Calcium intake and colon cancer biomarkers.
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Calcium, Dietary↗
Biomedical subjects
H Newmark
Publications and source records attributed to H Newmark.
Influence of dietary calcium and vitamin D on diet-induced epithelial cell hyperproliferation in mice.
BACKGROUND: Previous epidemiologic and laboratory studies, including some from our own laboratory, have suggested that a high-fat diet increases risk of cancer development in the pancreas, prostate, colon, and breast and that carcinogenesis in some of these organs may be influenced by alterations in dietary calcium and vitamin D. In this study, we sought to investigate the effect of added dietary calcium or vitamin D on the development of epithelial cell hyperproliferation induced by a Western-style diet in the exocrine pancreas, prostate, and mammary gland of mice. METHODS: Four-week-old C57BL/6J mice were given either a control diet (American Institute of Nutrition [AIN]-76A), a Western-style diet (containing reduced calcium and vitamin D and the fat level of the average human Western diet), or a putative chemopreventive diet (a Western-style diet with the addition of dietary calcium and vitamin D). Nine weeks after dietary intervention, osmotic pumps were implanted in the mice to provide 3 days of bromodeoxyuridine (BrdU) infusion. All P values are two-sided. RESULTS: Mice on the Western-style diet had statistically significant increases in BrdU-labeling indices of epithelial cells in the interlobular (P = .015) and intralobular (P = .012) ducts and centroacinar cells (P = .001) of the pancreatic duct system, the dorsal lobe of the prostate (P = .045), and the terminal ducts of the mammary gland (P = .032), compared with mice in the respective control diet groups. Adding dietary calcium and vitamin D markedly suppressed the Western-style diet-induced hyperproliferation of epithelial cells in those tissues (P = .001-.033). CONCLUSIONS: This study confirms previous findings that a Western-style diet produces hyperproliferation of epithelial cells in several organs and that the changes can be prevented by increasing dietary calcium and vitamin D alone.
Animals↗
Dietary modulation of carcinoma development in a mouse model for human familial adenomatous polyposis.
Familial adenomatous polyposis (FAP) is caused by a dominant mutation in the adenomatous polyposis coli (APC) gene. Individuals with FAP progressively develop adenomas and carcinomas of the colon and rectum. We developed a mouse model for this disorder by genetically modifying the Apc gene. The resulting mice Apc1638 progressively develop neoplasms in the colon and remainder of the gastrointestinal tract. In this study when Apc1638 mice were fed a Western-style diet, they developed an increased incidence of the end point of carcinomas and number of invasive tumors. The findings therefore demonstrated dietary modulation of carcinoma incidence in mice with a targeted mutation providing a model for the study of gene-environment interactions in cancer.
Adenoma↗
Effect of dietary curcumin and dibenzoylmethane on formation of 7,12-dimethylbenz[a]anthracene-induced mammary tumors and lymphomas/leukemias in Sencar mice.
Female Sencar mice (6 weeks old) were administered 1 mg of 7,12-dimethylbenz[a]anthracene (DMBA) by oral gavage once a week for 5 weeks. At 20 weeks after the first dose of DMBA, 68% of mice developed mammary tumors (the average 1.08 tumors per mouse) and 45% had lymphomas/leukemias. Feeding 1% dibenzoylmethane (DBM) in AIN 76A diet, starting at 2 weeks before the first dose of DMBA and continuing until the end of the experiment, inhibited both the multiplicity and incidence of DMBA-induced mammary tumor by 97%. The incidence of lymphomas/leukemias was completely inhibited by 1% DBM diet. In contrast, feeding 2% curcumin diet had little or no effect on the incidence of mammary tumors, and the incidence of lymphomas/leukemias was reduced by 53%.
9,10-Dimethyl-1,2-benzanthracene↗
Aspirin prevents tumors in a murine model of familial adenomatous polyposis.
BACKGROUND: Both human and murine studies suggest that anti-inflammatory drugs prevent intestinal neoplasia. The purpose of this study was to investigate the role of aspirin as a chemopreventive agent for colorectal cancer. METHODS: We administered aspirin to the Min/+ mouse, an animal with a germline mutation in Apc, a gene that is essential for normal epithelial cell growth and differentiation. Apc mutation increases cytoplasmic beta-catenin, a regulatory protein associated with the cytoskeleton. Min/+ mice develop multiple intestinal adenomas and exhibit altered cell growth in the preneoplastic intestinal epithelium. RESULTS: Aspirin decreased the rate of tumor formation in Min/+ mice by 44%. Aspirin also normalized enterocyte growth by increasing apoptosis and proliferation in the preneoplastic intestinal mucosa. Finally, aspirin produced a decrease in intracellular beta-catenin levels, suggesting that modulation of this protein is associated with tumor prevention. CONCLUSIONS: These data confirm a role for aspirin in suppression of Apc-associated intestinal carcinogenesis.
Adenomatous Polyposis Coli↗
Protective effects of tea polyphenols against oxidative damage to red blood cells.
Tea polyphenols (TPP) from black and green teas were evaluated for their antioxidant effects on normal red blood cells (RBC) and beta-thalassemic RBC membranes challenged with exogenous oxidants in vitro. The TPP of both types protected RBC against primaquine-induced lysis; they also protected the whole cells and the membranes against H2O2-induced lipid peroxidation so that about 80% protection was reached at [TPP] = 10 microg/mL. TPP from black tea at the same concentration protected normal RBC from morphological alterations caused by the peroxide treatment. The mechanism of the effects of TPP was investigated using a chemical system generating .OH (iron + ascorbic acid). TPP from both black and green teas inhibited the .OH fluxes in a concentration-dependent manner, indicating the possibility of iron chelation by TPP. Spectrophotometric titration revealed that TPP could stoichiometrically bind ferric iron to form a redox-inactive Fe-TPP complex. Quantitative analysis suggests that one or more major catechins from the TPP preparations are the likely iron-binding compounds accounting for the antioxidant effects of TPP on RBC.
Antioxidants↗
Prevention of mammary preneoplastic transformation by naturally-occurring tumor inhibitors.
Aberrant hyperproliferation (AH) is a late occurring post-initiational event that precedes mammary tumorigenesis in vivo. Experiments on the spontaneously immortalized, non-tumorigenic murine mammary epithelial C57/MG and MMEC cells were designed to validate AH as an in vitro cellular marker for preneoplastic transformation. Colony forming efficiency (% CFE) in anchorage-independent conditions of growth represented the quantitative parameter for AH. C57/MG and MMEC cells, upon treatment with chemical carcinogens or transfection with oncogenes, exhibited at least a 60-300-fold increase in AH relative to that seen in appropriate untreated controls. Transplantation of mammary epithelial cells initiated either by chemical carcinogens or by oncogenes into mammary fat pads of syngeneic mice produced rapidly growing tumors at the transplant site within 4-6 weeks. The tumor-derived T1/Pr1 and myc3/Pr1 cell lines (positive controls) exhibited at least an 800-900-fold increase in AH. Treatment of initiated cells with naturally occurring tumor inhibitors eicosapentaenoic acid (EPA), indole-3-carbinol (I3C), (-)epigallocatechin gallate (EGCG), squalene (SQE), and perillyl alcohol (PA) at non-toxic doses, resulted in a 70-99% inhibition of AH, depending on the initiator and the chemopreventive test compound. Upregulation of AH in initiated mammary epithelial cells in vitro prior to tumorigenesis in vivo, and persistent inhibition of AH by diverse naturally occurring tumor inhibitors, provides evidence for AH as a cellular surrogate endpoint for induction and modulation of mammary neoplastic transformation.
9,10-Dimethyl-1,2-benzanthracene↗
Induced hyperproliferation in epithelial cells of mouse prostate by a Western-style diet.
In this study the effects of a Western-style diet on epithelial cell proliferation in the prostate and bladder of C57BL/6J mice were investigated. The Western-style diet contained increased fat and low calcium and vitamin D, compared with AIN-76A control diet, at levels simulating human Western diets based on nutrient density. After feeding the Western-style and AIN-76A diets for 5 and 16 weeks, mice were infused with bromodeoxyuridine (BrdU) for 72 h using s.c. implanted osmotic pumps. Findings revealed that in bladder epithelium BrdU labeling indices were not significantly different (P > 0.05) between mice on the control and Western-style diets at both time periods. However, significant increases in BrdU labeling indices occurred in epithelial cells of the anterior (P = 0.024) and dorsal (P = 0.049) lobes, but not in the ventral lobe (P = 0.21), of the mouse prostate after feeding the Western-style diet for 16 weeks, compared with mice on the control diet. These findings demonstrate Western-style diet induction of epithelial cell hyperproliferation in anterior and dorsal lobes of the mouse prostate. The findings further suggest that these nutrients may have a role in human prostatic carcinogenesis, since the anterior and dorsal lobes of the mouse prostate are homologous with the human prostate in embryological origin and histological structure and carcinomas induced in rodent models have similar characteristics to those found in human prostatic cancer.
Animals↗
Epithelial cell hyperproliferation induced in the exocrine pancreas of mice by a western-style diet.
BACKGROUND: Pancreatic cancer is a common cause of mortality in the United States, with an estimated 27,800 people dying of the disease in this country in 1996. Epidemiologic studies have suggested that Western diets containing high fat, high protein, and low calcium contents are associated with increased incidence of pancreatic cancer. PURPOSE: We investigated whether a Western-style diet containing increased fat content and decreased calcium and vitamin D contents would induce epithelial cell hyperproliferation (excess cell duplication) or hyperplasia (excess cell accumulation) in the pancreas, as was previously demonstrated in the colon and mammary gland. METHODS: C57BL/6J mice at 4 weeks of age were randomly assigned to one of two groups of 14 mice each. One group received the control diet ad libitum, and the other group was given the Western-style diet ad libitum. After 6, 9, and 15 weeks on the diet, four or five mice per group were infused with 5-bromo-2'-deoxyuridine (BrdU) for 72 hours by use of subcutaneously implanted Alzet osmotic pumps. The mice were then killed, and the pancreas of each mouse was removed. In the exocrine pancreas with ductal secretion, the duct system (including interlobular and intralobular ducts and centroacinar [i.e., centroductular] cells) and acini were measured both histopathologically and immunohistochemically (BrdU) and were analyzed without knowledge of the source of the specimens. Two-way analysis of variance was carried out. All P values were generated from two-sided tests for statistical significance. RESULTS: The number of pancreatic ducts (interlobular, intralobular, and centro-acinar-cancer-prone regions in certain rodent models and in humans) and acini per mouse in the Western-style diet group was similar to that in the control diet group during the entire feeding period (P = .76, .32, .93, and .42, respectively). Statistically significant higher BrdU-labeling indices of the ductal interlobular and intralobular epithelial cells were seen in mice fed the Western-style diet than in mice fed the control diet during the entire observation period (P = .014 and .016, respectively). There was no statistically significant difference (P = .098) between both diet groups in the BrdU-labeling indices of the centroacinar epithelial cells. CONCLUSIONS: A Western-style diet induced pancreatic epithelial cell hyperproliferation in mice, further suggesting that increased fat content and decreased calcium and vitamin D contribute to the development of pancreatic neoplasms.
Animals↗
Apoptosis, cell replication, and Western-style diet-induced tumorigenesis in mouse colon.
In this study, feeding Western-style diets (WDs) to mice for a duration of two years without any chemical carcinogen led to the development of gross colonic lesions that were histologically classified as dysplastic crypts and focal hyperplasias with or without atypical nuclei. To better understand early biological events contributing to the development of colonic neoplasia, grossly normal colonic mucosa was investigated; mitotic and apoptotic colonic epithelial cells, atypical mitosis, and atypical nuclei were studied. A significant and transient increase of mitotic activity in the basal and intermediate portions of the colonic crypts was seen in young mice after feeding them the WDs. This was accompanied by diffuse activation of apoptosis of the colonic epithelial cells. In the middle of the rodents' life span, after administration of both the WDs and control diet, the rodents developed a marked depletion of apoptotic epithelial cells in the mid-region of the colonic crypts; this was followed by the expansion of an epithelial cell population containing atypical nuclei, and the emergence of the gross lesions noted above. With this sequence of events, prolonged feeding of WDs to mice produced single-crypt dysplastic lesions and focal hyperplasias indicative of tumorigenesis.
Animals↗
Cytokeratin, lectin, and acidic mucin modulation in differentiating colonic epithelial cells of mice after feeding Western-style diets.
Several studies have recently reported the development of colonic epithelial cell hyperproliferation in rodents following the ingestion of Western-style diets. In this study, additional measurements related to differentiation and maturation of the colonic epithelial cells were made after feeding this type of diet. Two Western-style diets high in fat and phosphate content and low in calcium and vitamin D were fed to C57BL/6J mice for 12, 24, and 52 weeks. Diet A contained American Blend fat as a source of lipids, diet B contained corn oil, and control diet C was a standard AIN-76A semisynthetic diet which is lower in fat content and higher in calcium and vitamin D. Colonic epithelial cells were studied for three biomarkers: cytokeratin catalogue no. 18 (clone LE64) expression, soybean agglutinin carbohydrate lectin binding, and acidic mucins including sialo- and sulfomucins. Feeding of diets A and B revealed that colonic epithelial cells had increased expression of cytokeratin catalogue 18 and SBA carbohydrate lectin binding compared to controls (P = 0.0001 for diet A versus C and diet B versus C). Significant differences were found between diets B and C (P = 0.0001) and diets A and C (P = 0.0001) in total acidic mucins and in the ratio of sialomucin:sulfomucin (P = 0.0001). These findings demonstrate that both functional and structural modifications occurred in colonic epithelial cells under these dietary conditions, and further defined this rodent model for preclinical evaluation of nutritional and chemopreventive interventions.
Animals↗
Inherited and acquired risk factors in colonic neoplasia and modulation by chemopreventive interventions.
The progressively abnormal development of epithelial cells prior to tumor development leads to widely differing chemopreventive approaches. The diversity of these approaches has resulted in different assays to measure the activities of the agents. To apply these assays to preclinical studies, we have developed rodent models in which different stages of evolution of colonic neoplasia are expressed. In one model mice carrying a truncated Apc allele with a nonsense mutation in exon 15 have been generated by gene targeting and embryonic stem cell technology (Apc 1638 mice). These mice develop multiple gastrointestinal lesions including adenomas and carcinomas, focal areas of high grade dysplasia (FAD) and polypoid hyperplasias with FADS. The incidence of inherited colonic neoplasms has now been modulated by a chemopreventive regimen. Colonic lesions significantly increased in Apc 1638 mice on a Western-style diet, compared to Apc 1638 mice on AIN-76A diet which has lower fat content and higher calcium and vitamin D. These studies have also been carried out in normal mice, and have demonstrated without any chemical carcinogen that a Western-style diet induced colonic tumorigenesis. Modulation of cell proliferation has also been induced by Western-style diets in other organs including mammary gland, pancreas and prostate. These findings are leading to the development of new preclinical models for evaluating the efficacy of many classes of chemopreventive agents.
Animals↗
Model of mouse mammary gland hyperproliferation and hyperplasia induced by a western-style diet.
Mammary glands of female C57BL/6J mice were analyzed after they were fed a Western-style diet or control AIN-76A diet. The Western-style diet contained several risk factors found in human diets in geographic regions having increased risk for breast cancer: high fat and phosphate and low calcium and vitamin D. After they were fed these diets for 8, 14, and 20 weeks, mice were sacrificed, and mammary glands were removed for morphometric and radioautographic measurements. Although after the animals were fed the Western-style diet for 8 weeks the number of terminal ducts per mouse mammary gland (NTDMG) was similar in the Western-style and control diet groups, after they were fed the Western-style diet for 14 weeks (p < 0.05) and 20 weeks (p < 0.01) the NTDMG significantly increased compared with the control group. Moreover, there was a significant increase (p < 0.01) in the tritiated thymidine labeling index of mammary terminal ductal epithelial cells after 14 and 20 weeks of Western-style diet administration. Thus the Western-style diet induced increased epithelial cell proliferation and increased NTDMG in female mice when fed during young adult growth and development. The findings raise the possibility that the ingestion of a diet with Western-style fat and phosphate content and with low calcium and vitamin D may induce similar changes during the early development of the human mammary gland.
Animals↗
Development of clinical chemoprevention trials.
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Animals↗
Calcium and the prevention of colon cancer.
Chemoprevention studies utilizing calcium have now progressed from basic measurements to clinical trials. Calcium's effects on epithelial cells have demonstrated decreased proliferation and induced cell differentiation with increasing levels of calcium in vitro, similar in vivo effects in rodent and human colon, and decreased carcinogen-induced colonic tumor formation in rodents. Current studies are attempting to inhibit colonic adenoma formation in human subjects. Most but not all epidemiologic studies also link increased dietary calcium with a decreased risk of colon cancer. In animal models, supplemental dietary calcium has decreased mammary epithelial cell hyperplasia and hyperproliferation and colonic cell hyperproliferation when the latter was induced by bile acids, fatty acids, and partial resection of the small intestine. Supplemental dietary calcium also decreased carcinogen-induced colonic tumors in several rodent models. In normal mice, and in mice carrying a targeted apc gene mutation, we recently increased colonic polypoid hyperplasias by a Western-style diet containing low calcium and vitamin D. In human subjects at increased risk for colon cancer, oral calcium supplementation significantly reduced colonic epithelial cell proliferation in most of the studies, including four randomized clinical trials. These studies have now progressed to short-term human clinical trials, including trials that measure the regrowth of transformed adenoma cells. Short-term adenoma-regrowth clinical trials, however, are limited in their ability to measure whether chemopreventive agents inhibit early genotoxic events, abnormal cellular metabolic activities involved in tumor promotion over many years, or the progression of adenoma cells to carcinoma.
Adenoma↗
Protective effects of rutin against hemoglobin oxidation.
A prooxidant drug, primaquine (PQ) was used to produce oxidative stress in human red blood cells (RBC) in vitro. Rutin, a plant flavonoid, did not prevent PQ-induced cell lysis but protected against hemoglobin (Hb) oxidation inside RBC. After PQ removal, rutin failed to reduce preformed met-Hb indicating that the rutin protective effect manifests only in the presence of PQ. Since H2O2 was proved to mediate PQ-induced Hb oxidation, authentic Hb was studied for its reaction with H2O2 and rutin in solution. Rutin partially protected oxy-Hb against H2O2-induced oxidation and heme loss. Rutin was also shown to delay H2O2-induced met-Hb oxidation to ferryl-Hb. Rutin directly reduced ferryl-Hb to met-Hb in stoichiometric (1:1) reaction characterized by a rate constant of 100 to 130/M/sec. It is assumed that by reducing ferryl-Hb, rutin prevents oxy-Hb from reacting with ferryl-Hb (comproportionation reaction), thus preventing half of the oxy-Hb molecules from being converted to met-Hb. This mechanism is consistent with 50% inhibition by rutin (at the maximum of its activity) of PQ-induced oxy-Hb oxidation in RBC. The present results demonstrate new antioxidant properties of rutin that may be useful in diminishing oxidative damage to pathological red blood cells.
Antioxidants↗
Omega-3 fatty acids and rectal epithelial cell proliferation.
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Adenomatous Polyposis Coli↗
Mammary ductal epithelial cell hyperproliferation and hyperplasia induced by a nutritional stress diet containing four components of a western-style diet.
We have studied effects of several nutrients on the proliferation of mammary ductal epithelial cells in C57BL/6J virgin female mice, using morphometry and [3H]dT in vivo labeling. A nutritional stress diet was given based on the AIN-76A semi-synthetic diet modified to contain four significant risk factors of a Western-style diet: high fat and phosphate and decreased calcium and vitamin D. The numbers of large, intermediate and terminal ducts and proliferating epithelial cells in mammary glands were assayed in control and stress diet groups. An increased number of mammary ducts and increased number of proliferating cells were found at the level of the small terminal ducts, a cancer-prone region in the mammary gland in the stress diet group compared to the control group after 20 weeks of diet administration. Thus, mammary terminal ductal hyperproliferation, expansion in the size of the proliferative epithelial cell compartment and excessive duplication of mammary ductal epithelial cells were found after this Western-style diet containing decreased dietary calcium and vitamin D. These changes are similar to those developing in colonic epithelium of mice maintained on the same diets and during chemically induced colonic carcinogenesis.
Animals↗