CORRESPONDENCE Reduction of Colon Cancer Risk by Dietary Cellulose Supplementation
Because a low dietary fiber intake has been associated with increased incidence of colon cancer (3-5), one might anticipate that fiber-rich wheat bran would have the beneficial effect of reducing the risk of large bowel cancer. However, neither the epidemiological (5) nor the experimental studies (2,5,7-9) are entirely consistent in showing a link between dietary fiber intake and colon cancer. The lack of agreement between these data sets is attributable to differing dietary factors and differing type, amount, and source of dietary fiber between studies. 1154
It has been suggested that biomarkers of abnormal gastrointestinal cell proliferation and differentiation can assist studies in the field of cancer prevention (13). Many animal and human studies have, for example, shown that a proportional expansion of the proliferative compart-
10 D Average percent cellulose intaki during a 32 week period Figure 1. Effect of increasing level of dietary cellulose on incidence of 1,2-dimethylhydrazioe-iiKluced adenocarcinomas in rats. Zero intercept = 91.8; slope = -3.08; correlation coefficient = -0.84; slope is significant at P< .01. Incidence at each point was determined by using 7-23 rats (12).
0 5 15 Percent Cellulose in Food (g/g Dry Weight) Figure 2. Effect of dietary cellulose on proliferative zone height. Proliferative zone height was calculated as a % of crypt height measured in No. of cells (12).
ment of colonic crypts is a consistent biomarker of increased susceptibility to colon cancer (14). Dietary cellulose supplementation in rats has resulted in a significant reversal, toward normal, of a carcinogen-induced increase in proliferative zone height when expressed as a percentage of crypt height (fig. 2) (72). Thus, the crypt biomarker change observed in animals is consistent with the crypt biomarker change observed in human colonic mucosa (75-77). In brief, we conclude that dietary cellulose intervention studies aimed at reducing the risk of colon cancer in humans are now warranted. This conclusion is based on the following: (a) Data from human studies show that dietary supplementation with wheat bran (of which cellulose is a major component) is effective in reversing benign large bowel neoplasia in patients with FAP. (b) Agreement between data from animal and human studies demonstrates that a proportional increase in proliferative zone height in colonic crypts is a biomarker for increased susceptibility to colon cancer, (c) Data from animal studies show that a carcinogen-induced increase in proliferative zone height can be reduced by dietary cellulose, (d) Data from animal studies demonstrate that an increase
*Correspondence to: David W. Heitman, Ph.D., Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 782847762.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Université Laval on July 11, 2015
The article by DeCosse et al. (7) reported that the addition of a wheat bran supplement to the normal diet of patients who have familial adenomatous polyposis (FAP) caused a significant reversal of benign large bowel neoplasia within a 4-year study period. This was an exceptionally well done clinical study showing the beneficial effect of dietary wheat bran on patients with FAP. However, we wish to emphasize that wheat bran is a multicomponent fiber source composed of approximately 70% carbohydrates and 30% noncarbohydrates. The carbohydrate fraction contains starch, sugar, hemicellulose, and cellulose, whereas the noncarbohydrate fraction contains lignin, protein, fat, vitamins, minerals, miscellaneous waxes, cutins, silica, and phytic acid. Wheat bran contains more than 50% fiber (hemicellulose, cellulose, and lignin). A question, therefore, remains: What constituent(s) of wheat bran is responsible for the observed beneficial effect? Another question is: Will dietary wheat bran supplementation at an earlier stage in the development of FAP reduce or enhance the expression of this disease (2)? Finally, the question remains: Can wheat bran or one of the fiber types in wheat bran reduce the incidence of malignant large bowel cancer?
To determine why wheat bran is beneficial in lowering the risk of colon cancer, it is necessary to establish which fiber component of wheat bran might be responsible for the observed beneficial effect and to study the role of this single fiber component. There is no epidemiological or experimental data on the effect of individual fiber types on the development of colon cancer in humans. Consequently, it is difficult to decide which fiber type to test first in human studies. Relevant biomarker and tumor incidence data collected from animal experiments can and should, therefore, be used as the basis for selection of a single fiber type for dietary intervention studies in humans. In this regard, one single dietary fiber type, cellulose, has consistently been shown to lower the incidence of colon carcinogenesis in rat experiments. In four of five published studies using rats (7,8,10-12), dietary cellulose supplementation (4.5% = 15% wt/wt) resulted in a reduced incidence of colon tumors. We recently reported (12) that the addition of cellulose to the diet of rats treated with a colon carcinogen resulted in a dose-dependent decrease in the incidence of colonic adenocarcinomas (fig. 1). An increase from 0% to 15% dietary cellulose was associated with a 50% reduction in incidence of colonic adenocarcinomas (72).
in dietary cellulose significantly reduces the incidence of colonic adenocarcinomas in a dose-dependent manner without detrimental side effects, (e) Cellulose is already approved as a human food supplement. DAVID W. HEITMAN* IVAN L. CAMERON
Department of Cellular and Structural Biology The University of Texas Health Science Center San Antonio, Tex
( / / ) FREEMAN HJ, SPILLER GA, KIM YS: A dou-
ble-blind study on the effects of differing purified cellulose and pectin fiber diets on 1,2-dimethylhydrazine-induced rat colonic neoplasia. Cancer Res 40:2661-2665, 1980 (12) HHTMAN DW, ORD VA, HUNTER KE, ET AL:
Effect of dietary cellulose on cell proliferation and progression of 1,2-dimethylhydrazineinduced colon carcinogenesis in rats. Cancel Res 49:5581-5585, 1989 (13) LJPKIN M: Biomarkers of increased susceptibility of gastrointestinal cancer. Their development and application to studies of cancer prevention. Gastroenterology 92:1083-1086, 1987 (14) LJPKIN M: Biomarkers of increased susceptibility to gastrointestinal cancer. New application to studies of cancer prevention in human subjects. Cancer Res 48:235-245, 1988 (15) COLE JW, MCKALEN A: Studies on the mor-
References
phogenesis of adenomatous polyps in the human colon. Cancer 16:998-1002, 1963 (16) DESCHNER EE, LEWIS CM, LJPKIN M: In vitro
(/) DECOSSE JJ, MILLER HH, LESSER ML: Effect
(6) NATIONAL ACADEMY OF SCIENCE, NATIONAL
RESEARCH COUNCIL: Diet, Nutrition, and
Cancer. Washington, DC: National Academy Press, 1982 (7) JACOBS LR, LUPTON JR: Relationship be-
tween colonic Iuminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine-treated rats fed high fiber diets. Cancer Res 46:1727-1734, 1986 (8) FREEMAN HJ, SPILLER GA, KIM YS: A dou-
ble-blind study on the effect of purified cellulose dietary fiber on 1,2-dimethylhydrazineinduced rat colonic neoplasia. Cancer Res 38:2912-2917, 1978 (9) BAUER HG, ASP NG, OSTER.ETAL: Effect of
dietary fiber on the induction of colorectal tumors and fecal fj-glucuronidase activity in the rat. Cancer Res 39:3752-3756, 1979 (70) NIGRO ND, BULL SW, KLOPFER BA, ET AL:
Effect of dietary fiber on azoxymethane-induced intestinal carcinogenesis in rats. JNCI 62:1097-1102,1979
Vol. 82, No. 13, July 4, 1990
Reference (/) DECOSSE JJ, MILLER HH, LESSER ML: Effect
of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81:1290-1297, 1989
study of human epithelial cells. I. Atypical zone of H3-thymidine incorporation in mucosa of multiple polyposis. J Clin Invest 42:1922-1928, 1963 (17) DESCHNER EE, LJPKIN M, SOLOMON C: Study
of human rectal epithelial cells in vitro. U. H3-thymidine incorporation into polyps and adjacent mucosa. J Natl Cancer Inst 36:849-857, 1966
Response
(5) ROGERS AE, NAUS KM: Contributions of
laboratory animal studies of colon carcinogenesis. In Large Bowel Cancer (Mastromarino AJ, Brattain MG, eds). New York: Praeger, 1984, pp 1-45
JEROME J. DECOSSE
Department of Surgery (F-1917) The New York HospitalCornell Medical Center 525 E. 68th St. New York, NY 10021
Drs. Heitman and Cameron address our recent article (7) in which we reported that a wheat bran supplement in excess of 11 g/day was associated with regression of rectal polyps in patients with familial adenomatous polyposis. The gist of their letter is that cellulose is the effective component of insoluble fiber and that human trials should now be initiated with cellulose. The data provided on cellulose are interesting and, indeed, trials of insoluble fiber need to be initiated in patients with an average risk of colon cancer. However, as a fundamental strategy in extending a study, one should go with what seems to work, namely, wheat bran, not one of its components. Moreover, in a long-term study that may extend beyond 5 years, the palatability of the treatment agent is critically important. Developing a reliably palatable form of cellulose would be a prerequisite for a cellulose trial. Finally, studies in
Gastrointestinal Peptide Hormones and Breast Cancer The recent paper by Goettler et al. (7) raises the issue of whether changes in gastrointestinal (GI) response are predisposing factors in the development of breast cancer. As noted by Goettler et al., we have reported a higher release of gastrin, but no release of vasoactive intestinal polypeptide or neurotensin in premenopausal patients with breast cancer (2-4). However, a number of conditions are related to such data. Initially, we compared the GI peptide hormone response to isocaloric carbohydrate or "fat" breakfasts in three groups of healthy premenopausal women, body mass index less than 23, 24-27, or more than 28, and in women with stage LT breast cancer to age- and weight-
Downloaded from http://jnci.oxfordjournals.org/ at Université Laval on July 11, 2015
of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81:1290-1297, 1989 (2) JACOBS LR: Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration. Cancer Res 43:4057-4061, 1983 (3) ZARIDZE DG: Environmental etiology of large-bowel cancer. JNCI 70:389^00, 1983 (4) WnxETT WC, MACMAHON B: Diet and cancer—an overview. I and D. N Engl J Med 310:633-^38,697-703,1984
patients with an average risk of colon cancer must also recognize the potential importance of a low-fat diet in risk reduction.
*Correspondence to: Peter Hill, Ph.D., Mahoney Institute, American Health Foundation, 320 E. 43rd St., New York, NY 10017.
CORRESPONDENCE 1155
Because a low dietary fiber intake has been associated with increased incidence of colon cancer (3-5), one might anticipate that fiber-rich wheat bran would have the beneficial effect of reducing the risk of large bowel cancer. However, neither the epidemiological (5) nor the experimental studies (2,5,7-9) are entirely consistent in showing a link between dietary fiber intake and colon cancer. The lack of agreement between these data sets is attributable to differing dietary factors and differing type, amount, and source of dietary fiber between studies. 1154
It has been suggested that biomarkers of abnormal gastrointestinal cell proliferation and differentiation can assist studies in the field of cancer prevention (13). Many animal and human studies have, for example, shown that a proportional expansion of the proliferative compart-
10 D Average percent cellulose intaki during a 32 week period Figure 1. Effect of increasing level of dietary cellulose on incidence of 1,2-dimethylhydrazioe-iiKluced adenocarcinomas in rats. Zero intercept = 91.8; slope = -3.08; correlation coefficient = -0.84; slope is significant at P< .01. Incidence at each point was determined by using 7-23 rats (12).
0 5 15 Percent Cellulose in Food (g/g Dry Weight) Figure 2. Effect of dietary cellulose on proliferative zone height. Proliferative zone height was calculated as a % of crypt height measured in No. of cells (12).
ment of colonic crypts is a consistent biomarker of increased susceptibility to colon cancer (14). Dietary cellulose supplementation in rats has resulted in a significant reversal, toward normal, of a carcinogen-induced increase in proliferative zone height when expressed as a percentage of crypt height (fig. 2) (72). Thus, the crypt biomarker change observed in animals is consistent with the crypt biomarker change observed in human colonic mucosa (75-77). In brief, we conclude that dietary cellulose intervention studies aimed at reducing the risk of colon cancer in humans are now warranted. This conclusion is based on the following: (a) Data from human studies show that dietary supplementation with wheat bran (of which cellulose is a major component) is effective in reversing benign large bowel neoplasia in patients with FAP. (b) Agreement between data from animal and human studies demonstrates that a proportional increase in proliferative zone height in colonic crypts is a biomarker for increased susceptibility to colon cancer, (c) Data from animal studies show that a carcinogen-induced increase in proliferative zone height can be reduced by dietary cellulose, (d) Data from animal studies demonstrate that an increase
*Correspondence to: David W. Heitman, Ph.D., Department of Cellular and Structural Biology, The University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 782847762.
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Université Laval on July 11, 2015
The article by DeCosse et al. (7) reported that the addition of a wheat bran supplement to the normal diet of patients who have familial adenomatous polyposis (FAP) caused a significant reversal of benign large bowel neoplasia within a 4-year study period. This was an exceptionally well done clinical study showing the beneficial effect of dietary wheat bran on patients with FAP. However, we wish to emphasize that wheat bran is a multicomponent fiber source composed of approximately 70% carbohydrates and 30% noncarbohydrates. The carbohydrate fraction contains starch, sugar, hemicellulose, and cellulose, whereas the noncarbohydrate fraction contains lignin, protein, fat, vitamins, minerals, miscellaneous waxes, cutins, silica, and phytic acid. Wheat bran contains more than 50% fiber (hemicellulose, cellulose, and lignin). A question, therefore, remains: What constituent(s) of wheat bran is responsible for the observed beneficial effect? Another question is: Will dietary wheat bran supplementation at an earlier stage in the development of FAP reduce or enhance the expression of this disease (2)? Finally, the question remains: Can wheat bran or one of the fiber types in wheat bran reduce the incidence of malignant large bowel cancer?
To determine why wheat bran is beneficial in lowering the risk of colon cancer, it is necessary to establish which fiber component of wheat bran might be responsible for the observed beneficial effect and to study the role of this single fiber component. There is no epidemiological or experimental data on the effect of individual fiber types on the development of colon cancer in humans. Consequently, it is difficult to decide which fiber type to test first in human studies. Relevant biomarker and tumor incidence data collected from animal experiments can and should, therefore, be used as the basis for selection of a single fiber type for dietary intervention studies in humans. In this regard, one single dietary fiber type, cellulose, has consistently been shown to lower the incidence of colon carcinogenesis in rat experiments. In four of five published studies using rats (7,8,10-12), dietary cellulose supplementation (4.5% = 15% wt/wt) resulted in a reduced incidence of colon tumors. We recently reported (12) that the addition of cellulose to the diet of rats treated with a colon carcinogen resulted in a dose-dependent decrease in the incidence of colonic adenocarcinomas (fig. 1). An increase from 0% to 15% dietary cellulose was associated with a 50% reduction in incidence of colonic adenocarcinomas (72).
in dietary cellulose significantly reduces the incidence of colonic adenocarcinomas in a dose-dependent manner without detrimental side effects, (e) Cellulose is already approved as a human food supplement. DAVID W. HEITMAN* IVAN L. CAMERON
Department of Cellular and Structural Biology The University of Texas Health Science Center San Antonio, Tex
( / / ) FREEMAN HJ, SPILLER GA, KIM YS: A dou-
ble-blind study on the effects of differing purified cellulose and pectin fiber diets on 1,2-dimethylhydrazine-induced rat colonic neoplasia. Cancer Res 40:2661-2665, 1980 (12) HHTMAN DW, ORD VA, HUNTER KE, ET AL:
Effect of dietary cellulose on cell proliferation and progression of 1,2-dimethylhydrazineinduced colon carcinogenesis in rats. Cancel Res 49:5581-5585, 1989 (13) LJPKIN M: Biomarkers of increased susceptibility of gastrointestinal cancer. Their development and application to studies of cancer prevention. Gastroenterology 92:1083-1086, 1987 (14) LJPKIN M: Biomarkers of increased susceptibility to gastrointestinal cancer. New application to studies of cancer prevention in human subjects. Cancer Res 48:235-245, 1988 (15) COLE JW, MCKALEN A: Studies on the mor-
References
phogenesis of adenomatous polyps in the human colon. Cancer 16:998-1002, 1963 (16) DESCHNER EE, LEWIS CM, LJPKIN M: In vitro
(/) DECOSSE JJ, MILLER HH, LESSER ML: Effect
(6) NATIONAL ACADEMY OF SCIENCE, NATIONAL
RESEARCH COUNCIL: Diet, Nutrition, and
Cancer. Washington, DC: National Academy Press, 1982 (7) JACOBS LR, LUPTON JR: Relationship be-
tween colonic Iuminal pH, cell proliferation, and colon carcinogenesis in 1,2-dimethylhydrazine-treated rats fed high fiber diets. Cancer Res 46:1727-1734, 1986 (8) FREEMAN HJ, SPILLER GA, KIM YS: A dou-
ble-blind study on the effect of purified cellulose dietary fiber on 1,2-dimethylhydrazineinduced rat colonic neoplasia. Cancer Res 38:2912-2917, 1978 (9) BAUER HG, ASP NG, OSTER.ETAL: Effect of
dietary fiber on the induction of colorectal tumors and fecal fj-glucuronidase activity in the rat. Cancer Res 39:3752-3756, 1979 (70) NIGRO ND, BULL SW, KLOPFER BA, ET AL:
Effect of dietary fiber on azoxymethane-induced intestinal carcinogenesis in rats. JNCI 62:1097-1102,1979
Vol. 82, No. 13, July 4, 1990
Reference (/) DECOSSE JJ, MILLER HH, LESSER ML: Effect
of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81:1290-1297, 1989
study of human epithelial cells. I. Atypical zone of H3-thymidine incorporation in mucosa of multiple polyposis. J Clin Invest 42:1922-1928, 1963 (17) DESCHNER EE, LJPKIN M, SOLOMON C: Study
of human rectal epithelial cells in vitro. U. H3-thymidine incorporation into polyps and adjacent mucosa. J Natl Cancer Inst 36:849-857, 1966
Response
(5) ROGERS AE, NAUS KM: Contributions of
laboratory animal studies of colon carcinogenesis. In Large Bowel Cancer (Mastromarino AJ, Brattain MG, eds). New York: Praeger, 1984, pp 1-45
JEROME J. DECOSSE
Department of Surgery (F-1917) The New York HospitalCornell Medical Center 525 E. 68th St. New York, NY 10021
Drs. Heitman and Cameron address our recent article (7) in which we reported that a wheat bran supplement in excess of 11 g/day was associated with regression of rectal polyps in patients with familial adenomatous polyposis. The gist of their letter is that cellulose is the effective component of insoluble fiber and that human trials should now be initiated with cellulose. The data provided on cellulose are interesting and, indeed, trials of insoluble fiber need to be initiated in patients with an average risk of colon cancer. However, as a fundamental strategy in extending a study, one should go with what seems to work, namely, wheat bran, not one of its components. Moreover, in a long-term study that may extend beyond 5 years, the palatability of the treatment agent is critically important. Developing a reliably palatable form of cellulose would be a prerequisite for a cellulose trial. Finally, studies in
Gastrointestinal Peptide Hormones and Breast Cancer The recent paper by Goettler et al. (7) raises the issue of whether changes in gastrointestinal (GI) response are predisposing factors in the development of breast cancer. As noted by Goettler et al., we have reported a higher release of gastrin, but no release of vasoactive intestinal polypeptide or neurotensin in premenopausal patients with breast cancer (2-4). However, a number of conditions are related to such data. Initially, we compared the GI peptide hormone response to isocaloric carbohydrate or "fat" breakfasts in three groups of healthy premenopausal women, body mass index less than 23, 24-27, or more than 28, and in women with stage LT breast cancer to age- and weight-
Downloaded from http://jnci.oxfordjournals.org/ at Université Laval on July 11, 2015
of wheat fiber and vitamins C and E on rectal polyps in patients with familial adenomatous polyposis. J Natl Cancer Inst 81:1290-1297, 1989 (2) JACOBS LR: Enhancement of rat colon carcinogenesis by wheat bran consumption during the stage of 1,2-dimethylhydrazine administration. Cancer Res 43:4057-4061, 1983 (3) ZARIDZE DG: Environmental etiology of large-bowel cancer. JNCI 70:389^00, 1983 (4) WnxETT WC, MACMAHON B: Diet and cancer—an overview. I and D. N Engl J Med 310:633-^38,697-703,1984
patients with an average risk of colon cancer must also recognize the potential importance of a low-fat diet in risk reduction.
*Correspondence to: Peter Hill, Ph.D., Mahoney Institute, American Health Foundation, 320 E. 43rd St., New York, NY 10017.
CORRESPONDENCE 1155
