-induced carcinogenesis was observed when the high fat diet was fed either during the entire experimental period or only after stopping UV administration (37
, 38)
. These results indicate a postinitiation effect of the high fat diet. Although corn oil and menhaden oil both contain unsaturated lipids, high levels of dietary corn oil (rich in 
-6 unsaturated fatty acids) enhanced UV-induced carcinogenesis, whereas high levels of dietary menhaden oil (rich in unsaturated -3 fatty acids) did not (37)
. Overall, the results indicate that high levels of dietary fat enhance UV-induced carcinogenesis in mice, and the kind of dietary lipid administered can influence the carcinogenic response.
Leyton et al. (39) observed that changes in the diet can influence the fatty acid composition of epidermal phospholipids in mice. Increasing the dietary linoleate levels resulted in an increased level of linoleate and a decreased level of arachidonate in phosphatidylcholine (39) . Similar diet-induced changes were observed for linoleate and arachidonate in other phospholipids (39) . It will be of interest to determine the effects of administration of tea and caffeine on the profile of fatty acids in epidermal phospholipids and in the neutral fat of the parametrial fat pads. Decreased levels of arachidonic acid in the epidermis could result in decreased levels of prostaglandins that have been implicated in carcinogenesis. Pariza et al. (40, 41, 42 ) recently identified CLA as an anticarcinogenic substance in grilled ground beef and in dairy products. Administration of this substance inhibited chemically induced tumorigenesis in several animal models (24 , 25 , 41) , and the levels of arachidonic acid and linoleic acid-derived polyunsaturated fatty acids in the mammary gland (a neutral fat-containing tissue) was decreased (43) . Total body fat was also decreased and total body protein and water were increased (44 , 45) . Mechanistic studies suggested a stimulatory effect of CLA administration on the rate-limiting enzyme for fatty acid ß-oxidation (increases in carnitine palmitoyltransferase activity in fat and muscle) and enhanced lipolysis (44) . Additional studies indicated an inhibitory effect of CLA on stearoyl-CoA desaturase (46 , 47) and an effect of CLA administration on monounsaturated fatty acid composition (48) . The effects of tea and caffeine on fatty acid synthesis, fatty acid ß-oxidation, stearoyl-CoA desaturase, and fatty acid composition have not yet been studied.
Although some case-control and prospective epidemiology studies indicated no relationship between fat intake and risk of nonmelanoma skin cancer in humans (49 , 50) , a recent large prospective epidemiology study in men suggested an inverse association between dietary intake of monounsaturated fat and basal cell carcinomas (51) . An additional case-control study suggested an inverse relationship between a high intake of polyunsaturated fatty acids and melanoma in women (52) . A more rigorous randomized intervention trial in human subjects indicated that reducing the percentage of fat calories from 39% to 21% of total calories caused a marked reduction in the number of actinic keratoses and skin cancers (53, 54, 55) . Although the latter rigorous intervention study indicates that decreasing the level of dietary fat can inhibit the formation of UV-induced nonmelanoma skin tumors in humans, an extension of these intervention trials is needed.
In conclusion, p.o. administration of caffeinated teas or caffeine to UVB-pretreated, high-risk mice decreased tumor multiplicity, the size of the parametrial fat pads, and the thickness of the dermal fat layer. The decaffeinated teas were essentially inactive, and adding back caffeine restored activity. There was a highly significant correlation between dermal fat thickness away from tumors and tumor multiplicity in individual mice. Additional studies are needed to determine whether the inhibitory effect of the caffeinated teas and caffeine on tumor multiplicity are caused by their effects on dermal fat (cause/effect relationship) and whether caffeinated teas or caffeine decrease the arachidonic acid content or modify the levels of other fatty acids in dermal fat or in epidermal phospholipids. Tea- or caffeine-induced decreases in the arachidonic acid level in fat could result in decreased levels of prostaglandins that are believed to play a role in the carcinogenic process. The possibility that administration of the caffeinated teas or caffeine inhibit tumorigenesis by decreasing the amount of fat available as a source of energy under tumors also requires exploration. Additional studies are also needed to determine whether other cancer chemopreventive agents inhibit carcinogenesis by decreasing body fat levels.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported in part by NIH Grant CA49756. 
2 To whom requests for reprints should be addressed, at Rutgers, The State University of New Jersey, Laboratory for Cancer Research, College of Pharmacy, 164 Frelinghuysen Road, Piscataway, NJ 08854-8020.
3 The abbreviations used are: UVB, ultraviolet B light; UVA, ultraviolet A light; EGCG, (-)-epigallocatechin gallate; CLA, conjugated linoleic acid.
Received 1/12/01. Accepted 4/30/01.
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