Stimulatory effects of retinoic acid on tumor growth and serum insulin-like growth factor-1 in rats bearing estrogen-responsive pituitary tumor MtT/Se

MtT/Se is one of 4 cell lines derived from an estrogen-dependent pituitary tumor, MtT/F84. The main difference between these tumor types is that MtT/F84 secretes both growth hormone (GH) and prolactin (PRL) whereas MtT/Se secretes only GH. MtT/Se grew slowly in ovariectomized (ovex) rats, but tumor growth was much faster in estrogen-treated ovex rats. Effects of dietary retinoic acid (RA) on tumor growth, serum GH and insulin-like growth factor-1 (IGF-1) levels were examined in ovex rats. Latency of tumor growth was shortened, and tumor take and weight were promoted by all-trans RA both in the presence and absence of exogenous estrogen. Serum GH and IGF-1 levels became increased in tumor-bearing rats whereas PRL levels remained unchanged. Serum IGF-1 levels exhibited a good correlation with tumor weights (r = 0.84). Our results suggest a close relationship between increase of tumor weight and stimulation of serum IGF-1 level by RA in tumor-bearing rats.     

Growth-promoting Effect of Retinoic Acid in Transplantable Pituitary Tumor of Rat

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all- trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose-dependently. ER level was elevated in tumor of RA-treated rats, whereas the retinoic acid-binding protein level remained unchanged. RA also elevated incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor-bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.     

Estrogen Receptor Levels and Tumor Growth in a Series of Pituitary Clonal Cell Lines in Rats

Four kinds of in vitro clonal pituitary tumor cell lines named MtT/Se, MtT/SM, MtT/S and MtT/ E, each of which shows different sensitivity to estrogen on proliferation, were inoculated into fat pad of ovariectomized rats and estrogen-loaded ovariectomized rats at 10⁵ and 10⁶ cells/site. They formed tumor with average latency ranging from 30 to 71 in ovariectomized rats and 13 to 63 days in estrogenized rats inoculated with 106 cells. MtT/Se was highly sensitive to estrogen for growth, and MtT/SM also grew well in estrogenized rats. With MtT/S and MtT/E, there was no significant shortening of average tumor latency in estrogenized rats. In vivo , the cytosolic estrogen receptor (ER) levels of MtT/Se, SM, S and E were measured to be 452 ±66, 370 ±115, 260 ±16 and 83 ±8 fmol/ mg protein, respectively. In vitro , however, the lowest ER level was noted in MtT/Se. Histologically, all four tumors grown in rats were composed of homogeneous round cells, and MtT/Se contained particularly large nucleated cells. In MtT/E, the cells appeared to be changing into ftbromatous cells. Three cell lines except MtT/E maintained the function of hormonal secretion in vivo as well as in vitro . Serum GH level was increased in rats with MtT/Se and MtT/S. Increased levels of both prolactin and growth hormone were measured in sera of rats with MtT/SM. Increases of hormones as well as tumor sizes were promoted by the estrogen.     

Growth-promoting effect of retinoic acid in transplantable pituitary tumor of rat

MtT/F84 grew well in Fischer rats (F344), but tumor growth was promoted in hyperestrogenized rats. Effects of dietary retinoic acid (RA) on tumor growth, estrogen receptor (ER) and serum growth hormone (GH) level were examined. Tumor latency became shortened, and tumor take and weight were promoted by all-trans RA at dosages of 50 and 200 mg/kg basal diet, but not dose-dependently. ER level was elevated in tumor of RA-treated rats, whereas the retinoic acid-binding protein level remained unchanged. RA also elevated incorporation of 5-bromo-2'-deoxyuridine, a thymidine analogue, into DNA of tumor cells. Average serum GH level was increased in tumor-bearing rats treated with RA and was well correlated with tumor weight. RA may directly affect ER level and enhance estrogenic action, resulting in promotion of tumor growth, or it may act independently for tumor growth and elevation of serum GH level.     

Functional and morphological characteristics of transplantable rat pituitary tumors established in nude mice

Two strains of transplantable rat pituitary tumors, MtT SA5 and MtT SA6, have been established in female nude mice from a single original pituitary tumor which had spontaneously occurred in a female Wistar rat at 759 days of age. MtT SA5 tumor produces prolactin (PRL), growth hormone, and adrenocorticotropic hormone, and MtT SA6 tumor secretes PRL and growth hormone. Additionally, both tumors induce severe nephropathy and promote pathogenicity of murine hepatitis virus, resulting in hepatic necrosis. Electron micrographs of MtT SA5 and MtT SA6 tumors revealed three and two types of cells, respectively, in reference to secretory granules. The tumors seem to consist of mixed population, each cell secreting each hormone. Since marked adrenal enlargement and relatively low serum corticosterone levels were found in MtT SA5-bearing rats, it is suggested that MtT SA5 tumor secretes adrenocorticotropic hormone and/or its related peptides which induce adrenal hyperplasia with little or no stimulation of corticoid production. In nude mice bearing MtT SA5 tumor, concentrations of growth hormone in serum and tumor tissue were exceedingly higher than those of PRL, while they were in the same magnitude in MtT SA6-bearing nude mice. We also found that PRL levels in serum and tumor tissue of MtT SA5-bearing nude mice were much higher in males than females, although those of MtT SA5-bearing rats were not significantly different in both sexes.     

Estrogen receptor levels and tumor growth in a series of pituitary clonal cell lines in rats.

Four kinds of in vitro clonal pituitary tumor cell lines named MtT/Se, MtT/SM, MtT/S and MtT/E, each of which shows different sensitivity to estrogen on proliferation, were inoculated into fat pad of ovariectomized rats and estrogen-loaded ovariectomized rats at 10(5) and 10(6) cells/site. They formed tumor with average latency ranging from 30 to 71 in ovariectomized rats and 13 to 63 days in estrogenized rats inoculated with 10(6) cells. MtT/Se was highly sensitive to estrogen for growth, and MtT/SM also grew well in estrogenized rats. With MtT/S and MtT/E, there was no significant shortening of average tumor latency in estrogenized rats. In vivo, the cytosolic estrogen receptor (ER) levels of MtT/Se, SM, S and E were measured to be 452 +/- 66, 370 +/- 115, 260 +/- 16 and 83 +/- 8 fmol/mg protein, respectively. In vitro, however, the lowest ER level was noted in MtT/Se. Histologically, all four tumors grown in rats were composed of homogeneous round cells, and MtT/Se contained particularly large nucleated cells. In MtT/E, the cells appeared to be changing into fibromatous cells. Three cell lines except MtT/E maintained the function of hormonal secretion in vivo as well as in vitro. Serum GH level was increased in rats with MtT/Se and MtT/S. Increased levels of both prolactin and growth hormone were measured in sera of rats with MtT/SM. Increases of hormones as well as tumor sizes were promoted by the estrogen.     

Inhibition of Mammary Tumors by Pretreatment with 17β-Estradiol in F344 Rats Induced with N-Methyl-N-nitrosourea

The influence of 17β-estradiol (E2) and prolactin was studied on N-methyl-N-nitrosourea (MNU)-induced mammary carcinomas (MCAs) in rats. MNU was intravenously injected once into seven-week-old female F344 rats at a dose of 50 mg/kg body weight. Groups of rats also received either 2.5 mg of E2 or a continuous supply of prolactin and/or growth hormone via transplanted MtT/F84 (mammo-somatotropic pituitary tumor). Rats were observed for up to 36 weeks after MNU administration. Although simultaneous administration of MNU and E2 did not much affect the occurrence of MCAs as compared to administration of MNU alone, rats treated with 2.5 mg of E2 for two weeks before MNU administration had significantly reduced occurrence of MCAs compared to those given MNU alone. In contrast, rats with MNU plus MtT/F84 showed high incidence and shortened latency of MCAs and they also had a high incidence of clitorial gland hyperplasias. Average pituitary weights and serum prolactin levels in E2-treated rats were greatly increased compared to those of MNU-alone rats. Average serum E2 levels were about 100 ng/ml in E2-treated rats and 0.05 ng/ml in rats without E2 treatment. Serum prolactin levels were greatly increased in rats with MtT/F84. The results indicated that pretreatment with E2 before MNU administration was inhibitory while increased prolactin caused by grafting MtT/F84 after MNU injection was promotive for the occurrence of MCAs in female F344 rats.     

Effects of estradiol on prolactin and growth hormone messenger RNAs in cultured normal and neoplastic (MtT/W15 and GH3) rat pituitary cells

The effects of 17 beta-estradiol (E17 beta) on prolactin (PRL) cell proliferation and on the expression of PRL and growth hormone (GH) proteins and mRNAs were analyzed in cultured pituitary cells by immunocytochemistry, in situ hybridization, and Northern blot hybridization studies. Three different cell cultures were used: (a) normal pituitary cells; (b) GH3 tumor cell line; and (c) MtT/W15, a transplantable PRL and GH-producing pituitary tumor. E17 beta (10(-7) M) caused a significant increase in PRL cell proliferation in normal pituitary [3.9 +/- 0.4 versus 7.7 +/- 0.9% (SEM) of immunostained PRL cells with thymidine incorporation] [P less than 0.01] but produced a significant decrease in PRL cell proliferation in MtT/W15 primary cell cultures [6.7 +/- 1.0 versus 3.7 +/- 0.8%] [P less than 0.05]. PRL mRNA was significantly increased in normal pituitary and in GH3 tumor cells by E17 beta treatment. There was a significant decrease in PRL mRNA and an increase in GH mRNA expression in cultured MtT/W15 tumor cells by immunocytochemistry and in situ hybridization analyses. The percentage of cells producing both PRL and GH or mammosomatotropic cells analyzed by two different techniques declined after one week in culture in normal pituitary cells and in cultured MtT/W15 tumor cells after E17 beta treatment. These results show that E17 beta has a direct stimulatory effect on normal pituitary and GH3 cells and a direct inhibitory effect on MtT/W15 tumor cells with respect to cell proliferation and PRL hormone and mRNA expression.     

Analysis of prolactin and growth hormone production in hyperplastic and neoplastic rat pituitary tissues by the hemolytic plaque assay

The reverse hemolytic plaque assay (RHPA) was used to detect hormone release from cultured normal, hyperplastic, and neoplastic rat pituitary cells. Hyperplastic pituitary cells were produced by s.c. diethylstilbestrol (DES) treatment (10 mg in Silastic tubes) for 3, 6, and 9 weeks. Neoplastic pituitary cells from rats with MtT/W15 transplantable tumors treated with DES for 3 weeks were also analyzed. Aliquots of the same cells were also analyzed by immunocytochemical staining. DES treatment resulted in an increase in prolactin (PRL)-producing cells in hyperplastic pituitaries compared to untreated pituitaries after 9 weeks of treatment by the RHPA [61.2 +/- 5.2 (SE) versus 32 +/- 3.0] and by immunocytochemical staining [70.9 +/- 2.4 versus 36 +/- 1.4]. The percentage of mammosomatotropic cells decreased from 11.3 +/- 3.8 to 4.2 +/- 2.6% in pituitary cells from these same groups of animals. After 3 weeks of DES treatment in rats with MtT/W15 tumor, there was an increase in growth hormone (GH)-producing cells and a decrease in PRL-producing cells when analyzed by the RHPA (control: percentage of GH, 36.3 +/- 6.2; percentage of PRL, 39.0 +/- 1.6 versus DES-treated tumors: percentage of GH of 68.2 +/- 1.9; and percentage of PRL, 3.2 +/- 1.8%). The percentage of mammosomatotropic cells declined from 12.4 +/- 2.3 to 0.77 +/- 2.4%. A combined procedure of RHPA followed by immunocytochemical staining on the same slides also revealed a decline in mammosomatotropic cells after chronic DES treatment in hyperplastic and neoplastic MtT/W15 tumor cells. These results show that DES has different effects on PRL and GH secretion and storage in hyperplastic pituitary and in the MtT/W15 pituitary tumor cells.     

SNPs in the Insulin-Like Growth Factor Gene and Obesity Impact on Colorectal Cancer in Egyptians

Background and aims: The insulin pathway may play a role in development of colorectal cancer (CRC). In this study, we investigated associations between CRC and obesity in Egyptians with reference to single nucleotide polymorphisms (SNPs) in the insulin-like growth factor-1 (IGF-I) gene. We also studied serum levels of IGF-1in Egyptian CRC patients with different BMI values. Methods: This prospective study included 66 CRC patients and 30 healthy individuals, for whom body mass index (BMI) was estimated, patients and controls being categorized into overweight or obese in one group and average weight in the other. Serum levels of IGF-1 were assessed by ELISA and SNPs in the IGF-I gene at rs6214C/T, rs6220 T/C and rs35767 C/T were examined by PCR- RFLP. Results: Serum levels of IGF-1 were significantly lower in both CRC average weight and overweight cases. IGF-1 could negatively predict CRC at a cut-off of 154 ng/ml with 87.5% sensitivity and 72.6 specificity. IGF-1 rs6214 CT and TT (T allele) genotypes were associated with a significantly increased risk of CRC. Univariate logistic regression showed that CRC risk significantly decreases by 0.14 for each one unit increase in IGF1. Conclusion: BMI could be considered as effect modifier for CRC risk. IGF-1 SNP rs6214 (TT and CT) are significantly associated with risk regardless of the BMI.     

The conversion of an ovariectomy-nonresponsive to an ovariectomy-responsive mammary tumor strain.

MTW9, a transplantable mammary tumor in Wistar Furth rats, shows little growth unless host serum prolactin is increased. This study compares the response to ovariectomy of MTW9-MtT, a tumor developed in rats bearing the mammosomatotropic tumor MtTW10 (serum prolactin 500 to 7000 ng/ml) with MTW9-P developed in rats given chronic perphenazine treatment (4 mg/kg/day). Serum prolactin concentrations were 150 to 600 ng/ml in MTW9-P bearing rats. MTW9-MtT does not regress after ovariectomy but does regress after surgical removal (resection) of MtT. Ovariectomy plus MtT resection leads to greater tumor regression than MtT resection alone. MTW9-P does not regress when perphenazine administration is stopped but does regress after ovariectomy, whether or not rats are given perphenazine. Administration of estradiol (10 mug/day) to rats with complete ovariectomy-induced regression of MTW9-P results in regrowth of tumor. These data suggest that MTW9-P may represent a clone of MTW9 with a lower requirement for prolactin.     

Rat prolactinoma cell growth regulation by epidermal growth factor receptor ligands

Epidermal growth factor (EGF) regulates pituitary development, hormone synthesis, and cell proliferation. Although ErbB receptor family members are expressed in pituitary tumors, the effects of EGF signaling on pituitary tumors are not known. Immunoprecipitation and Western blot confirmed EGF receptor (EGFR) and p185(c-neu) protein expression in GH3 lacto-somatotroph but not in adrenocorticotropic hormone-secreting AtT20 pituitary tumor cells. EGF (5 nmol/L) selectively enhanced baseline ( approximately 4-fold) and serum-induced (>6-fold) prolactin (PRL) mRNA levels, whereas gefitinib, an EGFR antagonist, suppressed serum-induced cell proliferation and Pttg1 expression, blocked PRL gene expression, and reversed EGF-mediated somatotroph-lactotroph phenotype switching. Downstream EGFR signaling by ERK, but not phosphoinositide-3-kinase or protein kinase C, mediated the gefitinib response. Tumors in athymic mice implanted s.c. with GH3 cells resulted in weight gain accompanied by increased serum PRL, growth hormone, and insulin growth factor 1. Gefitinib decreased tumor volumes and peripheral hormone levels by approximately 30% and restored normal mouse body weight patterns. Mice treated with gefitinib exhibited decreased tumor tissue ERK1/2 phosphorylation and down-regulated tumor PRL and Pttg1 mRNA abundance. These results show that EGFR inhibition controls tumor growth and PRL secretion in experimental lacto-somatotroph tumors. EGFR inhibitors could therefore be useful for the control of PRL secretion and tumor load in prolactinomas resistant to dopaminergic treatment, or for those prolactinomas undergoing rare malignant transformation.     

The in vitro and in vivo effects of human growth hormone administration on tumor growth of rats bearing a transplantable rat pituitary tumor (7315b)

The direct effects of human GH and IGF-I on PRL secretion and cell proliferation were studied on PRL secreting rat pituitary tumor 7315b cells in vitro, as well as the effects in vivo of human GH administration on body weight, IGF-I levels and tumor size in rats bearing this transplantable tumor. In the in vitro studies IGF-I levels above 5 nM stimulated PRL release in a dose-dependent manner while GH, in concentrations of 0.23–45 nM, did not affect PRL release. Cell proliferation was stimulated by IGF-I in a dose-dependent manner from 0.5 nM onwards, while GH did not have an effect. The in vivo studies showed that 1 mg GH/rat/day prevented tumor-induced cachexia and normalized the suppressed IGF-I levels without stimulating tumor growth. It is concluded that tumor-induced cachexia can be prevented by exogenous GH administration without an increase in tumor mass, even if a tumor model is used whose cultured tumor cells respond to exposure to IGF-I with a mitotic response.     

Growth hormone producing pituitary adenomas with concomitant hypersecretion of prolactin are particularly sensitive to photon irradiation

The effect of photon irradiation (50 Gy with a 3-field technique in fractionated doses) on growth hormone (GH), prolactin (PRL), and somatomedin A (SMA) was studied in 25 patients with acromegaly after previous unsuccessful surgery. In patients with concomitant hypersecretion of PRL, the GH reduction was 70 +/- 22% 1 year and 88 +/- 10% 3 years after radiotherapy. The corresponding reductions in patients with isolated GH hypersecretion were 42 +/- 25% and 60 +/- 22%. The reduction of GH levels was most notable the first year after radiotherapy in 16 patients and during the second year in 7 patients. Serum PRL decreased after radiotherapy in all patients with hyperprolactinemia, whereas PRL in normoprolactinemic patients showed inconsistent changes, including PRL increments in 8/12 patients. The effect of radiotherapy on GH and PRL was not correlated to the irradiation target volume or the cumulative radiation effect. SMA levels decreased after radiotherapy, but became normal only in 3 patients, all with pretreatment GH less than 5 micrograms/l. Radiotherapy, 3 years after treatment, appeared to be equivalent to the primary surgical intervention in reducing GH and SMA in patients with acromegaly due to advanced macroadenomas. Patients with concomitant hyperprolactinemia showed increased sensitivity to radiation compared to normoprolactinemic patients with acromegaly.     

Functional characteristics of transplantable rat pituitary tumor MtT SA5 inducing pronounced adrenal hyperplasia

Transplantable rat pituitary tumor MtT SA5 is characterized by the induction of pronounced adrenal enlargement. In spite of remarkable elevation of plasma ACTH levels, serum corticosterone levels in hypophysectomized tumor-bearing rats were lower than those in intact control rats. No immunohistochemical alterations were seen in corticotrophs of the pituitary in tumor-bearing rats. Ratio of bioactive ACTH (Bio-ACTH) to immunoreactive ACTH (Ir-ACTH) in the tumor tissues was 0.2%, being extraordinarily lower than in the pituitary tissues (23%). Gel chromatography of the tumor tissue showed large molecular weight forms of Ir-ACTH, which seem to result from abnormal processing of proopiomelanocortin, and are responsible for the lower levels of Bio-ACTH compared to Ir-ACTH. The MtT SA5 tumor is suggested to secrete ACTH-related peptides which induce pronounced adrenal enlargement with little or no stimulation of glucocorticoid production.     

不可切除或转移性胃肠道间质瘤患者伊马替尼治疗前后血清胰岛素样生长因子-1水平及其临床意义

 目的　探讨不可切除或转移性胃肠道间质瘤（GIST）患者伊马替尼治疗前后血清胰岛素样生长因子-1（IGF-1）水平变化及其临床意义。方法　收集27例不可切除或转移性GIST患者伊马替尼治疗前（治疗前组）、伊马替尼治疗3个月后（治疗后组）及20名健康志愿者（健康对照组）血清标本。用酶联免疫吸附法检测各血清标本IGF-1水平。结果　不可切除或转移性GIST患者伊马替尼治疗前组血清IGF-1平均水平为（463.61±120.98）ng／ml,高于健康对照组的（115.75±39.27 ）ng／ml,差异有统计学意义（t＝12.355,P＝0.000）。伊马替尼治疗后组血清IGF-1平均水平为（244.64±100.11）ng／ml,较治疗前组的（463.61±120.98）ng／ml明显降低,差异有统计学意义（t＝7.582,P＝0.000）。结论　血清IGF-1水平可能有助于判断GIST的疗效、进展、复发或转移。     

The role of prolactin and growth hormone in breast cancer

This review will focus on the role for prolactin (PRL) and growth hormone (GH) in mammary tumor formation. Much attention has previously been focused on circulating levels of GH/PRL in relation to mammary tumor formation. We will review data demonstrating that these ligands also could be produced locally in different organs, including the mammary gland and mammary tumors, and suggest that this local production may be of importance for pathological conditions. We will also discuss mechanisms for crosstalk between steroids and GH/PRL. A crosstalk between GH- and PRL response is possible at multiple levels. In the human, GH can activate both the prolactin receptor (PRLR) and the growth hormone receptor (GHR). We have demonstrated that activation of the PRLR, but not the GHR, is inducing mammary tumors in transgenic mice. Furthermore, the elevated levels of insulin-like growth factor 1 (IGF-I) seen in the GHR activating transgenic mice is not sufficient for tumor induction. The induced tumors express functionally active prolactin that could be of importance for the tumor formation. Paracrine/aurocrine stimulation by PRL may be more important than PRL transported via the circulation. In women, the role for stimulation of the PRLR and/or the GHR in mammary tumor formation has not been proven, although experiments from primates suggest that the PRLR could be of importance.     

Elevated Serum Growth Hormone Accelerates Gastric Tumorigenesis in F344 Rats after Treatment with N-Methyl-N-nitrosourea in Their Drinking Water

We examined the effects of growth hormone on tumorigenesis in F344 rats treated with N -methyl- N -nitrosourea (MNU). Four-week-old male F344 rats were exposed to 100 ppm MNU in their drinking water for 15 weeks. Thereafter Group II animals received 100 μCi/100 g body weight of ¹³¹I (radiothyroidectomy, Tx) injected i.p. and Group III rats were implanted with pituitary tumors (MtT) secreting growth hormone while Group I received no further treatment after MNU. Non-carcinogen control animals received MtT, Tx or no treatment. Animals were killed at 39 weeks after starting MNU administration. Gastric tumors were present in 13 of 31 (43%), 15 of 32 (47%) and 17 of 32 (53%) rats in Groups I to III, respectively. All tumors were of well-differentiated type. Spinal cord tumors appeared in 15 of 31 (47%) in Group I, 10 of 32 (32%) in Group II and 10 of 32 (32%) in Group III, most being malignant schwannomas. Thymic lymphornas also appeared in 10 of 31 (32%), 5 of 32 (16%) and 6 of 32 (19%) animals in Groups I to III, respectively. There were no significant differences among the groups. However, tumors in Group III developed significantly earlier than in Groups I or II. This was mainly due to gastric tumors, and cumulative incidence curves for spinal cord tumors or thymic lymphomas were similar in all groups. The results indicate that gastric tumors induced by MNU in F344 male rats are influenced by elevated levels of growth hormone.     

Growth hormone and experimental cancer cachexia

Plasma levels of growth hormone (GH) and the effect of GH treatment have been evaluated in adult nongrowing sarcoma-bearing mice (C57BL/6J). Prepubertal tumor-bearing mice, tumor-bearing hypophysectomized Sprague-Dawley rats, and malnourished non-tumor-bearing animals served as additional groups of study and control animals. Adult sarcoma-bearing mice showed an increase in plasma levels of GH early following tumor implantation. GH levels increased further with tumor progression. The anorexia and the state of malnutrition in sarcoma-bearing mice were the major factors behind increased GH levels. Muscle wasting and body composition in the tumor-bearing host were not improved by GH treatment at doses that increased growth rate in normal growing mice with intact pituitaries or partially normalized growth rate in hypophysectomized rats. Exogenous GH supported tumor growth and host body growth to the same extent in hypophysectomized rats. Exogenous GH in excess of endogenous GH did not stimulate tumor growth further. It is suggested that increased GH production in a tumor-bearing host acts in concert with other hormones to stimulate endogenous substrate mobilization and in tumor-bearing animals to prevent substrate deficiency and hypoglycemia. On the basis of this conclusion, it is unlikely that GH supplementation to a freely eating tumor-bearing host will support replenishment of host tissues.     

Mammary tumorigenesis in growth hormone deficient spontaneous dwarf rats; effects of hormonal treatments

This study was carried out to investigate mammary tumorigenesis in growth hormone (GH) deficient spontaneous dwarf rats (SDR). At 50–60 days of age, the rats were divided into five groups. Group 1 received bovine (b) GH (prolonged release formulation) administered at a dose of 40–50 mg/kg body wt. in 50 l weekly injections; group 2 received recombinant human insulin-like growth factor-I (IGF-I) at a dose of 1 mg/kg body wt./day administered via osmotic pumps; animals in group 3 were fitted with subcutaneous silastic capsule containing 30 g 17-estradiol (E2) plus 30 mg progesterone (P4), replaced every 2 months; group 4 received both bGH and E2 plus P4 treatments at the same doses as above, and control animals (group 5) received sham treatments (vegetable oil injection, silastic capsules containing cellulose). After 1week of treatment, all animals were injected intraperitoneally with the carcinogen N-methyl-N-nitrosourea (MNU) at a dose of 50 mg/kg body wt. Other groups of animals, receiving identical hormonal treatment to those exposed to MNU, were treated for 10 days only and then sacrificed for assessment of circulating concentrations of hormones and mammary gland characteristics at the time of carcinogen exposure. The hormonal treatments of the animals exposed to the MNU were continued for an additional 20 weeks and mammary tumor development monitored by weekly palpation and tumors collected as necessary. The rats were weighed weekly. At the end of the treatment period, all animals were sacrificed and remaining tumors were collected. Rats in all groups continued to gain weight throughout the experimental period, but the largest weight gain was see in animals receiving GH either alone or with E2 and P4. Animals treated with IGF-I also gained weight compared to controls, but this weight gain was less than that seen in GH-treated rats. GH treatment alone increased mammary tumor incidence from 4.8% in controls to 100%. Average tumor load and latency in the GH-treated rats were 7.0 ± 0.8 tumors/tumor-bearing rat (mean±SEM) and 57.3 ± 2.7 days (mean±SEM), respectively. As in intact Sprague–Dawley rats, approximately 90% of the tumors that developed in the GH-treated rats were ovarian dependent for growth. IGF-I treatment also increased mammary tumor development to 62.5%. Average tumor load and latency in the IGF-I-treated rats were 1.6 ± 0.4 tumors/tumor-bearing rat (mean±SEM) and 96.2 ± 14.5 days (mean±SEM), respectively. However E2+P4 treatments did not significantly alter tumorigenesis and, surprisingly, simultaneous treatment with E2+P4 and GH obliterated the GH-stimulated increase in tumor development. Prolactin (PRL) did not appear to influence mammary tumorigenesis in the SDRs, as untreated SDRs had significantly elevated serum concentration of PRL as compared with normal Sprague–Dawley (SD) rats, whereas GH-treated SDRs had PRL levels similar to that of normal SD rats. No obvious structural characteristics were associated with high or low susceptibility to mammary tumorigenesis, as assessed by mammary gland whole mounts from the different animal groups sacrificed at the time of carcinogen administration.Enhanced expression of the extracellular signal-regulated kinase 1/2 (ERK1/2), and activation (phosphorylation) of ERK1/2 were associated with an increase in mammary tumorigenesis. Similarly, the expression of the estrogen receptor- (ER) was significantly elevated in animal groups with the highest susceptibility to tumorigenesis, whereas the levels of cyclin D1 expression were not related to mammary tumorigenesis.