Intravenous but not intracolonic epidermal growth factor maintains colonocyte proliferation in defunctioned rat colorectum

Foster, Hamish McA.; Whitehead, Robert H.

doi:10.1016/0016-5085(90)90477-i

Cited by 24 publications

(5 citation statements)

References 22 publications

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“…A similar distinction between luminal and systemic effects has been reported previously for epidermal growth factor, which stimulated colonic proliferation when administered intravenously, but had no effect when administered via the lumen. 13 Clearly, the fecal stream is important in maintaining a healthy colonic epithelium (hence the hypoplasia induced with defunctioning), but our results suggest that progastrin-derived peptides secreted into the lumen of the gastrointestinal tract are unlikely to play any role in this process. In contrast the observation that gastrin-deficient mice have hypoplastic mucosa suggests that systemic gastrins may be important in maintaining the health of colonic epithelium.…”

Section: Discussionmentioning

confidence: 70%

“…FIGURE 1 -Effect of glycine-extended gastrin 17 treatment on metaphase index in defunctioned rectal mucosa. Rats that had been subjected to a colostomy to induce hypoplasia of the defunctioned rectal mucosa, 13 were infused with glycine-extended gastrin 17 (Ggly, 250 M in PBS containing 0.1% BSA) or with PBS alone (Defunct.) via Alzet miniosmotic pumps.…”

Section: Study 2: Aberrant Crypt Foci Studymentioning

confidence: 99%

“…12 Alternatively animals with a defunctioned colorectum are suitable for testing the effect of putative growth factors on colonic epithelium, because defunctioning reliably induces hypoplasia of the rectal mucosa and is simple to maintain. 13 A further advantage of the latter model is that the topical effect of test substances can be examined by direct instillation into the lumen of the defunctioned segment. We therefore studied the effect of glycine-extended gastrin 17 upon both the intact colon and the defunctioned colon in vivo.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 70%

Section: Study 2: Aberrant Crypt Foci Studymentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Significant differences in these proliferative effects were found depending on the route of administration (54). When the growth factor was given intravenously (16,21) or subcutaneously (44), there were more marked effects than either intragastric or intracolonic routes. In addition to stimulatory effects on stomach and intestine, EGF-related mitogenic effects have been described for pancreas (13) and liver (31,51).…”

Section: Introductionmentioning

confidence: 99%

Recombinant Human Epidermal Growth Factor1-48-Induced Structural Changes in the Digestive Tract of Cynomolgus Monkeys (Macaca fascicularis)

Reindel¹,

Pilcher²,

Gough³

et al. 1996

Toxicol Pathol

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To determine the cellular effects and potential toxicity of exogenously administered recombinant human epidermal growth factor1-48 (EGF1-48) in primates, intravenous bolus injections were given to 2 cynomolgus monkeys per sex at 0 (vehicle control). 10, 100, 500 (females only), and 1,000 micrograms/kg/day (males only) for up to 2 wk. Males given the suprapharmacologic dose of 1,000 micrograms/kg did not tolerate treatment and were necropsied after 5 days of dosing. All other monkeys completed the 2-wk study. Necropsy findings included enlarged, discolored, pale tan livers at 500 micrograms/kg and greater, firm, thickened pancreata in 500-micrograms/kg females, and enlarged salivary glands at all doses. Relative liver weights were increased at 500 and 1,000 micrograms/kg: mean salivary gland weights in all dose groups were greater than in controls. Histopathologic changes were primarily those of diffuse epithelial cell hypertrophy and hyperplasia in liver (hepatocytes and biliary tract), pancreas, salivary glands, tongue, esophagus, stomach, small and large intestine, and gallbladder. Alterations were dose-related in intensity and occurred in at last some tissues at the lowest dose. In gastric glands, colon crypts, pancreatic ducts, biliary tract, and salivary glands, differentiated epithelial cells were replaced by cells of less differentiated phenotype. These morphologic alterations were consistent with exuberant proliferation induced by this epithelial mitogen. The extent of the proliferative response in tissues of the digestive tract attests to the potency of this fragment of human EGF1-53 in primates. Furthermore, the epithelial proliferation was significantly greater than that reported previously in EGF-treated rodents.

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“…Dietary changes (i.e. cellulose content) can induce profound hyperplastic responses (Konishi et al 1984); indeed, the movement of faecal matter through the intestine is important for maintaining mucosal cellularity (Foster & Whitehead 1990). It is still not clear whether lumenal nutrition, physical distention or lymphoid antigen interactions are primary determinants of crypt or villus cellularity.…”

Section: Introductionmentioning

confidence: 99%

Growth control mechanisms in normal and transformed intestinal cells

Burgess

1998

Phil. Trans. R. Soc. Lond. B

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The cells populating the intestinal crypts are part of a dynamic tissue system which involves the self-renewal of stem cells, a commitment to proliferation, lineage-specific differentiation, movement and cell death. Our knowledge of these processes is limited, but even now there are important clues to the nature of the regulatory systems, and these clues are leading to a better understanding of intestinal cancers. Few intestinal-specific markers have been described; however, homeobox genes such as cdx-2 appear to be important for morphogenic events in the intestine. There are several intestinal cell surface proteins such as the A33 antigen which have been used as targets for immunotherapy. Many regulatory cytokines (lymphokines or growth factors) influence intestinal development: enteroglucagon, IL-2, FGF, EGF family members. In conjunction with cell-cell contact and/or ECM, these cytokines lead to specific differentiation signals. Although the tissue distribution of mitogens such as EGF, TGF alpha, amphiregulin, betacellulin, HB-EGF and cripto have been studied in detail, the physiological roles of these proteins have been difficult to determine. Clearly, these mitogens and the corresponding receptors are involved in the maintenance and progression of the tumorigenic state. The interactions between mitogenic, tumour suppressor and oncogenic systems are complex, but the tumorigenic effects of multiple lesions in intestinal carcinomas involve synergistic actions from lesions in these different systems. Together, the truncation of apc and activation of the ras oncogene are sufficient to induce colon tumorigenesis. If we are to improve cancer therapy, it is imperative that we discover the biological significance of these interactions, in particular the effects on cell division, movement and survival.

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Intravenous but not intracolonic epidermal growth factor maintains colonocyte proliferation in defunctioned rat colorectum

Cited by 24 publications

References 22 publications

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

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

Recombinant Human Epidermal Growth Factor1-48-Induced Structural Changes in the Digestive Tract of Cynomolgus Monkeys (Macaca fascicularis)

Growth control mechanisms in normal and transformed intestinal cells

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