Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen

Singh, Pomila; Velasco, Marco A. De; Given, Randall L.; Varró, Andrea; Wang, Yichen

doi:10.1053/gast.2000.8527

Cited by 99 publications

(94 citation statements)

References 30 publications

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“…17,18,34 ACF are preneoplastic lesions that have the propensity to progress and become neoplastic if further DNA damage occurs; they are considered to be reliable intermediate markers for tumor development in mice and humans, 40,41 as was confirmed in our previous studies. 17,18 Mice were treated with AOM at the optimal concentration of 12 mg/kg body weight, which previously was reported to be effective in promoting preneoplastic and neoplastic changes in the colonic mucosae of FVB/N mice. 18 Groups of 6-week-old transgenic mice (5-10 mice per group) and their wild-type littermates received an IP injection of AOM once weekly for 3 weeks, as was reported previously.…”

Section: Induction Of Acf and Colonic Tumorsmentioning

confidence: 54%

“…Specimens subsequently were removed for analysis of neoplastic lesions according to our published protocols. 17,34 Colonic tumors were counted, and their location (in cm from the anus) and size (in mm) were recorded. The total number of tumors per animal and the tumor burden (i.e., the sum of tumor sizes in a given group divided by the number of animals in that group) for Fabp-PG and wild-type mice were compared.…”

Section: Analysis Of Acf In Tumors and In The Colonmentioning

confidence: 99%

“…H & E-stained tumor sections were examined by bright-field microscopy and were further categorized as microadenomas (mAds; Ͻ 2 cm in diameter), Ads, or AdCas, as is described elsewhere. 17,34 The Student t test was used to compare different groups of mice in terms of ACF and tumor incidence, ACF multiplicity, tumor burden, and tumor pathology. All statistical tests were performed using SigmaStat software (SPSS Inc., Chicago, IL).…”

Section: Analysis Of Acf In Tumors and In The Colonmentioning

confidence: 99%

“…We observed that in the presence of carcinogens, pharmacologic levels of circulating PG led to a significant increase in the proliferative index of colonic crypts; this increase resulted in significant increases in the number and multiplicity of aberrant crypt foci (ACF) and the number of neoplastic lesions (Ads and AdCas) observed in hGAS mice. 5,17,18 Similarly, treatment with G-Gly increased the risk of developing ACF in rats. 29 Under physiologic conditions, circulatory levels of the full-length precursor peptide PG typically are undetectably low.…”

mentioning

confidence: 99%

“…6 PG and G-Gly represent the nonamidated forms of gastrin. Subsequent amidation at the carboxy-terminal end of a nonamidated gastrin generates an amidated gastrin (e.g., gastrin 17 [G17], gastrin 34 [G34]; Fig. 1A).…”

mentioning

confidence: 99%

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Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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Charcot–Marie–Tooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.

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Section: Induction Of Acf and Colonic Tumorsmentioning

confidence: 54%

Section: Analysis Of Acf In Tumors and In The Colonmentioning

confidence: 99%

Section: Analysis Of Acf In Tumors and In The Colonmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Cobb

Wood

Ceci

et al. 2004

Cancer

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Short term infusion of glycine-extended gastrin17 stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa

2001

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Evidence is accumulating that gastrin precursors may act as growth factors for the colonic mucosa in vivo and for colorectal carcinoma cell lines in vitro. The effect of short term administration of synthetic gastrins on the colonic mucosa in vivo, however, has not been reported. The aim of our study was to determine whether continuous systemic infusion of glycine-extended gastrin 17 stimulated proliferation and accelerated carcinogenesis in the colorectal mucosa. A significant increase in colonic mucosal proliferation as assessed by metaphase index was seen in the caecum (23%, p < 0.02) and distal colon (27%, p < 0.001), but not the rectum, after treatment of intact rats with glycine-extended gastrin 17 for 1 week using implanted miniosmotic pumps. Defunctioning of the rectum reduced both the proliferative index and crypt height of the rectal mucosa of untreated rats. Treatment of rectally defunctioned animals with glycine-extended gastrin 17 for either 1 or 4 weeks resulted in a significant increase in both the proliferative index (40% and 93%, respectively) and crypt height (11% and 19%, respectively) of the rectal mucosa. The total number of aberrant crypt foci in intact rats treated with the procarcinogen azoxymethane plus glycine-extended gastrin 17 was increased by 48% compared to the value in controls treated with azoxymethane only (p ‫؍‬ 0.01). We conclude that short term administration of glycine-extended gastrin 17 to mature rats not only has a proliferative effect upon colonic mucosa, but also increases the number of aberrant crypt foci formed in the colorectal mucosa after treatment with azoxymethane. Glycine-extended gastrin 17 Gastrin is a classical gut peptide hormone, which was identified originally as a stimulant of gastric acid secretion. Like many other peptide hormones, gastrin is synthesized as a large precursor molecule (101 amino acids), which is converted to progastrin (80 amino acids) by cleavage of the N-terminal signal peptide. Progastrin is processed further by endo-and carboxypeptidases and by C-terminal amidation to yield either glycine-extended gastrin 17 or amidated gastrin 17 . 1 Although amidated gastrin 17 was thought originally to be the only form of the hormone with biological activity, glycine-extended gastrin 17 has been shown to stimulate the proliferation of several cell lines, including some of colonic origin. [2][3][4][5][6] Non-amidated gastrins also seem to act as growth factors for normal colonic mucosa, as transgenic mice overexpressing either progastrin 7 or glycine-extended gastrin 17 8 have increased serum concentrations of the appropriate progastrin-derived peptides and a hyperplastic colonic mucosa.Progastrin-derived peptides may also stimulate the development or growth of colorectal carcinoma. 9 -11 Transgenic mice overexpressing progastrin have 2-3-fold more aberrant crypt foci than wildtype controls after treatment with azoxymethane (a colon specific carcinogen), 9 but no such increase was observed in transgenic mice overexpressing amidated gastrin 17 . 9 ...

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Colon carcinogenesis in liver‐specific IGF‐I‐deficient (LID) mice

Ealey

Xuan

Lü

et al. 2007

Intl Journal of Cancer

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Circulating insulin-like growth factor I (IGF-I) is associated with increased risk of colorectal cancer. It is not clear, however, whether IGF-1 plays a direct causative role in colon carcinogenesis or whether it mediates the known promoting effects of insulin. The objective of this study was to determine the role of IGF-1 in colon carcinogenesis using liver-specific IGF-I deficient (LID) mice that exhibit 70% reductions in circulating IGF-I. Female and male LID mice were treated with the colon-specific carcinogen azoxymethane to induce aberrant crypt foci (ACF) or colon tumors. Female LID mice developed significantly fewer ACF and had normal insulin levels compared to controls. Male LID mice, however, were hyperinsulinemic and exhibited no significant differences in ACF development compared to controls. In the tumor study, both male and female LID mice were hyperinsulinemic and had no significant differences in tumor incidence or multiplicity compared to their respective controls. There was a significant 25% reduction in tumor size, however, in both male and female LID mice compared to controls. These data suggest that IGF-I deficiency attenuates the promoting effect of insulin on colon carcinogenesis and that IGF-I is an independent promoter of the growth of established tumors. Our findings implicate both IGF-I and insulin as important promoters of colon cancer development. ' 2007 Wiley-Liss, Inc.

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Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen

Cited by 99 publications

References 30 publications

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Intestinal expression of mutant and wild‐type progastrin significantly increases colon carcinogenesis in response to azoxymethane in transgenic mice

Short term infusion of glycine-extended gastrin17 stimulates both proliferation and formation of aberrant crypt foci in rat colonic mucosa

Colon carcinogenesis in liver‐specific IGF‐I‐deficient (LID) mice

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