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Background: The impact of alcohol drinking on gastric precancerous lesions remains unclear. We investigated the relationship of alcohol intake with risk of atrophic gastritis (AG) and intestinal metaplasia (IM)., Methods: This study included 202,675 Korean adults free from AG and IM on their initial endoscopy who were followed with repeated endoscopic examinations. A parametric proportional hazards model was used to estimate the adjusted HR (aHR) with 95% confidence interval (CI) for incident AG and IM based on endoscopic diagnosis., Results: During a mean follow-up of 4.7 years, 64,853 incident AG cases and 4,536 IM cases were identified. Alcohol consumption including drinking frequency, quantity, and binge drinking were consistently associated with increased risk of both AG and IM in a dose-response manner. After adjustment for confounders, the multivariable aHRs (95% CIs) for incident IM comparing average alcohol intake of <10, 10-<20, 20-<40, and ≥40 g/day with lifetime abstainers were 1.27 (1.02-1.56), 1.34 (1.07-1.66), 1.50 (1.20-1.86), and 1.54 (1.23-1.93), respectively. Former drinkers were also at a higher risk for AG and IM compared with lifetime abstainers. These associations were consistently observed in never smokers and in time-dependent analyses., Conclusions: In a large cohort of Korean individuals, alcohol intake even at low levels was independently associated with increased risk of developing endoscopic AG and IM, supporting a role of alcohol consumption in the pathogenesis of AG and IM, the precursor lesions of stomach cancer., Impact: Alcohol consumption from low-level drinking may contribute to gastric carcinogenesis., (©2020 American Association for Cancer Research.)

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects., Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years ( n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls., Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11-1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05-2.49; P = 0.03)., Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors., Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence., (©2019 American Association for Cancer Research.)

The occurrence of intestinal polyps in people at high risk for developing colorectal cancer provides an opportunity to test the efficacy of chemoprevention agents. In this situation of treating otherwise healthy people, the potential for toxicity must be minimal. The small-molecule flexible heteroarotinoid (Flex-Het), called SHetA2, has chemoprevention activity in organotypic cultures in vitro and lack of toxicity at doses capable of inhibiting xenograft tumor growth in vivo. The objective of this study was to evaluate SHetA2 chemoprevention activity and toxicity in the APC(min/+) murine model. Oral administration of SHetA2 at 30 and 60 mg/kg five days per week for 12 weeks significantly reduced development of intestinal polyps by 40% to 60% depending on the dose and sex of the treatment group. Immunohistochemical and Western blot analysis of polyps showed reduced levels of cyclin D1 and proliferating cell nuclear antigen in both SHetA2 treatment groups. Western blot analysis also showed SHetA2 induction of E-cadherin, Bax, and caspase-3 cleavage along with reduction in Bcl-2, COX-2, and VEGF, consistent with SHetA2 regulation of apoptosis, inflammation, and angiogenesis. Neither dose caused weight loss nor gross toxicity in APC(min/+) or wild-type littermates. Magnetic resonance imaging (MRI) of cardiac function showed no evidence of SHetA2 toxicity. SHetA2 did not alter left ventricular wall thickness. In summary, SHetA2 exerts chemoprevention activity without overt or cardiac toxicity in the APC(min/+) model. SHetA2 modulation of biomarkers in colon polyps identifies potential pharmacodynamic endpoints for SHetA2 clinical trials.

To determine whether visceral fat (VF), independent of other confounders, is causally linked to intestinal tumorigenesis, we surgically removed visceral fat in Apc(1638/N+) mice. At 15 weeks of age, male and female Apc(1638/N+) mice were randomized to one of three groups: ad libitum, visceral fat removal (VF-) and ad libitum fed, or caloric restriction, and were studied for effects on tumorigenesis and survival. As compared with ad libitum, VF- and caloric restriction reduced macroadenomas to a similar extent (P < 0.05), but only caloric restriction significantly improved survival (P < 0.05). Given that a significant group × gender interaction was observed, we next examined males and females separately. In females, macroadenomas were markedly attenuated by VF- (1.33 ± 0.23 mean ± SE; P < 0.05), but not by caloric restriction (2.35 ± 0.25; P = 0.71), as compared with ad libitum (2.50 ± 0.34). In males, however, caloric restriction (1.71 ± 0.26; P < 0.01), but not VF- (2.94 ± 0.42; P = 0.29), reduced macroadenomas, as compared with ad libitum males (3.47 ± 0.30). In females, both VF- (P = 0.05) and caloric restriction (P < 0.01) improved survival, but not in male mice (P = 0.15). The benefits observed with caloric restriction were consistent with favorable metabolic adaptations, but protection conferred in VF- females was despite lower adiponectin levels (P < 0.05), and failure to reduce body mass, total adiposity, glucose, insulin, leptin, and chemokine (C-X-C motif) ligand 1 (CXCL-1) levels. In conclusion, these data provide the first causal evidence linking visceral fat to intestinal cancer risk, and suggest that factors, other than known metabolic mediators, may impact tumor development. Furthermore, these data emphasize that strategies designed to deplete visceral fat stores in humans should be considered in the prevention of intestinal cancer. Cancer Prev Res; 6(3); 177-87. ©2012 AACR., (©2012 AACR.)

Diets high in red and processed meats are associated with carcinogenesis of the large intestine, but no prospective study has examined meat and fat intake in relation to cancer of the small intestine. We prospectively investigated meat and fat intakes, estimated from a food frequency questionnaire, in relation to small intestinal cancer among half a million men and women enrolled in the NIH-AARP Diet and Health Study. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). During up to 8 years of follow-up, 60 adenocarcinomas and 80 carcinoid tumors of the small intestine were diagnosed. Despite slightly elevated HRs for red meat, there were no clear associations for red or processed meat intake and either adenocarcinoma or carcinoid tumors of the small intestine. In contrast, we noted a markedly elevated risk for carcinoid tumors of the small intestine with saturated fat intake in both the categorical (highest versus lowest tertile: HR, 3.18; 95% CI, 1.62-6.25) and continuous data (HR, 3.72; 95% CI, 1.79-7.74 for each 10-g increase in intake per 1,000 kcal). Our findings suggest that the positive associations for meat intake reported in previous case-control studies may partly be explained by saturated fat intake.

Clinical reports have suggested that low dietary folate increases risk for colorectal cancer. Animal studies for investigation of folate and tumorigenesis have used carcinogen induction or mice with germ-line mutations. We have developed a new spontaneous tumor model in which mice, with or without a null allele in a key folate-metabolizing enzyme, methylenetetrahydrofolate reductase (Mthfr), develop intestinal tumors due to low dietary folate alone. On folate-deficient diets, 12.5% of Mthfr(+/+) mice and 28.1% of Mthfr(+/-) mice developed tumors; mice on control diets were negative. Dietary and genotype effects on tumor development were significant. To investigate mechanisms of folate-dependent tumorigenesis, we examined levels of DNA damage and gene expression of two genes involved in DNA damage response and G(2)-M checkpoint regulation, polo-like kinase 1 (Plk1) and cell division cycle 25c (Cdc25c). Folate deficiency increased DNA damage and decreased expression of both genes (assessed by quantitative reverse transcription-PCR and immunofluorescence) in normal intestine compared with levels in mice on control diets. An immunofluorescence assay for CDC25c activity (phosphorylated CDC2) also found CDC25c activity to be decreased in folate-deficient normal intestine. In tumors, however, Plk1 and Cdc25c mRNA were found to be higher (11- and 3-fold, respectively) compared with normal intestine from folate-deficient mice; immunofluorescence studies of PLK1, CDC25c, and phosphorylated CDC2 supported these findings. Our data suggest that folate deficiency can initiate tumor development, that Mthfr mutation can enhance this phenomenon, and that altered expression of Plk1 and Cdc25c may contribute to folate-dependent intestinal tumorigenesis.

Mice with a targeted inactivation of both alleles of the cyclin-dependent kinase inhibitor p27(kip1) developed both small and large intestinal adenomas when fed a control AIN-76A diet. A Western-style diet that is high in fat and phosphate and low in calcium and vitamin D was also able to initiate adenoma formation in wild-type mice. The combination of p27(kip1) inactivation and the Western-style diet was additive in terms of tumor incidence, frequency and size, and in reducing the life span of the mice. The genetic and dietary combination also resulted in development of adenocarcinoma. Tumor formation was linked to a disruption in homeostasis of the intestinal mucosa, involving increased cell proliferation and decreased apoptosis. There was also decreased goblet cell differentiation as assessed by alcian blue staining and expression of the Muc2 gene, especially in mice fed the Western-style diet, although this differentiation lineage was still present as indicated by expression and staining for intestinal trefoil factor. The inactivation of p27(kip1) and the consequent disruption of normal colonic cell maturation in the mucosa were associated with modestly elevated c-myc, cdk4, and cyclin D1 expression. These data establish a fundamental role for p27(kip1) in maintenance of intestinal cell homeostasis and in suppressing tumor formation. The data also emphasize the critical role that dietary factors can have in both tumor initiation and progression through interaction with pathways that normally maintain intestinal homeostasis.

Ionizing radiation (IR) is a well-characterized carcinogen in humans and mice. The BALB/c mouse strain is unusually sensitive to IR-induced tissue damage and cancer development in a range of organs, suggestive of a partial defect in DNA damage response. This has been confirmed by finding BALB/c-specific functional polymorphism in Prkdc, a gene on mouse chromosome 16 that encodes the catalytic subunit of DNA-dependent protein kinase. Prkdc(BALB) has been associated with increased susceptibility to IR-induced mammary and lymphatic neoplasia. Here, we provide evidence that chromosome 16 segments from BALB/c interact with Apc(Min) (multiple intestinal neoplasia) and specifically enhance IR-induced adenoma development in the upper part of the small intestine.

Menopausal hormone replacement therapy has been widely used to alleviate the symptoms of menopause and to decrease the detrimental effects of ovarian hormone loss on bone density and cardiovascular health. Multiple studies of colorectal cancer epidemiology also support a role for hormone replacement therapy in prevention of colorectal cancer. We studied the effect of ovariectomy and estrogen replacement on tumor formation in C57BL/6J-Min/+ (Min/+) mice, animals that bear a germline mutation in murine Apc. These mice develop multiple intestinal tumors that show loss of wild-type Apc protein. After ovariectomy, intestinal adenomas in Min/+ mice increased by 77% (P = 0.0004). Ovariectomized Min/+ mice that were treated with a replacement dose of 17beta-estradiol had the same number of tumors as Min/+ mice that were neither castrated nor treated with estrogen replacement (P = 0.85). Examination of estrogen receptor (ER) levels in intestinal tissue by immunoblot showed changes in relative expression levels of ERalpha and ERbeta, with highest ERalpha and lowest ERbeta expression in the normal-appearing intestine of Min/+ mice, and lowest ERalpha and highest ERbeta expression in the enterocytes of animals that received 17beta-estradiol. These results suggest that endogenous estrogens protect against Apc-associated tumor formation and that tumor prevention by 17beta-estradiol is associated with an increase in ERbeta and a decrease in ERalpha expression in the target tissue.

Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P<0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P<0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G1 proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.

Despite its anatomical location between two regions of high cancer risk, the small bowel rarely develops a malignant tumor. However, in recent years, small bowel cancer incidence rates have begun to rise. The purpose of this review is to explore the descriptive and analytic epidemiology of small bowel cancer for those factors that protect this organ and those factors associated with loss of this protection. Within the small intestine, the sites at the highest risk are the duodenum, for adenocarcinomas, and the ileum, for carcinoids and lymphomas. In industrialized countries, small bowel cancers are predominantly adenocarcinomas; in developing countries, lymphomas are much more common. The incidence of small bowel cancer rises with age and has generally been higher among males than among females. The risk factors for small bowel cancer include dietary factors similar to those implicated in large bowel cancer, cigarette smoking, alcohol intake, and other medical conditions, including Crohn's disease, familial adenomatous polyposis, cholecystectomy, peptic ulcer disease, and cystic fibrosis. The protective factors may include rapid cell turnover, a general absence of bacteria, an alkaline environment, and low levels of activating enzymes of precarcinogens. Adenocarcinomas of the small and large bowel are similar in risk factors and geographic distribution but not in recent time trends; colorectal cancer incidence rates in the United States have been falling since the mid-1980s. Small bowel lymphoma may be associated with infectious agents, such as HIV. Given the differences in anatomic and geographic location among histological subtypes, much may be learned from well-designed, histology-specific epidemiological and genetic studies of cancer of the small bowel.

We have tested the hypothesis that enteric bacteria are necessary for formation of intestinal adenomas in C57BL/6-ApcMin/+ mouse. Germ-free mice developed 2-fold fewer adenomas than conventional controls in the medial small intestine (7.3 versus 14.9; P < 0.003), but there were no significant differences in the rest of the intestinal tract. We conclude that microbial status does not strongly alter the adenoma phenotype in this mouse model of familial adenomatous polyposis. In parallel, we have found that C57BL/6-ApcMin/+ mice mutated at the beige locus, which controls natural killer activity, are also unaltered in adenoma multiplicity.

Hereditary nonpolyposis colorectal cancer is associated with defects in DNA mismatch repair. Here, we characterize tumor susceptibility of the recently described Msh2-deficient mouse model. Within the first year of observation, all homozygous mice succumbed to disease, with lymphomas observed in at least 80% of the cases. The majority (70%) of animals 6 months or older developed intestinal neoplasms associated with APC inactivation. Microsatellite instability was more common in carcinomas than in adenomas, but uncommon in normal tissues. Some animals (7%) developed a variety of skin neoplasms analogous to the Muir-Torre syndrome. Msh2-/- mice implicate a direct role for mismatch repair in several neoplasms with striking phenotypic similarities to humans.

Although the small intestine contains 75% of the mucosal surface of the gastrointestinal tract, it is the site of only 2% as many malignancies as the large bowel. The association of Crohn's disease with small intestine adenocarcinoma is well known, but the analytic epidemiology of small intestine malignancies has not received much attention. We reviewed the medical records of 19 patients with adenocarcinoma and 17 with malignant carcinoids identified from the Columbia-Presbyterian Medical Center Tumor Registry in the years 1980-1987. These were compared with 52 controls with nonmalignant conditions from the same time period. Three adenocarcinoma patients but no carcinoid patients or controls had previous Crohn's disease (P < 0.004). Three adenocarcinomas and three carcinoids, but no controls, had previous cholecystectomy (P < 0.004). Previous peptic ulcer disease was recorded for two patients with adenocarcinoma and three with carcinoid but no controls (P < 0.02, P < 0.0002). The age and sex adjusted odds ratio for cigarette smoking was 4.6 (95% confidence interval, 1.0-20.7) for adenocarcinomas and 4.2 (0.8-22.4) for carcinoids. The adjusted odds ratio for alcohol consumption was 4.0 (1.0-15.9) for adenocarcinomas and 3.1 (0.7-13.9) for carcinoids. Further studies are warranted to confirm these associations and to identify potential protective factors in the small intestine.

Two 3 x 3 factorial experiments were conducted to examine the effects of dietary protein (8, 16, and 32% of energy from casein) and dietary fat (12, 24, and 48% of energy from corn oil) on the initiation and promotion of azoxymethane-induced carcinogenesis in rats. For the initiation study, 33 weanling male Sprague-Dawley rats were randomized to each of nine diets fed ad libitum. Azoxymethane was administered s.c. between the fourth to sixth weeks of feeding, providing a total dose of 6 mg/100 g body weight. All rats were subsequently fed a common diet containing 16% energy from protein and 24% energy from fat for an additional 30 to 38 weeks. For the promotion study, all rats were fed a common diet containing 16% of energy from protein and 12% of energy from fat until the completion of azoxymethane administration, when 33 rats were randomized to each of nine diets varying in fat and protein content and fed these diets until sacrifice. Low-protein diets during the initiation phase were associated with increased risk of renal adenocarcinomas (P less than 0.001) and mesenchymal (P = 0.005) malignancies. No other statistically significant relationships were found between the levels of dietary fat or protein and the prevalence of malignant lesions of the small intestine, colon, or kidney in either the initiation or promotion study (although polypoid adenocarcinoma of the colon increased suggestively from 13 to 19 to 26% of rats with increasing dietary protein during initiation). Results of a multiple logistic regression analysis, combining both studies, showed that ad libitum energy intake was significantly associated with intestinal carcinogenesis. The odds of finding an intestinal adenocarcinoma increased by 6.2 +/- 2.6% (SE) for each additional kilocalorie of mean daily ad libitum intake (P = 0.014). The quintile of rats which consumed the least averaged 60 kcal/day, while the most voracious quintile averaged 74 kcal/day. This 14 kcal/day difference in mean ad libitum intake corresponded to more than a doubling (146% increase) of the odds of developing an intestinal adenocarcinoma. These studies suggest that ad libitum energy intake is a critical factor modulating experimental colon carcinogenesis.

There is epidemiological and experimental evidenced that the ingestion of excessive amounts of fat enhances intestinal cancer formation. This may be due to the interaction of luminal steroids with the bacterial flora in the colon, forming carcinogens or promoting agents. Increased fecal steroids induced by drugs, diet, or by mechanical means enhance intestinal tumor formation in rats given injections of azoxymethane. The effect appears to be promotional rather than initiative. Dietary fiber inhibits carcinogenesis only when the fat content of the diet is not excessive. Apparently, a quantitative relationship exists between these two dietary elements that further studies may define for prevention of cancer in humans.

Studies in metabolic epidemiology have shown that the dietary intake of high fat affects the composition of the intestinal bacteria and their metabolic activity as well as the levels of certain neutral sterols and bile acids that may act as tumor promoters for the colon. A strong association has also been established between microbially modified bile acids and cholesterol metabolites and the risk of colon cancer among different populations. The patients with colon cancer had high concentrations of fecal bile acids and cholesterol metabolites compared with the controls. It remains to be shown whether this established association is causative in nature.

According to the hypothesis being tested by this laboratory, bacteria (in particular, certain clostridia) metabolize the bile acids to give unsaturated products that are important in the causation of colorectal cancer. In this paper, various dietary regimens are discussed in terms of their effect on the fecal steroid concentration and on the gut bacterial flora. The diets considered include high- and low-fiber, high- and low-meat, and high- and low-fat diets.

Compensatory hyperplasia after extensive loss of functioning small or large intestine might predispose to the development of neoplasia in the residual adapted bowel. To test this hypothesis, male Fischer rats were randomized to receive 85 to 90% jejunoileal resection or bypass, subtotal colectomy, or no operation (controls). One week later, the first of six weekly s.c. injections of azoxymethane (15 mg/kg/week) was given. At the 36th week postoperatively, mean body weight after enterectomy or colectomy it was 78 to 79% of control. Adaptation after all three operations was characterized by 22 to 84% increments in villous height and crypt depth in the residual functioning ileum (p = 0.05 to 0.001); the depth of colonic crypts was unchanged. Fewer rats developed intestinal tumors after enteric bypass (36%) than after any of the other treatments (80 to 91%) (p = 0.01 to 0.001); the depth of colonic crypts was unchanged. Fewer rats developed intestinal tumors after enteric bypass (36%) than after any of the other treatments (80 to 91%) (p = 0.01 to 0.001). Compared with controls, bypass reduced the number of colonic tumors by 77% (p less than 0.001). Although resection did not affect colonic tumor yield, it tripled the incidence of tumors in the duodenum and jejunum (p = 0.025). Colectomy promoted rectal carcinogenesis (p less than 0.05). Anastomotic tumors were commoner after intestinal resection. the lower frequency of tumors after jejunoileal bypass contrasts with enhanced carcinogenesis after enterectomy or colectomy. Profound reduction in body weight may prevent the promotional effect of adaptive hyperplasia.

Deaths from cancers of the large bowel, breast, and prostate were ascertained over a 21-year period among 21,295 white California Adventists. Compared to non-Adventists, the age-sex-adjusted mortality for large bowel cancer was substantially reduced among Adventists. Adventists also showed a minimum reduction in mortality for breast and prostate cancer. Fatal large bowel cancer within the Adventist group was unrelated to meat use. However, coffee use showed a substantial positive association with fatal large bowel cancer. Although this association may be indirect or spurious, it deserves further investigation. Weak nonsignificant associations were observed between cancers of the breast and prostate and meat use.

Results from epidemiogical studies have provided clues as to etiological factors involved in the development of large bowel cancer. Overnutrition, especially in terms of dietary fat consumed, appears to be a key etiological variable affecting the rate of colon cancer. Epidemiologists can provide the leads for chemists and bacteriologists to pursue in population groups and for experimentalists to test in laboratory animals. Coordination of and cooperation between many disciplines is necessary in order to contribute to the prevention of this man-made disease.

High-fat diets enhance the development of mammary and intestinal tumors on animals, and dietary fat also shows a strong positive correlation with mortality from cancers of the breast and colon in human populations. In animals, dietary fat appears to act as a promoter of carcinogenesis rather than as an influence in the initiation of tumors. Polyunsaturated fats enhance mammary tumorigenesis and stimulate tumor growth more effectively than do saturated fats. However, diets containing a small amount of polyunsaturated fat and a high level of saturated fat increase mammary tumor yields as effectively as do diets containing a high level of polyunsaturated fat. Fatty acids of either the linoleate or linolenate family appear to be able to satisfy the small requirement for polyunsaturated fat. The mechanism by which dietary fat influences mammary tumorigenesis is not known but may involve hormonal effects, immune responses, to alterations in cellular membranes. Dietary fat is thought to enhance the development of intestinal tumors by stimulating production of bile acids, some of which act as promoters of tumorigenesis.

Promotional properties of a high-fat diet in intestinal cancer were studied by feeding a 30% beef fat diet to 8 groups of rats (25 rats/group) for time periods varying from 1 to 21 weeks after 8 weekly s.c. injections of azoxymethane (AOM) (8 mg/ kg). Two other groups were fed the high-fat diet, one for 8 weeks prior to and the other during AOM injections. A 5% fat diet was fed to rats when not on the 30% fat diet and to a control group of 25 animals. High fat diet increased intestinal tumor frequency up to 2-fold when given for at least 4 weeks after but not during or prior to AOM injections; this increase occurred even after a prolonged interval (10 weeks) between the last AOM injection and the high-fat diet. In general, tumor frequency increased according to the length of time animals were fed the high-fat diet after AOM. Therefore, the high-fat diet in this model exhibited most of the properties of promoters developed from murine skin cancer, thus adding support to the concept that excess dietary fat acts at the promotional phase of carcinogenesis.