Hyperplasia induction

In breast cancer patients, total PR status is measured for hormonal treatment. The presence of PR is associated with increased survival rates and hormonal responsiveness of mammary tumors. PR agonists are widely used in contraception, HRT, breast cancer, and endometrial hyperplasia. Antiprogestins such as RU486 are used for blocking ovulation and preventing implantation, and in addition they are in clinical testing for the induction of labor and to control various neoplastic transformations. 

Nguyen ML, Nguyen MM, Lee D, Griep AE, Lambert PF (2003) The PDZ ligand domain of the human papiUomavims type 16 E6 protein is required for E6 s induction of epithehal hyperplasia in vivo. J Virol 77 6957-6964... 

Laham S, Long G, Broxup B. 1985. Induction of urinary bladder hyperplasia in Sprague-Dawley rats orally administered Tri-n-butyl Phosphate. Archives of Environmental Health 302-301-306. 

In those infections that are associated with enteropathy (exemplified by T. spiralis), no experimental manipulation has, until recently, been able to separate enteropathy and immune expulsion - if one is abrogated, so is the other. This chapter illustrates how the two processes can be separated, and discusses implications of this for understanding immune expulsion of gut nematodes and the prospects for anti-nematode vaccines that cause no ill effects at either the initial induction of immunity or the expression of protective responses. The definition of that which consitututes enteropathy may vary between authors, but we take as our primary definition the most destructive and quantifiable changes in intestinal tissue that are associated with expulsion, villus atrophy and crypt hyperplasia. 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

SR024 Vacherot, F., M. Azzouz, S. Gil-Diez-De-Medina, et al. Induction of apoptosis and inhibition of cell proliferation by the lipido-sterolic extract of Serenoa repens (LSESr, Permixon) in benign prostatic hyperplasia. Prostate 2000 45(3) 259-266. 

In the chronic gavage study by NTP (1986), dosed male rats had increased incidences of renal tubular cell hyperplasia, epithelial cell hyperplasia of the renal pelvis, and tubular mineralization. The male rats also had increased incidences of renal tubular cell tumors. The hyperplasia of the tubular cells, therefore, may represent a preneoplastic response (see discussion of cancer below). These proliferative kidney lesions were not observed in male or female mice or in female rats. The mechanism for the induction of proliferative kidney lesions may also be related to a2p-globulin-induced nephropathy (see discussion of cancer below), again raising the question of the relevance of the proliferative kidney lesions in male rats to humans. This issue is presently the subject of scientific investigation. 

Thyroid effects that have mainly included reduced serum T4 hormone levels and follicular cell hyperplasia were consistently observed in rats and mice orally exposed to PBDEs. Accompanying changes in serum TSH levels were not found and the depression of serum T4 is likely related to hepatic enzyme induction. Acute duration studies showed decreases in serum T4 in rats exposed to >10 mg/kg/day octaBDE or >30 mg/kg/day pentaBDE for 4 days and in rats and mice exposed to >18 mg/kg/day pentaBDE for 14 days. Effects observed in intermediate-duration studies include thyroid hyperplasia in rats exposed to >8 mg/kg/day octaBDE for 30 days and reduced serum T4 in rats exposed to >10 mg/kg/day pentaBDE for 90 days. Exposure to pentaBDE on gestation day 6 through postnatal day 21 caused serum T4... 

The receptor protein (52 kDa) is a member of the steroid hormone receptor superfamily, which has a DNA-binding as well as ligand-binding domain. Another receptor, the retinoid X receptor is also involved, and after binding of the peroxisome proliferator, the two receptors form a heterodimer. This binds to a regulatory DNA sequence known as the peroxisome proliferator response element. The end result of the interaction between peroxisome proliferators and this system is that genes are switched on, leading to increases in synthesis (induction) of both microsomal and peroxisomal enzymes and possibly hyperplasia. 

Fibrates (such as clofibrate) are hypolipidemic drugs. They cause a number of biological and biochemical effects, including enzyme induction, peroxisomal proliferation, liver hypertrophy and hyperplasia, and liver cancer. The mechanism is believed to be mediated through the PPARa receptor. Animals lacking this receptor do not show these effects. 

Frei JV, Stephens P. 1968. The correlation of promotion of tumor growth and of induction of hyperplasia in epidermal two-stage carcinogenesis. Br J Cancer 22 83-92. 

Ah receptor (AHR) A protein coded for by a gene of the Ah locus. The initial location of the Ah receptor is believed to be in the cytosol and, after binding to a ligand such as TCDD, is transported to the nucleus. Binding of aromatic hydrocarbons to the Ah receptor of mice is a prerequisite for the induction of many xenobiotic metabolizing enzymes, as well as for two responses to TCDD epidermal hyperplasia and thymic atrophy. Ah-responsive mice have a high-affinity receptor, whereas the Ah-nonresponsive mice have a low-affinity receptor. 

Other Species. The discussion of hepatic effects in the above subsections is based on effects in rats and mice. Not all animal species are equally susceptible to the hepatic effects of DEHP. Differences in responsiveness are particularly evident with respect to the increases in peroxisomal content of liver cells, induction of peroxisomal enzymes, and increased liver weight (hypertrophy and hyperplasia). Although these responses clearly occur in rats and mice, hamsters are only partially responsive and guinea pigs, and monkeys are refractory. 

Data on the toxicity of HFC-134a indicate that it is nontoxic in most circumstances. Most of the changes reported have been at high concentrations, which also induce narcosis. There is no evidence of genetic toxicity for HFC-134a. The primary effect reported is the induction of Leydig cell hyperplasia and adenomas in male rats exposed at 50,000 ppm for 6 h/d, 5 d/wk over a 2-yr period (Collins et al. 1995 Hext and Parr-Dobrzanski 1993). The NOAEL of 10,000 ppm from these data was the basis of the EPA s RfC. 

Fischer, S.M., Baldwin, J.K., Jasheway, R.W., Patrick, K.E., and Cameron, G.S., Phorbol ester induction of 8-hpoxygenase in inbred SENCAR (SSIN) but not C57BL/6J mice correlated with hyperplasia, edema, and oxidant generation by not ornithine decarboxylase induction. Cancer Res., 48, 658, 1988. 

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