Calcium regulation of colonic crypt cell kinetics: Evidence for a direct effect in mice

Nobre‐Leitão, Carlos; Chaves, Paula; Fidalgo, Paulo; Cravo, Marília; Oliveira, António G.; Ferra, Maria A.; Mira, F. Costa

doi:10.1016/0016-5085(95)90338-0

Cited by 19 publications

(4 citation statements)

References 30 publications

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“…In normal crypts, active cell division is restricted to the base of the crypt. In TMCH, as in other pre‐malignant conditions, there is an expansion of the proliferative zone to occupy 40–50% of the length of the crypt (Lipkin 1974; Nobre‐Leiato et al. 1985; Papatis et al.…”

Section: Resultsmentioning

confidence: 99%

“…We focused on increased proliferation as a functional intermediate marker. TMCH clearly exhibits both increased epithelial proliferation and an expanded proliferative zone, both of which have often been utilized as a surrogate for increased cancer risk (Lipkin 1974; Nobre‐Leiato et al. 1985).…”

Section: Discussionmentioning

confidence: 99%

“…1995). Calcium also has direct effects on epithelial biology independent of bile salts by modulating crypt kinetics, cell : cell interactions, calcium receptors and intracellular signalling (Nobre‐Leiato et al. 1985; Buras et al.…”

Section: Introductionmentioning

confidence: 99%

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Dietary pectin and calcium inhibit colonic proliferation in vivo by differing mechanisms

Umar¹,

Morris

Kourouma³

et al. 2003

Cell Proliferation

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Diet plays an important role in promoting and/or preventing colon cancer; however, the effects of specific nutrients remain uncertain because of the difficulties in correlating epidemiological and basic observations. Transmissible murine colonic hyperplasia (TMCH) induced by Citrobacter rodentium, causes significant hyperproliferation and hyperplasia in the mouse distal colon and increases the risk of subsequent neoplasia. We have recently shown that TMCH is associated with an increased abundance of cellular beta-catenin and its nuclear translocation coupled with up-regulation of its downstream targets, c-myc and cyclin D1. In this study, we examined the effects of two putatively protective nutrients, calcium and soluble fibre pectin, on molecular events linked to proliferation in the colonic epithelium during TMCH. Dietary intervention incorporating changes in calcium [high (1.0%) and low (0.1%)] and alterations in fibre content (6% pectin and fibre-free) were compared with the standard AIN-93 diet (0.5% calcium, 5% cellulose), followed by histomorphometry and immunochemical assessment of potential oncogenes. Dietary interventions did not alter the time course of Citrobacter infection. Both 1.0% calcium and 6% pectin diet inhibited increases in proliferation and crypt length typically seen in TMCH. Neither the low calcium nor fibre-free diets had significant effect. Pectin diet blocked increases in cellular beta-catenin, cyclin D1 and c-myc levels associated with TMCH by 70%, whereas neither high nor low calcium diet had significant effect on these molecules. Diets supplemented with either calcium or pectin therefore, exert anti-proliferative effects in mouse distal colon involving different molecular pathways. TMCH is thus a diet-sensitive model for examining the effect of specific nutrients on molecular characteristics of the pre-neoplastic colonic epithelium.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dietary pectin and calcium inhibit colonic proliferation in vivo by differing mechanisms

Umar¹,

Morris

Kourouma³

et al. 2003

Cell Proliferation

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“…Expansion of the proliferative compartment of the colonic crypt towards the lumen ("phase 2" defect) is a feature of neoplastic development, 35 and varying the calcium content of the diet can modulate this. 36 A downward shift in the region of apoptotic activity in the crypt might contribute to the beneficial eVects of calcium on these proliferative abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Dietary calcium supplementation increases apoptosis in the distal murine colonic epithelium

Penman

Liang²,

Bode³

et al. 2000

J Clin Pathol

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Background-Increased dietary calcium might reduce colorectal cancer risk, possibly by reduction of colonic epithelial hyperproliferation, but not all studies have demonstrated this. Little is known about the eVects of calcium on colonic apoptosis. Aim-To quantify the eVects of increasing calcium on apoptosis and cell proliferation in normal murine colonic crypt epithelium. Methods-Twenty one day old male C57Bl/6 mice were fed either control AIN-76 diet (0.5% calcium wt/wt; n = 10) or the same supplemented with calcium carbonate (1.0% calcium; n = 10) for 12 weeks. Apoptotic cells in proximal and distal segments were counted and expressed as an apoptotic index (AI: frequency of apoptosis/100 longitudinal crypts). The bromodeoxyuridine (BrdU) labelling index was also determined. DiVerences were analysed by the student's t test. Results-In control animals, the AI was significantly higher in the caecum/ proximal colon (mean, 28.6; SEM, 2.0) compared with the distal colon (mean, 19.9; SEM, 1.8; p = 0.004). In the calcium treated group, the AI in the caecum/ proximal colon (mean, 30.6; SEM, 1.7) was similar to controls (p = 0.71) but the AI in the distal colon was significantly greater (mean, 32.6; SEM, 1.8; p = 0.001) than in control mice and was raised to values similar to those in the proximal colon. Calcium was also associated with reduced crypt cellularity and, in the proximal colon, a downward shift in the crypt position at which apoptosis occurred. There were no significant diVerences in the BrdU labelling index between groups or between proximal and distal colonic segments in each group. Conclusions-Increased dietary calcium is associated with the induction of apoptosis in normal mouse distal colonic epithelium without aVecting cell proliferation. This might contribute to its putative chemopreventive role in colorectal carcinogenesis. Whether this eVect is direct or indirect requires further study. (J Clin Pathol 2000;53:302-307)

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Colorectal cancer in patients with inflammatory bowel disease: influence of nutritional habits and environmental clues

F¹,

Cravo²

Falk Symposium

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Calcium regulation of colonic crypt cell kinetics: Evidence for a direct effect in mice

Cited by 19 publications

References 30 publications

Dietary pectin and calcium inhibit colonic proliferation in vivo by differing mechanisms

Dietary pectin and calcium inhibit colonic proliferation in vivo by differing mechanisms

Dietary calcium supplementation increases apoptosis in the distal murine colonic epithelium

Colorectal cancer in patients with inflammatory bowel disease: influence of nutritional habits and environmental clues

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