[CANCER RESEARCH (SUPPL.) 52. 2055s-2059s. April 1. 1992|

Dietary Fiber-mediated Mechanisms in Carcinogenesis1

David M. Klurfeld2

The H'istar Institute of Anatomy and Biology, Philadelphia. Pennsylvania 19104

Abstract

Dietary fiber may affect the development of cancers of the gastrointestinal tract and the breast. The biological intermediates studied mosthave been fecal bile acids; both human and animal studies suggest atumor-promoting role of bile acids in the development of colon tumors,although there are conflicting data from human studies. Short-chain fattyacids are major fermentation products of bacterial degradation of dietaryfiber. If short-chain fatty acids explained the tumor-inhibiting propertiesof dietary fiber, the readily fermentable fibers such as guar and pectinwould be more protective than cellulose and wheat bran, which has notbeen observed. Because these two hypotheses do not adequately explainmodulation of tumor growth by dietary fiber, investigation of otherintermediates is indicated. These include physical characteristics of thefeces, such as abrasiveness; intestinal microflora; aqueous-phase bileacids, which may represent the bioavailable pool; alterations in mucins;mutagenicity of intestinal contents; alterations in mucosa! cytokinetics;activities of enzymes, such as ornithine decarboxylase or aryl hydrocarbon hydroxylase; neurogenic effects caused by changes in intestinal bulkor short-chain fatty acids; gut hormones or other peptide growth factors(local or systemic); enterohepatic circulation of hormones; transit time;pH; or decreased availability of total dietary energy.

Introduction

The protective role of dietary fiber against colon cancer wasproposed in 1960 (1) and was extended by Burkitt in 1971 (2)to include a variety of chronic diseases prevalent in affluentsocieties. One of the attractions of dietary fiber for the publicis that it is one of the few dietary components that are recommended to be consumed in greater quantities for improvedhealth. The claims for dietary fiber in the biomedicai literatureinclude reductions of virtually all noninfectious disorders (3).It is generally assumed that dietary fiber has metabolic influences that counter the tumor-promoting effects of dietary fat.The original description of the fiber hypothesis rested on theability of dietary fiber to decrease the exposure of the coloniemucosa to carcinogens and promoters (2). One significant problem in considering dietary fiber is that the definition haschanged over time and there is no universally accepted methodfor its quantitation. Another major related factor is that thereare multiple components of dietary fiber (Table 1). The broadgroupings of soluble and insoluble fibers seem to have disparateeffects on colonie physiology and development of colonie cancerin animal models (4, 5). There are carbohydrate and noncar-bohydrate constituents of dietary fiber, and only some of thecarbohydrates are well fermented when fed as isolated ingredients. In the typical diet, it has been estimated that 70% ofdietary fiber is broken down by colonie flora. Eastwood (6)proposed that simply giving total dietary fiber values for food,without describing specific physiological effects, is analogousto providing a total vitamin content. In 1979, Graham et al. (7)commented on the lack of unequivocal evidence supporting thefiber-fat relationship with cancer. They believed the case for fatpromoting cancer was much stronger than were the data on

' Presented at "Nutrition and Cancer." the first conference of the InternationalConference Series on Nutrition and Health Promotion, April 17-19, 1991,Atlanta. GA. This work was supported in part by Grant CA 43856 from the NIH.

2To whom requests for reprints should be addressed, at The Wistar Institute

of Anatomy and Biology, 36th Street at Spruce. Philadelphia. PA 19104.

fiber preventing cancer at that time. They stated, "It is likely

that the etiology of colon cancer and other cancers is morecomplex than heretofore suspected (Ref. 7, p. 881)." Because

we still do not understand the etiology of colon and othercancers, we are limited to discussing risk factors, i.e., statisticalodds, rather than medical diagnoses. Most of the putativeintermediates described below have been studied in normalpopulations (of both humans and animals) and, therefore, theirrelevance to development of cancer is uncertain. However, inthe absence of knowledge regarding the degree of genetic influence, we are limited to assuming that dietary factors have asimilar magnitude of effect across a population, even thoughthis seems extremely unlikely.

One factor that is often overlooked is the distinction betweencolonie and rectal tumors, because there appear to be differentrisk factors in the etiology of these two tumors. This differentiation is not always easy, because of the relatively high numberof tumors near the rectosigmoid junction. This raises the possibility that there are quantitative or qualitative differences inrisk factors for colonie tumors at different sites within thecolon. Differences in histological appearance of normal mucosawithin the colon and of growth characteristics of tumors atvarious sites in the colon also suggest that responses of theepithelium may differ at different locations. Carcinomas of theright colon are generally bulky and rapidly growing, whereastumors of the left colon tend to be flat and often grow in acharacteristic napkin-ring configuration. In countries with lowincidence of colon tumors most tumors are found in the proximal colon, but in affluent societies with high risk the majorityof tumors are in the distal colon. An example of the differencein risk of colon cancer can be found in the recently publishedresults of a large study of diet and mortality in China (8).Colon-cancer mortality ranges from 0.0 to 6.7/1000, and aboutone-third of the survey sites reported no colon cancer. Althoughthe incidence rate is low by Western standards, the range ofincidence within the country is greater than that seen in theUnited States. There was no correlation of colon-cancer mortality with total dietary fiber (r = —¿�0.01)or any of its compo

nents. There were, however, significant positive correlationswith schistosomiasis (r = 0.72) and percentage employed inindustry (r = 0.41).

Bile Acids

Most studies on dietary fiber and colon-cancer risk havefocused on the role of bile acids, and the majority of epidemi-ological reports have been ecological in nature. These studiesare inherently weakest in their ability to link a specific nutrientor biological intermediate with risk of disease, because theyalmost always report average levels across a sample of the entirepopulation. The average level may not be representative of highrisk. The strength of this type of study is the wide range ofdisease incidence, nutrient intake, or bile acid concentrationthat can be seen internationally. Studies sponsored by theInternational Agency for Research on Cancer have contributedsignificantly by studying countries of similar socioeconomicstatus that differ 4-fold in colon-cancer incidence. One compar-

2055s

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

DIETARY FIBER AND CARC1NOGENESIS

Table I Dietary fiber and related compounds

Insoluble (poorly fermented)CelluloseLignin. a phenylpropane polymerSome hemicelluloses

Soluble (highly fermented)PectinsGumsMucilagesAlgal polysaccharidcsSome hemicelluloses

Minor componentsCutins. waxes, phytic acid

Related componentsStarch and protein resistant to digestive enzymesLignans

¡sonof subjects in Copenhagen, Denmark, with subjects inKuopio, Finland, found almost twice as much fiber intake inFinland but no difference in total fecal bile acid concentrationper g dry weight during the spring, with a statistically significant15% reduction during the autumn (9). A study of rural andurban areas of Denmark and Finland found that the rural areasin each country had half the colon-cancer incidence of theirrespective urban counterparts (10). This study, conducted during the spring, reported no differences in fiber intake but didfind significantly lower bile acid concentrations in the Finns.Domellof et al. (11) compared healthy subjects in Umea, Sweden, with those in New York City and found fiber intake 2times higher in Sweden, which corresponded to almost a 50%reduction of deoxycholic, lithocholic, and total bile acids pergram dry feces. Japanese in Hawaii have 4 times higher colon-cancer incidence than do Japanese in Akita. Although dietaryfiber intake was not reported, marked differences in diet werefound between the two groups, without significant differencesin total fecal bile acids; there were reductions of deoxycholicacid and three minor unidentified bile acids for the subjects inAkita (12).

At the population level, the hypothesis relating fecal bile acidconcentrations to colon cancer is generally supported, but case-

control and intervention studies do not consistently supportthis relationship (13). Patients with colon cancer do not excretesignificantly more fecal bile acids when fiber intake is similarto that of normal control subjects (14). Doubling fiber intakeby including whole-wheat bread in the diet increased fecal wetand dry weight (15). Although there was no reported differencein the daily excretion of fecal bile acids, by inference there hadto be a reduction in concentration. Reddy et al. (16) addedwhole-wheat and oat-fiber-enriched bread to the diets of Finnish subjects, doubling their fiber intake, and found significantreductions in secondary and total bile acids.

Animal models have been used to study the effects of bileacids on normal colonie mucosal cytokinetics and tumorigene-sis after administration of a carcinogen. The earliest demonstration of this was reported by Chomchai et al. (17), whoimplanted the common bile duct at the midpoint of the smallintestine. After carcinogen treatment, rats with bile-duct implants had a >2-fold increase in colonie tumors (with a proportionately greater increase in the distal colon) and a 2-foldincrease in fecal bile acids. These data are correlative for bileacids and tumorigenesis, because other substances in bile, particularly phospholipids, may also be mediators of cytokinetics.Cholecystectomy (in species other than rats, which lack a gallbladder) should increase exposure of the mucosa to bile acids

but has not shown consistent promoting effects on coloniecarcinogenesis (18-20).

Although surgical diversion of bile increases exposure of theintestinal mucosa to higher but still physiological levels of bileacids, most studies that demonstrated a relationship amongincreased bile acid concentration, increased mucosal cytokinetics, and enhanced tumor growth used pharmacological levels ofbile salts. One study that used a nonpurified diet to which fat(2 versus 25% beef tallow) and fiber (2 versus 27% cellulose)were added to change fecal bile acid concentrations within thephysiological range found that fiber significantly reduced tumoryield and fecal bile acid concentrations; the difference in fecalweight between low- and high-fiber groups was approximately8-fold, which is far more than can be achieved in humans (21).

A study that specifically addressed the question of possiblewheat-bran protection against colon cancer in carcinogen-treated rats during the promotion-progression phase, by dilution of colonie bile acids, was reported by Calvert et al. (22),who added small amounts of bile salts to the diets of rats fed10% wheat bran, so that their fecal bile acid concentration wasequal to that of rats fed a fiber-free diet. With equal fecal bileacid concentrations for treatment groups, wheat bran still afforded significant protection against tumorigenesis.

The mechanism whereby bile and/or bile acids are thoughtto affect carcinogenesis has been addressed by many studies.The most commonly cited mechanism involves cytokinetics ofthe colonie mucosa. Although the work of Lipkin (23) makesit clear that turnover of normal colonie epithelium is related torisk of cancer, it is not likely that transformed cells respond tothe same qualitative or quantitative signals as do normal cells.There is disagreement as to the effect of cellulose on coloniemucosal cytokinetics, with some studies reporting decreasedproliferation and others finding increased proliferation. Suchproliferative effects do not always correlate with susceptibilityto carcinogenesis (24-27).

Short-Chain Fatty Acids

Another mechanism by which dietary fiber may modulatecarcinogenesis is via fermentation to SCFAs3 in the colon.

Butyrate is reported to be the preferred substrate for colonieepithelial cells. Infusions of SCFA mixtures were reported toincrease proliferation at all levels of the gastrointestinal tract(28). These data suggest that fermentable fiber should increasecarcinogenesis, whereas poorly fermented fiber should protectagainst tumor growth. Experimental results are far from unanimous on this issue (29-31 ). Butyric acid was reported to inducedifferentiation of colon-cancer cell lines in vitro (32). Twoexperiments were performed in which butyric acid was fed torodents treated with carcinogens, and opposite conclusions werereported. One study found dose-dependent increases in colonietumors of rats given 1 or 2% sodium butyrate in drinking water(33), and the other study found no difference in tumorigenesisin mice given 5% tributyrin (34). The former study reported adoubling of colonie butyric acid, whereas the latter reported a10-fold increase in fecal butyrate. Taken together, these datasuggest no beneficial effect of SCFAs on reducing developmentof colonie tumors. The in vivo and in vitro effects of SCFAs onnormal colonie epithelial proliferation also appear to be opposite (28).

'The abbreviations used are: SCFA. short-chain fatty acid; DMH. dimethyl-

hydrazine: AOM. azoxymethane: ODC. ornithine decarboxylase.

2056s

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

DIETARY FIBER AND CARCINOGENESIS

Intestinal Contents

The foregoing suggests the need to search out novel biologicalintermediates that might be better indicators of risk or actualpredictors of disease occurrence. One can make a list of multiplemediators that will be interrelated to some extent. The lumenalcontents are clearly modified by ingestion of dietary fiber, andthis aspect of colonie physiology has been studied extensively.Alterations in colonie microflora exert marked effects on thecolonie environment. These may be characterized by changesin bacterial species, functional changes in the bacteria as reflected by pH (35), or production of enzymes such as /3-glucu-

ronidase (36). Mutagenicity of intestinal contents, usually products of bacterial metabolism, may be a determinant of cancerrisk that is potentially modifiable by dietary fiber. AlthoughReddy et al. (16) found inhibition of mutagenicity by fibersupplements to humans, Kuhnlein et al. (37) found no effect onmutagenicity of pectin or cellulose additions to rat diets. Bileacids are reported to also function as co-mutagens with DMH,

which is not mutagenic by itself (38). Bile acids themselves mayindirectly damage DNA, on the basis of decreased transfectionefficiency in a bacterial system (39); when bile acids werepreincubated with cellulose and possibly lignin (but not psyl-

lium and pectin), transfection efficiency was not reduced. Cheahand Bernstein (39) hypothesized that cellulose catalyzed po-

lyesterification of bile acid molecules to a biologically inactiveform, on the basis of UV-absorption spectra of bile acids

preincubated with cellulose.The presence of bacteria in the colon can modify susceptibil

ity to carcinogenesis, but there appears to be no unidirectionaleffect. Surgical diversion of the fecal stream resulted in significantly fewer tumors in rats treated with AOM (40); a problemin interpreting this study is that all lumenal factors are eliminated and there is decreased turnover of the colonie mucosa.Study of germ-free rats can distinguish between the presence of

bacterial metabolites and other factors. Reddy et al. (41) reported that colonie tumorigenesis was higher in germ-free than

in conventional rats treated with AOM intrarectally but lowerin germ-free rats given DMH subcutaneously. Because AOM

is a metabolite of DMH, these results are difficult to interpret.However, in both studies no tumors of the ear canal were foundin the germ-free animals, whereas 48 and 87% of the rats givenAOM and DMH, respectively, developed this tumor. Thissuggests that the presence of bacteria alters some aspect ofcarcinogen metabolism.

Other intestinal lumenal factors potentially modifiable bydietary fiber include direct binding, as was demonstrated forbile acids and steroid hormones (42, 43), which would modifyenterohepatic circulation and subsequent excretion levels of thecompounds mentioned, as well as carcinogens. Rather thantotal or specific bile acids in feces, the water-soluble portion

that can contact the mucosa more intimately may be of greaterbiological significance. A final aspect of lumenal contents thatshould be considered is the physical characteristics of the stool.Because excess colonie tumors occur primarily in the distalcolon, after most water absorption has occurred, the abrasive-

ness of the stool may be an important determinant of nonspecific irritation that will increase risk of carcinogenesis. Severalof the characteristics described in the original fiber hypothesis(2), such as fecal bulk and water, may contribute to aspects ofabrasiveness.

Colonie Tissue Factors

Properties of the colonie mucosa itself that can be influencedby dietary fiber are likely to be important in determining riskof carcinogenesis. These include alterations in the type andamount of mucins produced (44), epithelial cytokinetics, metabolic activities of the mucosal cells, presence of and responsiveness to gut hormones and peptide growth factors, andneurogenic effects. Many enzymes were studied as indicatorsand as potential mediators of altered responsiveness to carcinogens. ODC was studied extensively in a variety of initiation-

promotion schemes and does seem relevant for the colon, eventhough absolute activity is much lower than that in other organs,particularly skin. Inhibition of ODC leads to significant reductions in carcinogen-induced colonie tumors (45). Bile acidsincrease ODC activity, as does starvation and refeeding (46).Addition of 10% cellulose or guar gum to a fiber-free rat dietcaused a 50% drop in colonie mucosal ODC, whereas 5% fiberadditions had no significant effect (47). However, it appearsthat a specific isozyme of ODC is a more accurate marker ofthe malignant phenotype than is the measure of total enzymeactivity (48). Protein kinase C is another marker enzyme thatappears to be related to rapid growth of both normal andmalignant cells. Bile acids stimulate this enzyme indirectly, byincreasing the diacylglycerol content of the colonie epithelium(49), so it is reasonable to expect this is potentially modifiableby dietary fiber. Dozens of enzymes and metabolic changes thatdemonstrate increased glycolysis (characteristic of most tumors) and increased pyrimidine metabolism (typical of increased cell growth) have been measured in human and rodentcolonie carcinogenesis (50).

An area that has only been explored by a few investigators,which should yield important information about control ofnormal and malignant cell proliferation, is the relationship ofpeptide growth factors and epithelial-cell renewal. Many pep-tide hormones have been shown to have trophic effects onspecific sections of the gut, including gastrin, enteroglucagon,peptide YY, bombesin, epidermal growth factor, cholecystoki-nin, somatostatin, and insulin-like growth factor I (51-53).Consuming wheat bran reduced epidermal growth factor content of the colonie mucosa in rats by >60%, whereas small-intestinal levels were unchanged (54). Some of these peptidegrowth factors are responsive to caloric intake, growth, andbody weight. Newberne et al. (55) showed that rats nursed inlitters of four gained more weight than did rats nursed in littersof eight; the former animals were always heavier and significantly more susceptible to the tumorigenic effects of DMH.One mechanism by which caloric intake early in life maymodulate susceptibility to carcinogens was presented by Al-banes et al. (56), who found that, although caloric restrictiondid not significantly reduce the rate of DNA synthesis, the totalnumber of colonie crypts was reduced and, therefore, the number of cells at risk was lower. This phenomenon may be mediated by systemic or local differences in one or more growthfactors. We demonstrated that insulin and insulin-like growthfactor I plasma levels and mammary-tumor receptor activityare modulated by caloric intake (57, 58). Both growth-factorlevels and receptor expression correlate with tumor growth.Receptors for insulin and insulin-like growth factor I wereidentified on colonie epithelial cells (52), suggesting the possibility that these peptides regulate growth in the colon. Dietaryfiber may act to decrease energy availability (59) or act throughsome other mechanism that would modulate levels of thesegrowth factors.

2057s

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

DIETARY FIBER AND CARCINOGENESIS

Limited data are available concerning the relationship ofdietary fiber to tumors outside the colon. A large case-controlstudy conducted in Israel presented evidence that diet charac- 20.terized by low fiber, high fat, and high animal protein wasassociated with higher risk of breast cancer (60). Rose (61)reviewed much of the data on this issue and suggested that 2Idietary fiber may protect against breast cancer because of itsinfluence on estrogen metabolism or its association with 22.lignans.

It is clear that the alterations in bile acids and SCFA contentof the colon do not adequately explain differences in colon- 23.cancer development in humans or experimental animals. Although there are some correlations between the biological in- 24.termediates and the presence of tumors or regulation of mucosa!growth, this relationship is not convincing enough to relate bileacids or SCFA causally with colon cancer. Although the evi- 25.dence for most of the other potential mediators discussed aboveis even weaker, much less research has been carried out in these 20.other areas. It is likely that one or more avenues of novelresearch will bring us closer to an understanding of how dietary 2?fiber modulates the carcinogenic process.

28.References

1. Higginson, J., and Oettle. A. G. Cancer incidence in Bantu and "Capecoloured" races of South Africa: report of a cancer survey of the Transvaal 29.(1953-1955). J. Nail. Cancer Inst.. 24: 589-671. 1960.

2. Hm kin. D. Epidemiology of cancer of the colon and rectum. Cancer (Phila.).28: 3-13, 1971.

3. Leeds, A. R., ed. Dietary Fibre Perspectives: Reviews and Bibliography, Vol. 30.1. London: John Libbey. 1985.

4. Roth. G.. and Leitzman. C. Fibre and the large gut. In: A. R. Leeds (ed.).Dietary Fibre Perspectives: Reviews and Bibliography, Vol. 1. pp. 3-22.London: John Libbey. 1985. 31.

5. Cummings, J. Cancer of the large bowel, ¡n:H. Trowell, D. Burkitt, and K.Heaton (eds.). Dietary Fibre. Fibre-Depleted Foods and Disease, pp. 161- 32.189. London: Academic Press, 1985.

6. Eastwood. M. A. What does the measurement of dietary fibre mean? Lancet,1: 1487-1488. 1986.

7. Graham, S., Haenszel, W., Bock. F. G.. and Lyon, J. L. Need to pursue new 33.leads in the epidemiology of colorectal cancer. J. Nati. Cancer Inst.. 63:879-881, 1979.

8. Chen, J.. Campbell. T. C, Li, J., and Peto. R. Diet. Life-style and Mortality 34.in China. Oxford, UK: Oxford University Press. 1990.

9. International Agency for Research on Cancer Intestinal Microecology Group.Dietary fibre, transit-time, faecal bacteria, steroids, and colon cancer in two 35.Scandinavian populations. Lancet. 2: 207-211. 1977.

10. Jensen. O. M., MacLennan, R., and Wahrendorf, J. Diet, bowel function.fecal characteristics, and large bowel cancer in Denmark and Finland. Nutr. 36.Cancer. 4:5-19, 1982.

11. Domellof, L. Darby. L., Hanson, D., Mathews, L., Simi, B., and Reddy, B.S. Fecal sterols and bacterial /i-glucuronidase activity: a preliminary metabolic epidemiology study of healthy volunteers from Umea. Sweden, and 37.metropolitan New York. Nutr. Cancer, 4: 120-127, 1982.

12. Mower, H. F., Ray, R. M.. Shoff, R., Stemmermann, G. N., Nomura. A..Glober, G. A.. Kamiyama. S.. Shimada. A., and Yamakawa. H. Fecal bile 38.acids in two Japanese populations with different colon cancer risks. CancerRes., 39: 328-331. 1979.

13. Hill, M. J. Metabolic epidemiology of large bowel cancer. In: S. DeCosse, 39.and P. Sherlock (eds.). Gastrointestinal Cancer, pp. 187-226. The Hague:Nijhoff, 1981.

14. Moskovitz. M.. White. C.. Barnett. R. N., Stevens. S., Russell, E.. Vargo. 40.D., and Floch. M. H. Diet, fecal bile acids, and neutral sterols in carcinomaof the colon. Dig. Dis. Sci., 24: 746-751, 1979.

15. Eastwood. M. A.. Elton, R. A., and Smith, J. H. Long-term effect of 41.wholemeal bread on stool weight, transit time, fecal bile acids, fats, andneutral sterols. Am. J. Clin. Nutr., 43: 343-349. 1986.

16. Reddy, B. S.. Sharma, C., Simi. B., Engle, A.. Laakso. K., Puska, P.. and 42.Korpela. R. Metabolic epidemiology of colon cancer: effect of dietary fiberon fecal mutagens and bile acids in healthy subjects. Cancer Res., 47: 644-648, 1987. 43.

17. Chomchai, C., Bhadrachari, N., and Nigro, N. D. The effect of bile on theinduction of experimental intestinal tumors in rats. Dis. Colon Rectum. 17: 44.310-312, 1974.

18. Schattenkerk. M. E., Li, A. K., Jeppson. B. W., el al. Cholecystectomy hasno influence on frequency of chemically induced colonie cancer in mice. Br. 45.J. Cancer, 42:791-793, 1980.

19. Narisawa, T., Sano, M., Sato. M.. Takahashi, T., Tañida,N., and Shimoy-

2058s

ama. T. The correlation between Cholecystectomy and fecal bile acids, andlarge-bowel cancer induced with 1,2-dimethylhydrazine in mice. Dis. ColonRectum, 28: 27-30. 1985.Kuniyasu, T., Tanaka, T.. Shima, H.. Sugie. S., Mori, H., and Takahashi,M. Enhancing effect of cholecystectomy on colon carcinogenesis induced bymethylazoxymethanol acetate in hamsters. Dis. Colon Rectum. 29:492-494,1986.Galloway. D. J., Owen. R. W., Jarrett, F.. Boyle. P.. Hill. M. J., and George,W. D. Experimental colorectal cancer: the relationship of diet and faecal bileacid concentration to tumour induction. Br. J. Surg., 73: 233-237, 1986.Calven. R. J.. Klurfeld. D. M., Satchithanandam, S., Vahouny, G. V., andKritchevsky. D. Reduction of colonie carcinogenesis by wheat bran independent of fecal bile acid concentration. J. Nati. Cancer Inst.. 79: 875-880,1987.Lipkin, M. Phase 1 and phase 2 proliferarne lesions of colonie epithelialcells in diseases leading to colonie cancer. Cancer (Phila.), 34: 878-888,1974.Cameron, L. Ord. V. A., Hunter. K. E.. Padilla, G. M., and Heitman, D. W.Suppression of a carcinogen (1,2-dimethylhydrazine dihydrochloride)-in-duced increase in mitotic activity in the colonie crypts of rats by addition ofdietary cellulose. Cancer Res.. 49: 991-995, 1989.Heitman. D. W., Ord, V. A., Hunter, K. E., and Cameron. I. L. Effect ofdietary cellulose on cell proliferation and progression of 1,2-dimethylhydra-zine-induced colon carcinogenesis in rats. Cancer Res.. 49:5581-5585,1989.Caderni. G.. Bianchini. F.. Dolara. P.. and Kriebel. D. Proliferarne activityin the colon of the mouse and its modulation by dietary starch, fat, andcellulose. Cancer Res., 49: 1655-1659, 1989.Galloway, D. J., Jarrett, F., Boyle, P.. Indra, M., Carr, K., Owen, R. W., andGeorge. W. D. Morphological and cell kinetic effects of dietary manipulationduring colorectal carcinogenesis. Gut, 28: 754-763, 1987.Sakata. T. Stimulatory effect of short-chain fatty acids on epithelial cellproliferation in the rat intestine: a possible explanation for trophic effects offermentable fibre, gut microbes and luminal trophic factors. Br. J. Nutr., 58:95-103, 1987.Jacobs, L. R. Influence of soluble fibers on experimental colon carcinogenesis.In: D. Kritchevsky, C. Bonfield, and J. W. Anderson (eds.). Dietary Fiber:Chemistry. Physiology, and Health Effects, pp. 389-401. New York: PlenumPress, 1990.Klurfeld, D. M. Insoluble dietary fiber and experimental colon cancer: arewe asking the proper questions? In: D. Kritchevsky. C. Bonfield, and J. W.Anderson (eds.). Dietary Fiber: Chemistry, Physiology, and Health Effects,pp. 402-415. New York: Plenum Press. 1990.Klurfeld. D. M. The role of dietary fiber in gastrointestinal disease. J. Am.Diet. Assoc., 87: 1172-1177, 1987.Kim, Y. S., Tsao, D., Siddiqui, B., Whitehead. J. S., Arnstein, P., Bennett.J., and Hicks. J. Effects of sodium butyrate and dimethylsulfoxide onbiochemical properties of human colon cells. Cancer (Phila.), 45:1185-1192,1981.Freeman, H. J. Effects of differing concentrations of sodium butyrate on 1,2-dimethylhydrazine-induced rat intestinal neoplasia. Gastroenterology, 91:596-602. 1986.Deschner, E. E.. Ruperto. J. F.. Lupton, J. R.. and Newmark, H. L. Dietarybutyrate (tributyrin) does not enhance AOM-induced colon tumorigenesis.Cancer Lett.. 52: 79-82, 1990.Jacobs, L. R.. and Lupton. J. R. Relationship between colonie luminal pH,cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine treatedrats fed high fiber diets. Cancer Res., 46: 1727-1734, 1986.Arakawa, S.. Okumura. M.. Yamada. S., Ito, M., and Tejima. S. Enhancingeffect of carragccnan on the induction of rat colonie tumors by 1,2-dimethylhydrazine and its relation to /i-glucuronidase activities in feces and othertissues. J. Nutr. Sci. Vitaminol., 32: 481-485, 1986.Kuhnlein, U.. Gallagher. R., and Freeman, H. J. Effects of purified celluloseand pectin fiber diets on mutagenicity of feces and luminal contents ofstomach, small and large bowel in rats. Clin. Invest. Med., 6: 253-260. 1983.Wilpart. M.. Mainguet, P., Maskens, A., and Roberfroid, M. Structure-activity relationship amongst biliary acids showing co-mutagenic activitytowards 1,2-dimethylhydrazine. Carcinogenesis (Lond.), 4:1239-1241,1983.Cheah, P. Y.. and Bernstein, H. Colon cancer and dietary fiber: celluloseinhibits the DNA-damaging ability of bile acids. Nutr. Cancer, 13: 51-57,1990.Campbell. R. L., Singh. D. V.. and Nigro, N. D. Importance of the fecalstream on the induction of colon tumors by azoxymethane in rats. CancerRes., 35: 1369-1371, 1975.Reddy. B. S.. Narisawa. T., Wright, P., Vukusich. D.. Weisburger, J. H., andWynder, E. L. Colon carcinogenesis with azoxymethane and dimethylhydra-zine in germ-free rats. Cancer Res., 35: 287-290, 1975.Story, J. A. Modification of steroid excretion in response to dietary fiber. In:G. V. Vahouny and D. Kritchevsky (eds.). Dietary Fiber: Basic and ClinicalAspects, pp. 253-264. New York: Plenum Publishing Corp., 1986.Shultz, T. D.. and Howie, B. J. In vitro binding of steroid hormones bynatural and purified fibers. Nutr. Cancer, *: 141-147. 1986.Filipe, M. !.. and Branfoot, A. C. Abnormal patterns of mucus secretion inapparently normal mucosa of large intestine with carcinoma. Cancer (Phila.),34: 282-290. 1974.Kingsnorth. A. N., King, W. W. K., Diekema, K. A., McCann, P. P., Ross,J. S., and Malt. R. A. Inhibition of ornithine decarboxylase with 2-difluoro-methylornithine: reduced incidence of dimethylhydrazine-induced colon tu-

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

DIETARY FIBER AND CARCINOGENESIS

mors in mice. Cancer Res., 43: 2545-2549. 1983.46. Stanley, B. A., and Kazarinoff, M. N. Ornithine decarboxylase induction in

rat colon: synergistic effects of intrarectal instillation of sodium deoxycholateand starvation-refeeding. J. Nutr.. 114: 404-410. 1984.

47. Klurfeld, D. M., Adamson. I., and Kritchevsky. D. Ornithine decarboxylase(ODC) activity in colonie mucosa: modulation by dietary fiber. FASEB J.. i:A943. 1989.

48. O'Brien, T. G., Madara. T., Pyle, J. A., and Holmes, M. Ornithine decar

boxylase from mouse epidermis and epidermal papillomas: differences inenzymatic properties and structure. Proc. Nati. Acad. Sci. USA. 83: 9448-9452. 1986.

49. Craven. P. A.. Pfanstiel. J.. and DeRubertis. F. R. Role of activation ofprotein kinase C in the stimulation of colonie epithelial proliferation andreactive oxygen formation by bile acids. J. Clin. Invest., 79: 532-541, 1987.

50. Kim, Y. S., and Mclntyre. L. J. Colon carcinogencsis: biochemical changes.In: H. Autrup and G. M. Williams (eds.). Experimental Colon Carcinogen-esis, pp. 155-167. Boca Raton. FL: CRC Press, 1983.

51. Goodlad. R. A., and Wright, N. A. Peptides and epithelial growth regulation.Experientia (Basel). 43: 780-784, 1987.

52. Pillion, D. J., Haskell. J. F., Atchison. J. A.. Ganapathy. V., and Leibach.F. H. Receptors for 1GF-I, but not for IGF-I1. on proximal colon epithelialcell apical membranes. Am. J. Physiol., 257: E27-E34. 1989.

53. Hill. F. L. C. Zhang. T., Gomez, G.. and Greeley. G. H., Jr. Peptide YY, anew gut hormone (a mini-review). Steroids. 56: 77-82. 1991.

54. Schaudies. R. P.. Satchithanandam. S.. and Calven. R. J. Alteration in levels

of ¡mmunoreactive epidermal growth factor in the gastrointestinal mucosaof Fischer rats fed a diet containing I0°¿wheat bran. J. Nutr., 121:800-805,

1991.55. Newberne, P. M., Bueche, D.. Supiphat, V., Schräger,T. F., and Sahaphong,

S. The influence of pre- and postnatal caloric intake on colon carcinogenesis.Nutr. Cancer, 13: 165-173. 1990.

56. Albanes. D., Salbe. A. D.. Levander. O. A.. Taylor, P. R.. Nixon. D. W.. andWinick, M. The effect of early caloric restriction on colonie cellular growthin rats. Nutr. Cancer. 13: 73-80, 1990.

57. Ruggeri. B. A.. Klurfeld. D. M., Kritchevsky, D.. and Furlanetto, R. W.Caloric restriction and 7,12-dimethylbenz(a)anthracene-induced mammarytumor growth in rats: alterations in circulating insulin, insulin-like growthfactors I and II. and epidermal growth factor. Cancer Res.. 49: 4130-4134.1989.

58. Ruggeri. B. A., Klurfeld. D. M., Kritchevsky, D., and Furlanetto, R. W.Growth factor binding to 7,12-dimethylbenz(a)anthraccne-induced mammary tumors from rats subject to chronic caloric restriction. Cancer Res., 49:4135-4141. 1989.

59. Nauss. K. M., Jacobs, L. R., and Newberne. P. M. Dietary fat and fiber:relationship to caloric intake, body growth, and colon tumorigenesis. Am. J.Clin. Nutr., 45: 243-251, 1987.

60. Lubin. F.. Wax, Y., and Modan. B. Role of fat. animal protein, and dietaryfiber in breast cancer etiology: a case-control study. J. Nati. Cancer Inst.. 77:605-612. 1986.

61. Rose. D. P. Dietary fiber and breast cancer. Nutr. Cancer. 13: 1-8. 1990.

2059s

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from

1992;52:2055s-2059s. Cancer Res   David M. Klurfeld  Dietary Fiber-mediated Mechanisms in Carcinogenesis

  Updated version

  http://cancerres.aacrjournals.org/content/52/7_Supplement/2055s

Access the most recent version of this article at:

   

   

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerres.aacrjournals.org/content/52/7_Supplement/2055sTo request permission to re-use all or part of this article, use this link

Research. on January 11, 2020. © 1992 American Association for Cancercancerres.aacrjournals.org Downloaded from