High, persistent hepatocellular proliferation and apoptosis precede hepatocarcinogenesis in growth hormone transgenic mice

Snibson, Kenneth J.; Bhathal, Prithi S.; Hardy, Charles L.; Brandon, Malcolm R.; Adams, Timothy E.

doi:10.1111/j.1478-3231.1999.tb00042.x

Cited by 49 publications

(52 citation statements)

References 43 publications

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“…It seems possible that a rapid and prolonged cell turnover in several tissues increases the risk of cell mutations that are not repaired or eliminated, also resulting in more rapid cellular senescence and thus contributing to those diseases producing a shortened life span (Campisi 2008). There is evidence for these life span-related events in rapidly growing animals (Coile 2005;Galis et al 2007;Samaras 2009;Deeb and Wolf 1994;Miller et al 2002;Snibson et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Connecting serum IGF-1, body size, and age in the domestic dog

Greer

Hughes

Masternak

2010

AGE

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Many investigations in recent years have targeted understanding the genetic and biochemical basis of aging. Collectively, genetic factors and biological mechanisms appear to influence longevity in general and specifically; reduction of the insulin/IGF-1 signaling cascade has extended life span in diverse species. Genetic alteration of mammals for life extension indicates correlation to serum IGF-1 levels in mice, and IGF-1 levels have been demonstrated as a physiological predictor of frailty with aging in man. Longevity and aging data in the dog offer a close measure of the natural multifactorial longevity interactions of genetic influence, IGF-1 signaling, and environmental factors such as exposure, exercise, and lifestyle. The absence of genetic alteration more closely represents the human longevity status, and the unique species structure of the canine facilitates analyses not possible in other species. These investigations aimed to measure serum IGF-1 in numerous purebred and mixed-breed dogs of variable size and longevity in comparison to age, gender, and spay/neuter differences. The primary objective of this investigation was to determine plasma IGF-1 levels in the adult dog, including a wide range of breeds and adult body weight. The sample set includes animals ranging from just a few months of age through 204 months and ranging in size from 5 to 160 lb. Four groups were evaluated for serum IGF-1 levels, including intact and neutered males, and intact and spayed females. IGF-1 loss over time, as a function of age, decreases in all groups with significant differences between males and females. The relationship between IGF-1 and weight differs depending upon spay/neuter status, but there is an overall increase in IGF-1 levels with increasing weight. The data, currently being interrogated further for delineation of IGF-1 receptor variants and sex differences, are being collected longitudinally and explored for longevity associations previously unavailable in non-genetically modified mammals.

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Section: Discussionmentioning

confidence: 99%

Connecting serum IGF-1, body size, and age in the domestic dog

Greer

Hughes

Masternak

2010

AGE

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“…The enlarged livers are likely due to a direct stimulatory action of GH, in that MT-bGH transgenic mice, but not MT-IGF-I mice, have enlarged livers characterized by hepatocyte hyperplasia and hypertrophy (Quaife et al, 1989). In fact, sustained GH stimulation in MToGH mice can lead to hepatic carcinomas (Snibson et al, 1999). In contrast, disproportionate growth of the spleen is likely due to secondary elevations in IGF-I, since MT-IGF-I transgenic mice, as well as MT-bGH mice, display splenic hyperplasia (Mathews et al, 1988;Blazar et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

et al. 2000

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p27 Kip1 (p27) controls cell cycle progression by binding to and inhibiting the activity of cyclin dependent kinases. Disruption of the p27 gene in mice (p277/7) results in increased body growth with a disproportionate enlargement of the spleen, thymus, testis, ovary and pituitary. The increase in pituitary size is due to selective hyperplasia of the intermediate lobe (IL) while the anterior lobe (AL) is not overtly a ected. p27 heterozygous mice (p27+/7), as well as p277/7 mice, are hypersensitive to radiation-and chemical-induced tumors compared to wildtype (p27+/+) littermates. Therefore, unlike classical tumor suppressors, only a reduction in p27 levels is necessary to predispose tissues to secondary tumor promoters. Consistent with these studies is the fact that the p27 gene sequence and mRNA levels appear normal in human pituitary adenomas while p27 protein levels are decreased. Therefore, a reduction in p27 levels could be su cient to sensitize pituitary cells to tumorigenic factors. To test this hypothesis, metallothionein promoter-driven, human growth hormone-releasing hormone (MT-hGHRH) transgenic mice, that exhibit somatotrope hyperplasia before 9 months of age and subsequent adenoma formation with 30 ± 40% penetrance, were crossbred with p27+/7 mice for two successive generations to produce p27+/+, p27+/7 and p277/7 mice that expressed the hGHRH transgene. At 10 ± 12 weeks of age, p277/7 and p27+/+, hGHRH mice were larger than their p27+/+ littermates and displayed characteristic hyperplasia of the IL and AL, respectively. Expression of the hGHRH transgene in both p27+/7 and p277/7 mice selectively expanded the population of somatotropes within the AL, where pituitaries of p27+/7, hGHRH and p277/7, hGHRH mice were two-and ®vefold larger than p27+/+, hGHRH pituitaries, respectively. There was also a synergistic e ect of hGHRH transgene expression and p27-de®ciency on liver, spleen and ovarian growth. At 6 ± 8 months of age, 83% of p27+/7, hGHRH mice displayed macroscopic AL adenomas (4100 mg), while all pituitaries from p27+/+, hGHRH mice remained hyperplastic (520 mg). In contrast to the dramatic e ects of p27-de®ciency on hGHRH-induced organ growth, elimination of p53, by crossbreeding MT-hGHRH mice to p53-de®cient mice, did not augment the hyperplastic/ tumorigenic e ects of hGHRH transgene expression.Taken together these results demonstrate that a reduction in p27 expression is su cient to sensitize somatotropes to the proliferative actions of excess GHRH, resulting in the earlier appearance and increased penetrance of hGHRH-induced pituitary tumors.

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“…These and other studies indicate that during hepatocarcinogenesis, the selective, proliferative advantage of altered hepatocytes is associated with enhanced apoptosis. 4,6,7 To analyze the relationships between hepatocyte proliferation and apoptosis in hepatocarcinogenesis, we established a line of double transgenic mice that overexpress TGF-␣, a hepatocyte mitogen, and Bcl-2, an antiapoptotic gene (TGF-␣/Bcl-2 mice). Surprisingly, we found that Bcl-2 expression in these animals inhibited and delayed the development of TGF-␣-induced hepatic tumors.…”

mentioning

confidence: 99%

Bcl-2 Expression Inhibits Liver Carcinogenesis and Delays the Development of Proliferating Foci

Pierce

Vail

Ralph

et al. 2002

The American Journal of Pathology

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Tumor development is thought to require both increased proliferation and inhibition of apoptosis. However, the relationship between cell replication and cell death in liver tumorigenesis is complex because both proliferation and apoptosis increase during hepatocarcinogenesis. To investigate the effect of the anti-apoptotic gene Bcl-2 in liver carcinogenesis, we established a line of double transgenic mice that express transforming growth factor-␣ (TGF-␣), a liver mitogen, and Bcl-2. Double transgenic mice, TGF-␣ and Bcl-2 single transgenics, and wild type received an injection of diethylnitrosamine at 15 days of age. This alkylating agent induces liver carcinogenesis and its effect is greatly enhanced by TGF-␣. We report that Bcl-2 expression inhibited diethylnitrosamine-induced liver carcinogenesis and counteracted the enhancing effect of TGF-␣. Bcl-2 delayed the growth of proliferative foci at the early stages of carcinogenesis and inhibited cell proliferation in these foci. The effect of Bcl-2 on liver carcinogenesis is consistent with its reported ability to interfere with cell replication. The data demonstrate that the expression of an antiapoptotic gene during liver carcinogenesis causes a delay rather than an increase in tumorigenesis. The discovery that overexpression of Bcl-2 in follicular lymphomas, caused by a chromosomal translocation, inhibits apoptosis without increasing cell proliferation established a new mode of action for oncogenes.

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High, persistent hepatocellular proliferation and apoptosis precede hepatocarcinogenesis in growth hormone transgenic mice

Abstract: Relatively high and enduring levels of hepatocellular replication and apoptosis precede hepatocarcinogenesis in GH-transgenic mice. Increased cellular proliferation and resistance to apoptosis were evident in tumour growth in older animals.

Cited by 49 publications

References 43 publications

Connecting serum IGF-1, body size, and age in the domestic dog

Connecting serum IGF-1, body size, and age in the domestic dog

p27Kip1-deficient mice exhibit accelerated growth hormone-releasing hormone (GHRH)-induced somatotrope proliferation and adenoma formation

Bcl-2 Expression Inhibits Liver Carcinogenesis and Delays the Development of Proliferating Foci

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