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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of long-term, high-dose therapy with bromocriptine (BR) on the clinical and hormonal response, tumor size and neuro-ophthalmological status was studied in seven acromegalic patients. The mean BR dose was 64 mg/day (range 35 to 80) for a mean period of 11 months (range 10 to 12). In six patients there was a clinical improvement already manifest at low BR doses (10 to 20 mg). Serum growth hormone levels fell substantially (greater than 50%) in five patients, and the growth hormone response to thyrotropin-releasing hormone (TRH) and glucose were similar to those previously reported at lower doses of the drug, as were the prolactin and thyroid-stimulating hormone responses to TRH. In three patients, repeat CT scan disclosed a reduction in tumor size. In none of the patients was there evidence of tumor progression, with the possible exception of one patient who developed an impairment of the visual evoked potential response. These results suggest that when compared to previous studies in which lower doses of BR were used, a high BR dose is not superior in terms of clinical response and hormone secretion, but does appear to increase the percentage of patients who respond with a reduction in tumor size.
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PMID:Bromocriptine treatment of acromegaly: possible dose dependency of the tumor size-reducing effect. 249 29

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.
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PMID:Growth hormone and experimental cancer cachexia. 348 Mar 85

Rat Nb 2 lymphoma cells have been widely used to bioassay human growth hormone and many species of prolactin. Because their morphologic characterization suggests a T-cell lineage, Nb 2 cells were examined for their response to the T-cell mitogens concanavalin A, pokeweed mitogen, and phytohemagglutinin P. As expected, a dose-response to rat prolactin was observed; however, attempts to induce proliferation using the conventional T-cell mitogens failed at concentrations normally stimulatory for rat primary lymphocytes. Moreover, when Nb 2 cells were simultaneously incubated with lectin plus a suboptimal concentration of prolactin, a dose-dependent suppression of the stimulatory effects of prolactin was observed with phytohemagglutinin P and pokeweed mitogen, although not with concanavalin A. Culture medium of prolactin-stimulated Nb 2 cells also contained a factor which inhibited normal rat lymphocyte activation by concanavalin A. The factor did not block induction of the IL-2 receptor and proliferation of IL-2-dependent CTLL-2 cells could be restored by exogenous IL-2. Because Nb 2 cells evolved from a lactogen-dependent lymph node tumor, these results may have implications for further understanding the role of pituitary hormones, particularly prolactin, in the immune response to hormone-dependent tumor progression.
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PMID:Mechanisms of activation and suppression in rat Nb 2 lymphoma cells: a model for interactions between prolactin and the immune system. 779 91

Male and female Wistar rats were treated according to a slightly modified resistant hepatocyte model, i.e. initiation with diethylnitrosamine and selection of initiated cells with 2-acetylaminofluorene and partial hepatectomy. Two weeks after selection, rats of each sex received daily subcutaneous injections of either recombinant human growth hormone (2.5 IU/kg) or saline for 6 weeks. No effects on growth of early enzyme-altered liver lesions were recorded. The long-term part of the experiment did not show any differences due to growth hormone treatment in terms of incidence or latency time for development of either malignant liver tumors or kidney tumors. Male rats developed liver tumors more frequently than the female rats whereas a higher incidence of kidney tumors was observed in the female rats. Several different malignancies at other sites were also recorded, with no differences between the groups with or without growth hormone treatment. In conclusion, no modifying effects of human growth hormone administration during the post selection phase of the resistant hepatocyte model could be demonstrated on either tumor promotion or tumor progression.
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PMID:Growth hormone administration after treatment in the resistant hepatocyte model does not affect progression of rat liver carcinogenesis. 801 79

The clinical behavior of growth hormone (GH)-producing pituitary tumors is known to vary greatly; however, the events underlying this variability remain poorly understood. Herein we demonstrate that tumor overexpression of the GH-releasing hormone (GHRH) gene is one prognostically informative event associated with the clinical aggressiveness of somatotroph pituitary tumors. Accumulation of GHRH mRNA transcripts was demonstrated in 91 of a consecutive series of 100 somatotroph tumors by in situ hybridization; these findings were corroborated by Northern analysis and reverse transcriptase polymerase chain reaction, and protein translation was confirmed by Western blotting. By comparison, transcript accumulation was absent or negligibly low in 30 normal pituitary glands. GHRH transcripts were found to preferentially accumulate among clinically aggressive tumors. Specifically, GHRH mRNA signal intensity was 1) linearly correlated with Ki-67 tumor growth fractions (r = 0.71; P < 0.001), 2) linearly correlated with preoperative serum GH levels (r = 0.56; p = 0.01), 3) higher among invasive tumors (P < 0.001), and 4) highest in those tumors in which post-operative remission was not achieved (P < 0.001). Using multivariate logistic regression, a model of postoperative remission likelihood was derived wherein remission was defined by the single criterion of suppressibility of GH levels to less than 2 ng/ml during an oral glucose tolerance test. In this outcome model, GHRH mRNA signal intensity proved to be the most important explanatory variable overall, eclipsing any and all conventional clinicopathological predictors as the single most significant predictor of postoperative remission; increases in GHRH mRNA signal were associated with marked declines in remission likelihood. The generalizability of this outcome model was further validated by the model's significant performance in predicting postoperative remission in a random sample of 30 somatotroph tumors treated at another institution. These data indicate that overexpression of GHRH gene is an event associated with the neoplastic progression and clinical aggressiveness of somatotroph adenomas. More generally, these data merge essential elements of the hypothalamic and pituitary hypotheses of pituitary tumorigenesis, providing for a more unified concept of neoplastic progression in the pituitary.
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PMID:Overexpression of the growth-hormone-releasing hormone gene in acromegaly-associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. 928 26

The authors report on the morphological features of a pituitary adenoma that produced growth hormone (GH) and adrenocorticotropic hormone (ACTH). This hormone combination produced by a single adenoma is extremely rare; a review of the available literature showed that only one previous case has been published. The tumor, which was removed from a 62-year-old man with acromegaly, was studied by histological and immunocytochemical analyses, transmission electron microscopy, immunoelectron microscopy, and in situ hybridization. When the authors used light microscopy, the tumor appeared to be a bimorphous mixed pituitary adenoma composed of two separate cell types: one cell population synthesized GH and the other ACTH. The cytogenesis of pituitary adenomas that produce more than one hormone is obscure. It may be that two separate cells--one somatotroph and one corticotroph--transformed into neoplastic cells, or that the adenoma arose in a common stem cell that differentiated into two separate cell types. In this case immunoelectron microscopy conclusively demonstrated ACTH in the secretory granules of several somatotrophs. This was associated with a change in the morphological characteristics of secretory granules. Thus it is possible that the tumor was originally a somatotropic adenoma that began to produce ACTH as a result of mutations that occurred during tumor progression.
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PMID:Pituitary adenoma producing growth hormone and adrenocorticotropin: a histological, immunocytochemical, electron microscopic, and in situ hybridization study. Case report. 1006 42

Aberrant promoter methylation and resultant silencing of several tumor suppressor genes play an important role in the pathogenesis of many tumor types. The human Ras association domain family 1A gene (RASSF1A), recently cloned from the lung tumor locus at 3p21.3, was shown to be frequently inactivated by hypermethylation of its promoter region in a number of malignancies. We have investigated the expression and epigenetic changes of this novel universal tumor suppressor gene in pituitary adenomas and correlated the data with clinicopathologic findings. Fresh frozen normal pituitary tissues and 52 primary pituitary adenomas including all major types were examined. Methylation-specific polymerase chain reaction (MSP), combined bisulfite restriction analysis (COBRA), bisulfite sequencing and semiquantitative reverse transcription-polymerase chain reaction were used to analyze DNA promoter methylation status and the mRNA expression of RASSF1A, respectively. High levels of RASSF1A transcript and no methylation of the RASSF1A promoter were found in normal pituitary tissues. RASSF1A promoter methylation was detected in 20 of 52 (38%) adenomas including all major types of pituitary adenomas. However, a lower frequency of methylation of the RASSF1A promoter was found in gonadotroph cell adenomas (15%) compared with growth hormone cell, prolactin cell, or adrenocorticotropic hormone cell adenomas (54, 46 and 50%, respectively). Methylation frequency was higher in the most aggressive adenomas (87% in grade IV tumors, P=0.0163). In addition, methylation of the RASSF1A promoter potentially correlated with higher labeling index of the proliferation marker Ki-67 (P=0.1475). Loss or significant reduction of RASSF1A messenger RNA transcripts was identified in 18 of 20 (90%) adenomas with hypermethylation of RASSF1A (P<0.0001). Our data suggest that promoter hypermethylation of RASSF1A and resultant alterations of RASSF1A expression may play a critical role in pituitary tumorigenesis and may be involved in tumor progression.
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PMID:Inactivation of RASSF1A tumor suppressor gene by aberrant promoter hypermethylation in human pituitary adenomas. 1571 68

Circulating insulin-like growth factor-I (IGF-I) levels have been shown to be related to risk of prostate cancer in epidemiologic studies. While specific genetic loci responsible for interindividual variation in circulating IGF-I levels in normal men have not been identified, candidate genes include those involved in the growth hormone (GH)-IGF-I axis such as the hypothalamic factors GH releasing hormone (GHRH) and somatostatin and their receptors. To investigate the role of the GH-IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I. The lit mutation significantly reduced the percentage of the prostate gland showing neoplastic changes at 35 weeks of age (P=0.0005) and was also associated with improved survival (P<0.01). These data provide an example of a germ line mutation that reduces risk in an experimental prostate carcinogenesis model. The results suggest that prostate carcinogenesis and progression may be influenced by germ line variation of genes encoding signalling molecules in the GH-IGF-I axis.
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PMID:A germ line mutation that delays prostate cancer progression and prolongs survival in a murine prostate cancer model. 1587 Jul 5

Signaling networks play important roles in cancer progression. For example, overexpression of the epidermal growth factor receptor (EGFR) is a poor prognostic indicator in multiple tumor types. Recent studies have postulated that the EGFR functions as a central conduit for signaling by different classes of cell surface receptors. In this study, we demonstrated that c-Src-dependent phosphorylation of tyrosine 845 (Tyr 845) on EGFR was required for DNA synthesis induced by the G protein-coupled agonists, endothelin (ET) and lysophosphatidic acid (LPA), and the cytokine, growth hormone (GH), in murine fibroblast and breast cancer model systems. In addition, we showed that a dominant interfering form of signal transducer and activator of transcription (STAT)5b (a downstream effector of phospho-Tyr 845 [pY845] in fibroblasts) abrogates DNA synthesis induced by all agonists in the breast cancer model. To further characterize the role of Tyr 845, a pY845-containing peptide was microinjected into SKBr3 breast cancer cells and murine fibroblasts, and was found to ablate EGF-stimulated S-phase entry in both cell systems. Taken together, these findings suggested that pY845 is critical for DNA synthesis induced by a variety of mitogens and that its signaling effectors may include but are not limited to STAT5b.
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PMID:Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. 1616 50

Microvessel density (MVD) has been studied in a number of neoplasias, and apparently, there is a relationship between angiogenesis and tumor progression, response to treatment, and outcome. In pituitary adenoma, the association between MVD and vascular endothelial growth factor (VEGF) with tumor behavior has been described, but correlation with other angiogenic factors such as fetal liver kinase 1 (Flk-1) or proliferative markers is unknown. We investigated MVD, VEGF, and its receptor Flk-1 expression in 60 human pituitary adenomas: 13 growth hormone cell adenomas, 7 prolactin cell adenomas, 5 corticotroph cell adenomas, 2 thyrotroph cell adenomas, and 33 nonfunctioning adenomas (30 gonadotroph cell adenomas and 3 null cell adenomas). We performed immunohistochemistry for CD34, Ki-67, VEGF, and Flk-1. To evaluate MVD, we used 2 methods: the number of vessels per square millimeter and the Chalkley method. Immunohistochemistry results were correlated, as well as with clinicopathologic factors. Adenomas with higher MVD were thyrotroph cell adenomas (299.9 +/- 87.5), and those with lower MVD were prolactin cell adenomas (168.6 +/- 63.3; P = .45, analysis of variance). We found a trend toward higher MVD in the adenomas of older patients (P = .142), but no difference was found regarding sex, extrasellar extension, or Ki-67 (P > .05). However, extrasellar extension was nearly significant when the Chalkley method score was high (P = .056). Low expression of VEGF was seen predominantly in prolactin cell adenomas, and high in nonfunctioning adenomas, or in cases of older patients (P < or = .032). Flk-1 score correlated with VEGF (P = .006). High expression was observed in nonfunctioning adenomas, cases presenting at older ages, and with extrasellar extension (P < or = .022). Our study shows that VEGF and Flk-1 are widely expressed in pituitary adenomas, predominantly in nonfunctioning adenomas and those presenting at older ages. Moreover, Flk-1 is associated with a more aggressive phenotype, and it may have potential therapeutic interest.
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PMID:Immunohistochemical analysis of tumor angiogenic factors in human pituitary adenomas. 1622 8


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