Mammotropic Tumor Research Articles

Adrenal Hyperplasia in Hyperprolactinemia Rats

Using mammotropic tumor (MtT/W5) bearing rats as hyperprolactinemia rats, we showed that circulating high prolactin levels caused adrenal hyperplasia. Also, we could clearly demonstrate a positive correlation between the serum levels of prolactin and the adrenal gland weights. The findings suggest that prolactin acts to stimulate primary adrenal hyperplasia.

Nucleic acids, glycogen deposition and adrenal gland steroidogenesis in rats with a pituitary mammotropic tumor (MtTF4).

Rats which have an excess of ACTH, growth hormone and prolactin from a pituitary mammotropic tumor (MtT) show a marked growth of adrenal glands, liver, spleen and kidneys. Protein, DNA, RNA and cell numbers were increased in liver, adrenal glands, spleen and decreased in thymus of tumor bearing rats as compared to intact rats. MtT tumor decreased glycogen deposition in liver, adrenal glands, thymus and pituitary of MtT tumor bearing rats. Adrenal glands of intact and MtT tumor bearing rats incubated in vitro with 4-14C progesterone synthetized radioactive 11-deoxycorticosterone, corticosterone, 18-hydroxy-11-deoxycorticosterone, 18-hydroxy-corticosterone, 11-dehydro-corticosterone and aldosterone. Intact adrenals synthetized in vitro per mg tissues 60% higher amount of corticosteroids than adrenal glands of MtT tumor bearing rats. These results show that pituitary hormones from MtT tumor have multicellular effects. They increased nucleic acid content, cell multiplication and depressed steroid hydroxylation in adrenal mitochondria and glycogen deposition in some tissues of MtTF4 rats.

Kidney Damage in Rats Bearing an Adrenocorticotropin and Prolactin Secreting Tumor

The effect of chronic high plasma corticosteroids' concentration upon renal function was studied in rats bearing a transplantable pituitary mammotropic tumor which produces large quantities of ACTH and prolactin (MtTF4S). Kidney splanchnomegaly and degenerative changes of renal cortex, particularly in proximal tubules, as well as cytolysis and appearance of vacuoles were noticed in tumor bearing rats. (Na+ + K+)-ATPase activity in renal plasma membranes decreased 67% in rats with a tumor secreting ACTH and prolactin, and 64% in rats with a tumor secreting growth hormone and prolactin when compared with controls. After adrenalectomy of MtTF4S rats, kidney weight as well as plasma concentrations of urea, sodium, chloride and phosphate ions were normalized indicating the involvement of adrenal glands in the development of disturbances in renal function.

Mechanism of thyrotropin releasing hormone stimulation of pituitary hormone secretion.

During the past several years, the mechanism of action of thyrotropin-releasing hormone (TRH; thyroliberin) has been studied intensively in GH cells, cloned rat mammotropic tumor cell lines that appear to be valid models for in vitro study of mammotroph function (30,34,48). In this article I review the recent findings (see 26 for previous review) that form the basis for a detailed hypoth­ esis to explain the transduction of the TRH signal at the cell surface into stimulation of prolactin secretion. It is generally agreed that an elevation of cyt9plasmic free calcium ion concentration ([Ca2+]i) serves to couple, at least in part, the binding of many hormones and neurotransmitters to plasma membrane receptors with the stimulation of a variety of cellular processes (51). The elevation of [Ca2+]i induced by these stimulants may be caused by mobilization (or redistribution) of intracellular calcium, or by enhancement of influx of extracellular Ca2+ , or both (17). It has been demonstrated that in some of these cells a very rapid effect after stimulant-receptor interaction is enhanced hydrolysis of phosphatidylin­ ositoI4,5-bisphosphate [PtdIns( 4,5)P2] by a phospholipase C (or phosphodies­ terase) to yield 1 ,2-diacylglycerol (DG) and inositoltrisphosphate (InsP3) (18). Furthermore, it has been proposed that both DG (50) and InsP3 (11) may serve as intracellular mediators (or second messengers) to transduce and amplify the signal, leading to stimulation of the physiologic response(s). DG appears to

Lipolytic response, cyclic AMP and cyclic GMP accumulation in rat adipocytes stimulated with ACTH: Effect of MtT-F4 tumor and clofibrate treatment

A hyperlipidemia was induced in male Fisher rats by implantation for 31 days of a mammotropic tumor (MtT-F4) which secretes large quantities of ACTH, GH, and prolactin. Following stimulation of isolated adipose tissue cells with ACTH, the lipolytic response and the accumulation of cyclic AMP were higher in cells derived from the rats with the tumor, while the accumulation of cyclic GMP was not different from control adipocytes. Further, when the isolated adipose tissue cells were stimulated with dibutyryl cyclic AMP the lipolytic response was increased to the same extent in both control and tumor-bearing groups. Clofibrate treatment did not alter the increased lipolytic response though it partially decreased the accumulation of cyclic AMP following stimulation by ACTH in adipocytes derived from tumor-bearing rats. However, clofibrate treatment resulted in a significantly greater accumulation of cyclic GMP in fat cells stimulated with ACTH from both control and tumor-bearing rats. Clofibrate in the diet did not alter the levels of GH or prolactin in the control rats nor were the elevated hormone levels of the tumor-bearing rats changed. Thus the adipose tissue cells from fasted rats treated with clofibrate and treatment withdrawn 24 h prior to sacrifice did not exhibit a decrease in the lipolytic response to ACTH. However, the decrease in the accumulation of cyclic AMP and the increase in the accumulation of cyclic GMP observed may suggest an involvement of these nucleotides in the mechanism of action of clofibrate on the adipose tissue.

Development of Hyperlipidemia Associated with Increased Lipolytic Response of Isolated Adipose Tissue Cells Following Prolonged Stimulation by an Ectopic Pituitary Tumor

Implantation of MtT-F4 tumor, a mammotropic tumor that secretes large quantities of ACTH, GH and prolactin, into male Fisher rats induced the development of hyperlipidemia. Free fatty acid, triglyceride and cholesterol levels in the plasma were significantly increased at 31 days after tumor implantation. Blood glucose and glycerol levels remained normal, while uric acid concentration in the blood was significantly decreased. The lipolytic response of isolated adipose tissue cells to ACTH was significantly higher in cells derived from rats bearing an MtT-F4 tumor for 31 days than from their corresponding controls. However, the activity of adenylate cyclase in fat cells stimulated with ACTH was not significantly higher in cells derived from tumor bearing rats than in cells from control rats.

Deveolpment of hypertension in rats maintained on a sodium deficient diet and bearing a mammotropic tumor (MtTF4).

Implantation of a mammotropic tumor (MtTF4), secreting growth hormone, prolactin, and corticotropin, in female rats of Fischer F344 strain causes hypertension, vasculitis, renal and cardiac hypertrophy, and extensive renal and cardiac lesions. When rats of the same strain were implanted with the MtTF4 tumor but sodium was withheld from the diet, systolic blood pressure rose more slowly but by six weeks reached the same values recorded in the animals implanted with the tumor and allowed to consume sodium ad libitum. In the rats, on sodium deficient diet, however, the vascular damage as well as the renal and cardiac lesions were minimal or absent. Implantation of the tumor caused adrenal cortical dysfunction, and elevated levels of deoxycorticosterone were seen in the peripheral plasma of the rats of all three groups. Nonetheless, plasma deoxycorticosterone was significantly lower in rats on a sodium deficient diet as compared with those having sodium added to the diet. Light microscopic and ultrastructural studies of the adrenal glands revealed that the lack of dietary sodium largely prevented the extensive damage of the zona fasciculata cells usually seen in the tumor-bearing rats, consuming sodium ad libitum. Both hypertensive MtT tumor-bearing animals and normotensive controls on a sodium deficient diet had a conspicuous increase of renal content of renin. It is evident that hypertension may be produced in rats bearing the MtTF4 tumor even in the virtual absence of dietary sodium. It does not appear that the hypersecretion of renal renin sustains the hypertension in these rats, since high levels of this substance were seen in the kidney of normotensive controls on the same sodium deficient diet. Elevated levels of plasma DOC may possibly explain the hypertension. In addition, it is likely that the animals may also have elevated levels of glucocorticoids.

Quantitative Ultrastructural Study of the Adrenal Cortex: Effects of a Mammotropic Pituitary Tumor Producing Growth Hormone and Prolactin (MtT-W10), and of Injected Growth Hormone in the Rat

The ultrastructure of the adrenal cortex has been examined in animals bearing a growth hormone and prolactin secreting mammotropic tumor (MtT-W 10). The large quantities of hormone secreted by the tumor caused a stimulation of zona fasciculata cells. The adrenal weight increased approximately 2-fold in tumor bearing animals. There were increases in the cellular volume of zona fasciculata cells and in the volume of mithchondria and smooth endoplasmic reticulum per cell as determined by quantitative morphometric techniques. The surface area of smooth endoplasmic reticulum and total mitochondrial membranes showed a significant increase in zona fasciculata cells as well. Injections of purified bovine growth hormone caused small but not significant increases in mitochondrial and smooth endoplasmic reticulum volumes. Growth hormone however did induce a significant increase in the surface area of mitochondrial membrane.

Evolution and selective reduction of hormonal secretion in the mammotropic pituitary tumor (MtT-F4).

Severe hypertensive vascular disease was produced in 1969 in our laboratory by implantation of the mammotropic tumor MtT-F4, secreting very large amounts of corticotropin, prolactin and growth hormone in Fischer F 344 female rats. The hypertension was caused by adrenal cortical dysfunction with hyperproduction of deoxycorticosterone (DOC), and consequent sodium retention. Ultrastructural changes in the zona fasciculata cells of the adrenal glands were also evident in the tumor-implanted hypertensive rats, thus confirming the impaired adrenal steroidogenesis. The tumor has been maintained in our laboratory by continuous passages from rat to rat or it was being stored frozen for 3 years and then reimplanted. Implants with these new strains of tumor resulted in marked reduction or total loss of its hypertensinogenic ability. In addition to the failure to develop hypertension, the same strains of tumor also showed a reduced secretion of corticotropin, reflected in a smaller increase of the adrenal weight, a smaller reduction of thymic weight and a less marked sodium retention with normal levels of plasma sodium. The less elevated secretion of corticotropin was also indicated by a more normal ultrastructural appearance of the zona fasciculata cells. No alterations in the tumor secretion of growth hormone and prolactin was evident with the continuous passage from rat to rat, at least judging from the effect of the two hormones on their target organs. It is still controversial as to whether a synergistic action of corticotropin, growth hormone and prolactin is necessary in order to cause severe hypertensive vascular disease in the rats implanted with the mammotropic tumor. However, the present experiment has outlined, that among the three hormones secreted, corticotropin definitely plays a major role in the development of such disease.

Potentiation of Effect of Prolactin by Adrenocorticotropic and Growth Hormones Upon Weight and Nucleic Acids Contents of Female Rat Mammary Gland

Effects of prolactin, adrenocorticotropic hormone, growth hormone, adrenalectomy, adrenalectomy and corticoids, and adrenalectomy plus prolactin or growth hormone upon the adult female rat mammary gland were investigated.Endogenous hormone effects were studied in rats bearing a transplantable pituitary mammotropic tumor which secretes large quantities of adrenocorticotropic hormone and prolactin. In 40 days the tumor produced a 380% weight increase and 460% increase in deoxyribonucleic acid content of mammary glands in intact rats in contrast to 95% and 297% increase in adrenalectomized rats (10 days after the rats were adrenalectomized). Inhibitory effects of adrenalectomy were prevented by administration of hydrocorticosterone but not by deoxycorticosterone. Administration of growth hormone elicited an increase in gland weight and deoxyribonucleic acid content (70% and 110%) in intact tumor bearing females but not in adrenalectomized animals (—50% and —10%).Prolactin produced mammogenic effects in normal adrenalectomized female rats. Adrenocorticotropic hormone or growth hormone administered separately did not produce any noticeable change in the mammary gland, but effects of prolactin on mammary gland weight and deoxyribonucleic acid content were greatly potentiated by simultaneous injections of adrenocorticotropic hormone and/or growth hormone.

Altered rat hepatic drug metabolism after implantation of a pituitary mammotropic tumor (MtT), Walker carcinosarcoma or adenocarcinoma and after removal of the MtT.

The liver metabolism of hexobarbital and aminopyrine was studied at various times after implantation and removal of the Furth pituitary mammotropic tumor (MtT). A decrease in liver metabolism of these 2 compounds was noted 12 days after implantation of the MtT, and this decrease was maximum after 20 days of MtT growth. No decrease in hepatic microsomal protein was observed. Enlargement of adrenals, kidneys, liver and a decrease in testicular weight were noted in MtT-bearing animals. No relationship between organ weight changes and the reduction in liver metabolism was observed. Removal of the MtT produced a gradual return in liver drug metabolic enzyme activity to control levels by 16 days. The weight of liver, kidneys, adrenals and testes also returned to normal levels in animals without the MtT, and no relationship between changes in drug metabolism and organ weight was noted. Implantation of 2 tumors of nonpituitary origin, the Hilf adenocarcinoma R3230AC and the Walker carcinosarcoma 256, revealed a decrease in drug metabolism which occurred in rats with large tumors. This decrease was related to tumor mass, but no such relationship was established for animals with the MtT. Pituitary hormones produced by the MtT probably affect hepatic drug metabolism, and this accounts for a lack of similarity between the effect of this tumor on drug metabolism as compared with 2 tumors of nonpituitary origin. These time course studies with the MtT support the hypothesis that small amounts of pituitary hormones from a grossly undetectable tumor mass decreased hepatic microsomal drug metabolism in the rat. (Endocrinology88: 185, 1971)

The effect of a pituitary mammotropic tumor on hepatic microsomal drug metabolism in the rat

The efiect of a transplantable hormone-producing pituitary mamrnotropic tumor (MtT) on the hepatic microsomal metabolism of eight compounds was studied in male and female Fischer rats. Growth of this tumor for about 31 days decreased the hepatic metabolism of most compounds studied as well as liver microsomal NADPH oxidase activity and the amount of hepatic cytochrome CO-binding pigment (P-450). The activity of glucose 6-phosphate dehydrogenase in the liver 104,000 g supernatant fraction of tumor-bearing rats, however, was increased as compared with that of control animals. Another tumor, adrenocarcinoma R-3230AC, did not decrease the hepatic metabolism of hexobarbital, aminopyrine or p-nitrobenzoic acid. High blood levels of rat somatotropin, prolactin and corticotropin produced by the MtT, individually or in combination, may have been responsible for the decrease in the metabolism of some compounds which was found in liver from MtT-bearing rats.

Hepatic drug metabolism after phenobarbital or 3-methylcholanthrene pretreatment of rats bearing a pituitary tumor.

The administration of phenobarbital to rats bearing a pituitary mammotropic tumor (MtT) produced an increase in the hepatic metabolism of hexobarbital which was greater than that of similarly treated control rats. The formation of formaldehyde from aminopyrine by liver from MtT-bearing rats, however, was not increased by an amount comparable to that of control rats following phenobarbital pretreatment. The metabolism of benzpyrene was increased more than that of zoxazolamine by liver from MtT rats after an injection of 3-MC, and the metabolism of both compounds was increased more than that found after control rats were injected with 3-MC. An increase in the liver metabolism of four drugs which followed phenobarbital or 3-MC pretreatment of control rats, therefore, was not prevented by growth in rats of a corticotropin, somatotropin, and prolactin producing pituitary tumor.

Comparison of two different transplantable mammotropic pituitary tumors. Hormone content and effect on host.

A pituitary tumor (7315a) from a rat treated with 2,4,6-trimethylaniline was transplantable. Studies during the eighth and twelfth transfer generation of 7315a showed the tumor to be similar to the mammotropic tumor MtT F4 established by Furth in that it contained the same 3 pituitary hormones, which produced similar changes in the organs of the host. MtT 7315a and MtT F4 contained the same concentration of prolactin (2 IU/g dry weight) but MtT F4 contained more than 10 times the, concentration of growth hormone and ACTH found in MtT 7315a, Correspondingly rats with MtT 7315a grew less rapidly and had less hypertrophy of the liver, kidney and preputial gland than rats with MtT F4, but the mammary glands were larger. Both tumor lines induced equally large adrenals (9 X normal) and blood levels of corticosterone (8 X normal) but the ascorbic acid concentration of the adrenal was different (7315a: 94 vs F4: 180 mg/100g) due to difference in growth hormone levels.

Induction of permanent diabetes in rats by pituitary hormones from a transplantable mammotropic tumor. Concomitant changes in organ weights and the effect of adrenalectomy.

No diabetes was observed inrats after 80% of the pancreas was removed (80 P) or in unoperated rats bearing large transplantable mammotropic pituitary tumors (MtT) that produce very high blood levels of 3 diabetogenic hormones, growth hormone, prolactin and ACTH. Diabetes developed in 32 of 33 rats that were 80 % P and had MtT; in 8 of 9 rats that were 65 % P and hadMtT; and in only 3 of 11 rats that were 40 % P and had MtT. The persistence of the diabeticstate (blood sugar 300–400 mg/100 ml) in 80 % P rats for 3 weeks after surgical removal of the MtT was demonstrated. Typical diabetic histological changes were observed in the β-cells. Adrenalectomy of 80% P rats with MtT prevented the development of diabetes in about half of the rats. The other half had only mild diabetes. The usual growth-producing effect of MtT was inhibited by 80 % P in intact rats which became diabetic but was not inhibited by 80 % P in adrenalectomized rats; 80% P had no effect on organ weights of rats with or without MtT unless diabetes developed. Diabetes led to an increased food intake with a concomitant increase in the length and weight of the intestine. (Endocrinology78: 826, 1966)

MAMMARY CARCINOMA IN MICE BEARING A TRANSPLANTABLE MAMMOTROPIC TUMOR, CARRYING THE BITTNER VIRUS.

Summary1. A subline of mammotropic tumor strain 38, used in previous co-carcinogenesis studies with Bittner's virus (MTV), now appears to carry this virus and causes mammary tumors in adult mice of a strain (LAF1) in which spontaneous mammary tumors are very rare. This strain has marked mammary gland stimulating, marked adrenotropic and moderate growth-promoting activities. 2. Numerous similar MtT strains studied earlier failed to induce mammary tumors. 3. Electronmicrographs showed MTV-like particles in both mammotropic tumor and mammary gland. 4. In a small experiment no mammary tumors developed in bilaterally adrenalectomized mice bearing this mammotropic tumor, even though adrenalectomy enhanced the growth of the mammotropic tumor. Prevention of induction of mammary tumor by adrenalectomy might be related to inhibition of milk secretion and reduction of viral concentration. 5. Cancerization by this mammotropic tumor is extraordinary so that almost every mammary pad examined had microscopic mammary car...

Identification of the hormones secreted by an autonomous mammotropic pituitary tumor in rats.

SummaryThe autonomous mammotropic tumor of Furth (MtT-F4) has been shown to secrete growth hormone and ACTH. The previous observation of mammotropin production has been confirmed.

Relation of mammotropes to mammary tumors. IV. Development of highly hormone-dependent mammary tumors.

Summary1. Highly hormone dependent mammary tumors were induced in rats by a combined treatment of a subthreshold dose of 3-methylcholanthrene and mammotropic hormone(s) (administered by grafts of a functional mammotropic tumor). 2. Growth of these mammary tumors was dependent upon continuation of stimulation by mammotropic hormone(s). 3. Grafts of the mammary tumors remained latent up to 262 days, growing only after mammotropic hormone(s) was administered. 4. Upon resection of mammotropic tumor, a primary mammary tumor promptly and completely regressed; 5 other primary tumors in rats carrying functional mammotropic tumors grew progressively.The authors acknowledge the technical assistance of Mary Campbell.