RESUMO
Thyroid carcinomas are the most common endocrine neoplasms in humans, with a globally increasing incidence. Thyroid follicular cells and neuroendocrine (parafollicular) C cells are each susceptible to neoplastic transformation, resulting in thyroid cancers of differing phenotypes with unique associated genetic mutations and clinical outcomes. Over the past 15 years, several sophisticated genetically engineered mouse models of thyroid cancer have been created to further our understanding of the genetic events leading to thyroid carcinogenesis in vivo. The most significant mouse models of papillary, follicular, anaplastic, and medullary thyroid carcinoma are highlighted, with particular emphasis on the relationship between the relevant oncogenes in these models and genetic events in the naturally occurring human disease. Limitations of each model are presented, and the need for additional models to better recapitulate certain aspects of the human disease is discussed.
Assuntos
Modelos Animais de Doenças , Neoplasias da Glândula Tireoide/genética , Animais , Animais Geneticamente Modificados , Feminino , Humanos , Masculino , Camundongos , Oncogenes , Neoplasias da Glândula Tireoide/patologiaRESUMO
The carcinogenic potential of nelfinavir mesylate (nelfinavir) was evaluated in a 2-year oral (gavage) study on Sprague-Dawley rats at dose levels of 0 (control), 0 (vehicle control), 100, 300 and 1000 mg/kg per day. At the end of the treatment, increased incidences of thyroid follicular cell hyperplasia and neoplasms were observed at 300 (males) and 1000 mg/kg per day (both sexes). There were no other treatment-related effects and no tumors at other sites. Results from previous studies indicated a number of effects in the liver and thyroid, as well as metabolic profiles that suggested nelfinavir might cause thyroid hyperplasia/neoplasia secondary to hormone imbalance by altering thyroid hormone disposition. To investigate this hypothesis, the effects of nelfinavir on gene expression in rat hepatocytes and liver slices (in vitro), thyroxine plasma clearance, and thyroid gland function were evaluated. Compared to controls, gene expression analyses demonstrated an increased expression of glucuronyltransferase (UDPGT) and CYP450 3A1 in nelfinavir-treated rat hepatocytes and liver slices. In rats treated with nelfinavir (1000 mg/kg per day) for 4 weeks, liver weights and centrilobular hepatocellular hypertrophy were increased and minimal to mild diffuse thyroid follicular cell hypertrophy and follicular cell hyperplasia were evident in the thyroid gland. Thyroid-stimulating hormone (TSH) levels were significantly increased (three-fold), while tri-iodothyronine (T3)/tetra-iodothyronine (T4) and reverse T3(rT3) levels were unchanged, indicating that a compensated state to maintain homeostasis of T3/T4 had been achieved. Plasma 125I-thyroxine clearance was increased and the plasma thyroxine AUC0-48 was decreased (24%) compared to control. In conclusion, these data indicate that thyroid neoplasms observed in the nelfinavir-treated rats were secondary to thyroid hormone imbalance. Increased thyroxine clearance contributes to the effects of nelfinavir on thyroid gland function and is probably a result of UDPGT induction that leads to elevated TSH levels in the rat and eventual thyroid neoplasia. These results are consistent with a well-recognized rat-specific mechanism for thyroid neoplasms.
Assuntos
Adenocarcinoma Folicular/induzido quimicamente , Inibidores da Protease de HIV/toxicidade , Nelfinavir/toxicidade , Glândula Tireoide/efeitos dos fármacos , Neoplasias da Glândula Tireoide/induzido quimicamente , Adenocarcinoma Folicular/metabolismo , Adenocarcinoma Folicular/patologia , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Hidrocarboneto de Aril Hidroxilases/metabolismo , Testes de Carcinogenicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocromo P-450 CYP3A , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Glucuronosiltransferase/genética , Glucuronosiltransferase/metabolismo , Inibidores da Protease de HIV/farmacocinética , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/metabolismo , Hiperplasia/patologia , Longevidade/efeitos dos fármacos , Masculino , Nelfinavir/farmacocinética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/sangue , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Tiroxina/sangue , Tiroxina/farmacocinéticaRESUMO
The aim of this study was to investigate effects of 1,25(OH)(2)D(3) (calcitriol), 25OHD(3), and EB1089 on cell growth and on Vitamin D receptor (VDR) mRNA and 1alpha-hydroxylase (1alpha-OHase) mRNA expression in normal canine prostatic primary cultures. Canine prostatic epithelial cells were isolated, cultured, and treated with vehicle (ethanol), calcitriol, 25OHD(3), and EB1089 at 10(-9) and 10(-7)M. The VDR was present in epithelial and stromal cells of the canine prostate gland. 1,25(OH)(2)D(3), 25OHD(3), and EB1089 inhibited epithelial cell growth at 10(-7)M compared to vehicle-treated controls [calcitriol (P < 0.01), EB1089 (P < 0.01), and 25OHD(3) (P < 0.05)]. Epithelial cells treated with calcitriol and EB1089 at 10(-7)M had slightly increased VDR mRNA expression (0.2-0.3-fold) at 6 and 12h compared to controls. There was no difference in 1alpha-OHase mRNA expression in epithelial cells treated with these three compounds. 1,25(OH)(2)D(3) and its analogs may be effective antiproliferative agents of epithelial cells in certain types of prostate cancer.
Assuntos
Calcifediol/farmacologia , Calcitriol/farmacologia , Divisão Celular/efeitos dos fármacos , Próstata/efeitos dos fármacos , RNA Mensageiro/genética , Receptores de Calcitriol/genética , Esteroide Hidroxilases/genética , Animais , Células Cultivadas , Cães , Imuno-Histoquímica , Masculino , Próstata/citologia , Próstata/enzimologia , Próstata/metabolismo , RNA Mensageiro/metabolismoRESUMO
Adrenocortical neoplasms are a common cause of morbidity in neutered ferrets. Recently we showed that gonadectomized DBA/2J mice develop adrenocortical tumors that express transcription factor GATA-4. Therefore, we screened archival specimens of adrenocortical neoplasms from neutered ferrets to determine whether GATA-4 could be used as a tumor marker in this species. Nuclear immunoreactivity for GATA-4 was evident in 19/22 (86%) of ferret adrenocortical carcinomas and was prominent in areas exhibiting myxoid differentiation. Normal adrenocortical cells lacked GATA-4 expression. Two other markers of adrenocortical tumors in gonadectomized mice, inhibin-alpha and luteinizing hormone receptor, were coexpressed with GATA-4 in some of the ferret tumors. No GATA-4 expression was observed in three cases of nodular hyperplasia, but patches of anaplastic cells expressing GATA-4 were evident in 7/14 (50%) of tumors classified as adenomas. We conclude that GATA-4 can function as a marker of anaplasia in ferret adrenocortical tumors.
Assuntos
Neoplasias do Córtex Suprarrenal/veterinária , Carcinoma Adrenocortical/veterinária , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA/metabolismo , Furões , Fatores de Transcrição/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/metabolismo , Carcinoma Adrenocortical/patologia , Animais , Fator de Transcrição GATA4 , Imuno-Histoquímica/veterinária , Inibinas/metabolismo , Receptores do LH/metabolismoRESUMO
Parathyroid hormone (PTH) is secreted by the chief cells of the parathyroid gland in response to changes in ionized calcium (Ca(2+)) concentrations. In this study, we measured PTH secretion, and PTH mRNA and calcium-sensing receptor (CaR) mRNA expression by equine parathyroid chief cells in vitro. We also evaluated the effects of interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha on PTH secretion, and PTH and CaR mRNA expression. The relationship between PTH and Ca(2+) was inversely related. PTH secretion decreased from 100% (day 0) to 13% (day 30). PTH mRNA expression declined from 100% (day 0) to 25% (day 30). CaR mRNA decreased from 100% (day 0) to 16% (day 30). Chief cells exposed to high (2.0 mM) Ca(2+) concentrations had a lower PTH mRNA expression compared with low Ca(2+) concentrations. Ca(2+) concentrations had no effect on CaR mRNA expression. The inhibitory effect of high Ca(2+) concentrations on PTH secretion also declined over time. After day 10, there was no significant difference in PTH secretion between low and high Ca(2+ )concentrations. IL-1beta decreased both PTH secretion (75%) and PTH mRNA expression (73%), and resulted in a significant overexpression of CaR mRNA (up to 142%). The effects of IL-1beta were blocked by an IL-1 receptor antagonist. IL-1beta decreased the Ca(2+) set-point from 1.4 mM to 1.2 mM. IL-6 decreased PTH secretion (74%), but had no effect on PTH and CaR mRNA expression. TNF-alpha had no effect on PTH secretion, and PTH and CaR mRNA expression. In summary, the decreased responsiveness of parathyroid cells to Ca(2+) from 0 to 30 days can be explained, in part, by the reduced CaR expression. IL-1beta and IL-6 but not TNF-alpha affected parathyroid function in vitro and may be important in influencing PTH secretion in the septic horse.
Assuntos
Interleucina-1/farmacologia , Interleucina-6/farmacologia , Glândulas Paratireoides/metabolismo , Hormônio Paratireóideo/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Cavalos/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
A total of 15 adrenocortical carcinomas with myxoid differentiation from 15 ferrets were evaluated in this retrospective study. Six of these ferrets (40%) either were euthanatized or died due to invasive and/or metastatic disease. The myxoid component was a variable part (between 5% and 95%) of the adrenal cortical neoplasm and consisted of sheets and cords of small, polygonal neoplastic cells that formed lumenlike spaces. Such spaces contained a variable amount of alcian blue (pH 2.5)-positive mucinous product (i.e., acidic mucopolysaccharides). Neoplastic cells were negative for the argentaffin reaction, but immunohistochemically they were strongly positive for vimentin and alpha-inhibin and lightly positive for synaptophysin. Proliferating cell nuclear antigen (PCNA)-labeling indices (LI) of adrenal cortical neoplastic cells within the myxoid component of the neoplasm were significantly elevated (P < 0.05) compared with those of typical neoplastic adrenal cortical cells or the adjacent nonneoplastic zona reticularis. Ultrastructurally, cells in the myxoid component exhibited a typical adrenocortical phenotype characterized by cytoplasmic lipid vacuoles, prominent rough and smooth endoplasmic reticulum, and zonula adherens. This lesion was interpreted as an adrenal cortical carcinoma with myxoid differentiation and appeared to be highly malignant based on PCNA LI, rate of invasion into adjacent tissue, and metastasis (6/15). This report is the first description of this histologic variant in the ferret, which morphologically resembled the rare myxoid variant of adrenocortical carcinoma described in humans.
Assuntos
Neoplasias do Córtex Suprarrenal/veterinária , Carcinoma Adrenocortical/veterinária , Furões , Mixoma/veterinária , Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Animais , Biópsia , Feminino , Imuno-Histoquímica/veterinária , Inibinas/metabolismo , Masculino , Microscopia Eletrônica , Mixoma/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Estudos Retrospectivos , Sinaptofisina/metabolismo , Vimentina/metabolismoRESUMO
A canine genomic library in Lambda FIX II vector was screened with a 281-base pair canine PTHrP cDNA to the prepro- and coding regions. Two genomic clones were isolated and mapped to the 3'-end of the PTHrP gene by polymerase chain reaction (PCR) amplification of exons in this region. One clone (3.5 kb) was amplified by PCR, partially sequenced, and compared to the human PTHrP gene. Regions were identified with a high degree of homology to exons 6, 7, and 8 of the human PTHrP gene. A polyadenylation site was present 3' to the exon 8-like region. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that exon 7 of the PTHrP gene was transcribed in two canine carcinomas (SCC 2/88 cells and CAC-8 tumor line) which produce PTHrP. This confirmed that the 3'-region of the canine PTHrP gene is alternately spliced with splicing of exon 6 to exons 7 or 9. Transcription of exon 8 was not demonstrated by RT-PCR and suggests that the exon 8-like region of the dog PTHrP gene is not utilized. The exon 8-like region contained an early stop codon that was not present in exon 8 of the human PTHrP gene.
Assuntos
Processamento Alternativo , Clonagem Molecular , Doenças do Cão/genética , Neoplasias/veterinária , Proteínas/genética , Análise de Sequência de DNA , Adenocarcinoma/genética , Adenocarcinoma/veterinária , Sequência de Aminoácidos , Animais , Glândulas Apócrinas , Sequência de Bases , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/veterinária , Cães , Biblioteca Gênica , Dados de Sequência Molecular , Neoplasias/genética , Proteína Relacionada ao Hormônio Paratireóideo , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , RNA Neoplásico/química , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias das Glândulas Sudoríparas/genética , Neoplasias das Glândulas Sudoríparas/veterinária , Células Tumorais CultivadasRESUMO
Humoral hypercalcemia of malignancy (HHM), a paraneoplastic syndrome associated with epithelial cancers, including squamous cell carcinoma (SCC), is due to expression and secretion of parathyroid hormone-related protein (PTHrP). Transforming growth factor-beta1 (TGFbeta1), expressed by many tumors, has been demonstrated in vitro to increase the half-life of PTHrP mRNA. In this study, oral squamous carcinoma cells (SCC2/88) had a two-fold increase in PTHrP mRNA stability (from 45 to 90 min) in response to treatment with TGFbeta1. In order to examine the mechanism of TGFbeta1-mediated PTHrP mRNA stability, a cell-free assay of mRNA degradation was utilized in which the degradation of in vitro-transcribed mRNA incubated with cytoplasmic protein extracts from SCC2/88 treated with vehicle or TGFbeta1 was measured. In this assay, full-length PTHrP mRNA was not significantly stabilized in TGFbeta1-treated samples when compared to vehicle treated samples. However, there was a striking (>5-fold) increase in PTHrP mRNA half-life in TGFbeta1-treated samples when PTHrP mRNA lacked the 3'-untranslated region (3'-UTR). In contrast, the degradation of 3'-UTR-truncated PTHrP mRNA using the cell-free assay was not altered in vehicle-treated samples. UV cross-linking of PTHrP mRNA and cytoplasmic proteins from cells treated with either vehicle or TGFbeta1 revealed numerous mRNA-binding proteins. TGFbeta1 treatment resulting in decreased binding of 33, 31, 27, 20 and 18 kDa binding proteins to the terminal coding region. These studies revealed that TGFbeta1-induced PTHrP mRNA stability might be, in part, the result of cis-acting sequences within the coding region of the PTHrP mRNA.
Assuntos
Regiões 3' não Traduzidas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Expressão Gênica/efeitos dos fármacos , Proteínas/genética , Proteínas/metabolismo , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Regiões 3' não Traduzidas/genética , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Sistema Livre de Células , Reagentes de Ligações Cruzadas , Primers do DNA/química , Diclororribofuranosilbenzimidazol/farmacologia , Cães , Inibidores Enzimáticos/farmacologia , Humanos , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Mutagênese Sítio-Dirigida , Proteína Relacionada ao Hormônio Paratireóideo , Reação em Cadeia da Polimerase , Biossíntese de Proteínas , Células Tumorais Cultivadas , Raios UltravioletaRESUMO
This study assessed the effects of raloxifene, a selective estrogen receptor modulator (SERM), on ovarian morphology and circulating hormone levels in rats. Female Fischer-344 rats (65/group) were given dietary raloxifene for 6 months at average daily doses of 0, 15, 75, and 365 mg/kg. Morphologic evaluation of ovaries was conducted on 25 rats/group at the end of the treatment period and from 20 rats per group after 1 and 3 months withdrawal from treatment. Plasma hormone analyses were conducted on 10 rats pergroup at the end of the treatment period and aftereach withdrawal period. Treatment with raloxifene for 6 months resulted in disruption of the hypothalamic-pituitary-ovarian axis, manifested by increased plasma concentrations of luteinizing hormone (LH) and estradiol-17beta (E2), and failure of ovulation, manifested by ovarian follicular prominence (retained anovulatory follicles), lack of corpora lutea (CL), and depressed plasma progesterone (P4). Many (56% to 80%) rats in all raloxifene treated groups had focal, minimal to slight hyperplasia of granulosa cells within individual retained follicles. A few treated rats in the mid- and high-dose groups (2 of 25 and 3 of 25, respectively) had more extensive focal proliferation of granulosa cells. These foci were approximately 3 to 6 mm in overall size and were characterized by moderate papillary proliferation of large granulosa cells associated with cystic spaces, often with hemorrhage. In 4 of the 5 rats with this focal cystic granulosa cell hyperplasia, the remainder of the involved ovary and the contralateral ovary were atrophic. After 1 or 3 months of drug withdrawal, most previously treated rats examined had morphologic evidence of ovarian cyclic changes. including developing follicles, various stages of CL, and normal plasma levels of LH, E2, and P4. Continued lack of cyclic changes was limited to 4 of 20 rats from the low-dose group after 1 month of recovery and to 1 low dose rat after 3 months. Intrafollicular granulosa cell hyperplasia was not seen in rats in the reversibility phase. Areas of prior focal cystic granulosa cell hyperplasia were represented by focal sclerosis that included hemorrhage and/or hemosiderin. The foci of sclerosis were associated with cystic spaces after 1 month and were solid after 3 months. A granulosa cell tumor, approximately 12-13 mm diameter, was present in a high-dose rat in the 3-month reversibility group. This tumor effaced 1 ovary and was characterized by proliferative granulosa cells, usually in papillary formations and cords within cystic spaces. This rat had atrophy of the uninvolved ovary, excessive plasma levels of E2 and prolactin, and high P4 levels considering the absence of CL. The results of this study indicate that ovarian granulosa cells in rats are susceptible to proliferative changes when stimulated chronically with excessive trophic hormones. Most of these proliferative changes were reversible upon cessation of the hormonal stimulation. However, the proliferative lesion in one treated rat progressed to apparent autonomous (neoplastic) growth.
Assuntos
Carcinógenos/toxicidade , Tumor de Células da Granulosa/induzido quimicamente , Células da Granulosa/patologia , Hormônios/sangue , Neoplasias Ovarianas/induzido quimicamente , Cloridrato de Raloxifeno/toxicidade , Moduladores Seletivos de Receptor Estrogênico/toxicidade , Animais , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Tumor de Células da Granulosa/sangue , Tumor de Células da Granulosa/patologia , Células da Granulosa/efeitos dos fármacos , Hiperplasia , Hormônio Luteinizante/sangue , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Progesterona/sangue , Ratos , Ratos Endogâmicos F344RESUMO
The adrenal gland is one of the most common endocrine organs affected by chemically induced lesions. In the adrenal cortex, lesions are more frequent in the zona fasciculata and reticularis than in the zona glomerulosa. The adrenal cortex produces steroid hormones with a 17-carbon nucleus following a series of hydroxylation reactions that occur in the mitochondria and endoplasmic reticulum. Toxic agents for the adrenal cortex include short-chain aliphatic compounds, lipidosis inducers, amphiphilic compounds, natural and synthetic steroids, and chemicals that affect hydroxylation. Morphologic evaluation of cortical lesions provides insight into the sites of inhibition of steroidogenesis. The adrenal cortex response to injury is varied. Degeneration (vacuolar and granular), necrosis, and hemorrhage are common findings of acute injury. In contrast, chronic reparative processes are typically atrophy, fibrosis, and nodular hyperplasia. Chemically induced proliferative lesions are uncommon in the adrenal cortex. The adrenal medulla contains chromaffin cells (that produce epinephrine, norepinephrine, chromogranin, and neuropeptides) and ganglion cells. Proliferative lesions of the medulla are common in the rat and include diffuse or nodular hyperplasia and benign and malignant pheochromocytoma. Mechanisms of chromaffin cell proliferation in rats include excess growth hormone or prolactin, stimulation of cholinergic nerves, and diet-induced hypercalcemia. There often are species specificity and age dependence in the development of chemically induced adrenal lesions that should be considered when interpreting toxicity data.
Assuntos
Doenças das Glândulas Suprarrenais/induzido quimicamente , Glândulas Suprarrenais/anatomia & histologia , Glândulas Suprarrenais/fisiologia , Doenças das Glândulas Suprarrenais/fisiopatologia , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/fisiopatologia , Animais , HumanosRESUMO
The objective of this review is to summarize the pathogenic mechanisms responsible for perturbations of endocrine function and development of structural lesions that result in important diseases in domestic and laboratory animals. For each major category, several specific disease problems have been selected to illustrate the functional and morphologic lesions that are characteristic for either a naturally occurring endocrinopathy or endocrine disturbances induced by the administration of large doses of xenobiotic chemicals. The major pathogenic mechanisms responsible for disruption of endocrine function include primary hyperfunction, secondary hyperfunction, primary hypofunction, secondary hypofunction, endocrine hyperactivity secondary to other conditions, hypersecretion of hormones by nonendocrine tumors, failure of target cells to respond to a hormone, failure of fetal endocrine function, abnormal degradation (increased or decreased rate) of hormone, and iatrogenic syndromes of hormone excess (direct and indirect). Disorders of the endocrine system are encountered in a wide variety of domestic and laboratory animal species and often present challenging diagnostic problems. The development of proliferative lesions, usually hyperplasia and benign tumors, in endocrine organs and hormone-responsive tissues are common findings in chronic studies with high doses of many nongenotoxic xenobiotic chemicals administered to sensitive rodent species and may have limited significance for human safety assessment.
Assuntos
Glândulas Endócrinas/patologia , Doenças do Sistema Endócrino/induzido quimicamente , Doenças do Sistema Endócrino/patologia , Animais , Neoplasias das Glândulas Endócrinas/patologia , HumanosRESUMO
This study assessed the effects of raloxifene. a selective estrogen receptor modulator (SERM), on ovarian morphology and circulating hormone levels in rats. Female Fischer-344 rats (65/group) were given dietary raloxifene for 6 months at average daily doses of 0, 15, 75, and 365 mg/kg. Morphologic evaluation of ovaries was conducted on 25 rats/group at the end of the treatment period and from 20 rats per group after 1 and 3 months withdrawal from treatment. Plasma hormone analyses were conducted on 10 rats per group at the end of the treatment period and after each withdrawal period. Treatment with raloxifene for 6 months resulted in disruption of the hypothalamic-pituitary-ovarian axis, manifested by increased plasma concentrations of luteinizing hormone (LH) and estradiol-17beta (E2), and failure of ovulation, manifested by ovarian follicular prominence (retained anovulatory follicles), lack of corpora lutea (CL), and depressed plasma progesterone (P4). Many (56% to 80%) rats in all raloxifene treated groups had focal, minimal to slight hyperplasia of granulosa cells within individual retained follicles. A few treated rats in the mid- and high-dose groups (2 of 25 and 3 of 25, respectively) had more extensive focal proliferation of granulosa cells. These foci were approximately 3 to 6 mm in overall size and were characterized by moderate papillary proliferation of large granulosa cells associated with cystic spaces, often with hemorrhage. In 4 of the 5 rats with this focal cystic granulosa cell hyperplasia, the remainder of the involved ovary and the contralateral ovary were atrophic. After 1 or 3 months of drug withdrawal, most previously treated rats examined had morphologic evidence of ovarian cyclic changes, including developing follicles, various stages of CL, and normal plasma levels of LH, E2, and P4. Continued lack of cyclic changes was limited to 4 of 20 rats from the low-dose group after 1 month of recovery and to 1 low dose rat after 3 months. Intrafollicular granulosa cell hyperplasia was not seen in rats in the reversibility phase. Areas of prior focal cystic granulosa cell hyperplasia were represented by focal sclerosis that included hemorrhage and/or hemosiderin. The foci of sclerosis were associated with cystic spaces after 1 month and were solid after 3 months. A granulosa cell tumor, approximately 12-13 mm diameter, was present in a high-dose rat in the 3-month reversibility group. This tumor effaced 1 ovary and was characterized by proliferative granulosa cells, usually in papillary formations and cords within cystic spaces. This rat had atrophy of the uninvolved ovary, excessive plasma levels of E2 and prolactin, and high P4 levels considering the absence of CL. The results of this study indicate that ovarian granulosa cells in rats are susceptible to proliferative changes when stimulated chronically with excessive trophic hormones. Most of these proliferative changes were reversible upon cessation of the hormonal stimulation. However, the proliferative lesion in one treated rat progressed to apparent autonomous (neoplastic) growth.
Assuntos
Carcinógenos/toxicidade , Tumor de Células da Granulosa/induzido quimicamente , Células da Granulosa/patologia , Hormônios/sangue , Neoplasias Ovarianas/induzido quimicamente , Cloridrato de Raloxifeno/toxicidade , Moduladores Seletivos de Receptor Estrogênico/toxicidade , Animais , Relação Dose-Resposta a Droga , Estradiol/sangue , Feminino , Tumor de Células da Granulosa/sangue , Tumor de Células da Granulosa/patologia , Células da Granulosa/efeitos dos fármacos , Hiperplasia , Hormônio Luteinizante/sangue , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/patologia , Progesterona/sangue , Ratos , Ratos Endogâmicos F344RESUMO
BACKGROUND: We investigated the effects of 1,25(OH)2D3 and selected analogs on canine squamous carcinoma cells (SCC 2/88) and tested whether these compounds could effectively decrease proliferation, induce differentiation, and inhibit PTHrP production and PTHrP mRNA expression. MATERIALS AND METHODS: SCC 2/88 cells were cultured and treated with three substrates. The media were collected for PTHrP immunoradiometric assay. The cells were analyzed for DNA concentration and PTHrP mRNA expression by Northern blot analysis, involucrin by Western blot analysis and 1,25(OH)2D3-receptor (VDR) and PTHrP by immunohistochemistry. RESULTS: The SCC 2/88 cells were stained positively for VDR and PTHrP by immunohistochemistry. 1,25(OH)2D3 and its analogs inhibited cell growth and stimulated differentiation in a dose-dependent manner. All three substrate-treated groups had significantly increased PTHrP secretion at 10(-7) M. Cells treated with 1,25(OH)2D3 at 10(-7) M had 2- to 4-fold increased PTHrP mRNA expression at 12 and 24 hours compared to the vehicle-treated controL PTHrP mRNA in cells treated with TGF-beta (1.5 ng/ml) was increased 7- to 17-fold at 6, 12 and 24 hours compared to the vehicle-treated controL PTHrP mRNA expression was reduced by 0.5- to 2-fold in cells treated with 1,25(OH)2D3 at 10(-7) M and TGF-beta (1.5 ng/ml) together compared to cells treated with TGF-beta alone. CONCLUSION: 1,25(OH)2D3, EB1089, and analog V inhibited SCC 2/88 growth and induced differentiation in a dose-dependent manner, but did not inhibit PTHrP production. 1,25(OH)2D3 treatment led to increased PTHrP mRNA expression and reduced the stimulatory effect of TGF-beta on PTHrP mRNA expression in SCC 2/88 cells.
Assuntos
Antineoplásicos/farmacologia , Calcitriol/análogos & derivados , Biossíntese de Proteínas , Animais , Calcitriol/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Diferenciação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Cães , Imuno-Histoquímica , Proteína Relacionada ao Hormônio Paratireóideo , Proteínas/antagonistas & inibidores , Proteínas/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Calcitriol/biossíntese , Fator de Crescimento Transformador beta/biossíntese , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/farmacologiaRESUMO
OBJECTIVES: Parathyroid hormone-related protein (PTHrP) is expressed by squamous cell carcinomas. Our first objective was to examine the stability of PTHrP in normal human plasma. Our second objective was to determine whether plasma PTHrP could be used in patients with head and neck squamous cell carcinoma (HNSCC) as an indicator of tumor burden or relapse. STUDY DESIGN AND SETTING: Blood and urine samples from 55 HNSCC patients undergoing tumor resection at The Ohio State University were measured for plasma PTHrP (1-86) concentration, serum ionized calcium concentration, and urine calcium/creatinine ratio. RESULTS: Two of 55 HNSCC patients had detectable levels of plasma PTHrP. Serum ionized calcium concentrations and urinary calcium/creatinine ratios were within normal limits in all patients. CONCLUSIONS: Plasma PTHrP was not a valuable indicator of tumor presence or recurrence in our patient population. SIGNIFICANCE: Plasma PTHrP is not a useful marker of tumor presence or recurrence in patients with stage II to IV or recurrent HNSCC.
Assuntos
Biomarcadores Tumorais/sangue , Cálcio/sangue , Cálcio/urina , Carcinoma de Células Escamosas/sangue , Neoplasias de Cabeça e Pescoço/sangue , Proteínas de Neoplasias/sangue , Proteínas/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Relacionada ao Hormônio Paratireóideo , Proteínas Recombinantes/sangueRESUMO
It examines the scientific basis for possible species differences in mechanisms by which thyroid follicular-cell tumours in mice and rats, renal tubule-cell tumours in male rats and urinary bladder tumours in rats may be produced.
Assuntos
Neoplasias Renais/etiologia , Neoplasias Urológicas/etiologia , Ratos , Animais de Laboratório , Toxicologia , OncologiaRESUMO
Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice =28 weeks of age or p53-/- mice = 17 weeks of age; however, an older (170-day-old) male p53-/- mouse used to maintain the colony developed anaplastic thyroid carcinoma with liver metastases. These findings demonstrate that the lack of functional p53 in ret/PTC1 mice promotes anaplasia and invasiveness of thyroid carcinomas.
Assuntos
Proteínas de Fusão Oncogênica/genética , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/genética , Proteína Supressora de Tumor p53/genética , Anaplasia , Animais , Modelos Animais de Doenças , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Índice Mitótico , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Tirosina Quinases , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/patologia , Fatores de TempoRESUMO
Subchronic/chronic toxicity studies on antimony potassium tartrate (APT) have been reviewed. One of the older studies (H. A. Schroeder et al., 1970, J. Nutr. 100 (1), 59-68), on which are based the EPA reference dose value and a number of state, national, and international drinking water criteria for antimony, has severe inadequacies in study conduct making it uninterpretable and inappropriate for characterization of APT toxicity. In particular, the manner in which control data were generated and utilized in this study is considered invalid. More recent drinking water studies conducted by the NTP (1992, "NTP Technical Report on Toxicity Studies of Antimony Potassium Tartrate in F344/N Rats and B6C3F(1) Mice (Drinking Water and Intraperitoneal Injection Studies)," NTP Toxicity Report Series, No. 11) and Poon et al. (1998, Food Chem. Toxicol. 36, 20-35) showed antimony to be of low toxicity. The NOAEL in the 14-day NTP study was 2500 ppm by the oral route in both rats and mice, while Poon et al. (1998) suggested a NOAEL of 0.5 ppm in their 90-day study. However, upon close examination, it was determined that this value was based on subtle histological changes in the thyroid gland that were physiological, not toxicological, in nature. This conclusion is supported further by an absence of these changes in a well-conducted 13-week intraperitoneal exposure study in rats that utilized APT at much higher doses (NTP, 1992). Thus, the NOAEL by Poon et al. (1998) should more appropriately be 50 ppm. When regulatory criteria for antimony are established and/or reviewed, the findings in the NTP study and this critical reevaluation of the Poon et al. (1998) study should be considered when establishing a NOAEL for subchronic exposure to antimony in the future.
Assuntos
Tartarato de Antimônio e Potássio/toxicidade , Esquistossomicidas/toxicidade , Animais , Humanos , Nível de Efeito Adverso não ObservadoRESUMO
Parathyroid hormone-related protein (PTHrP), an important factor in the pathogenesis of humoral hypercalcemia of malignancy, is produced by many normal tissues, including the skin, where it regulates keratinocyte growth and differentiation and dermal fibroblast function. Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is a secretory product of stromal cells and functions as a mediator of epithelial cell growth and differentiation. Phenotypes of the skin in several transgenic mouse models, in which the KGF and PTHrP genes have been overexpressed or disrupted, suggest that these two factors interact in vivo to regulate homeostasis of the skin. In this study, we investigated the effects of KGF on PTHrP secretion and expression by normal human foreskin keratinocytes (NHFK) and the effects of PTHrP on KGF secretion and expression by normal human dermal fibroblasts (NHDF) in vitro. N-terminal PTHrP(1-36) increased KGF secretion, protein expression and mRNA expression by NHDF in a dose-dependent manner, however, KGF did not regulate PTHrP expression and secretion by NHFK. By flow cytometry, PTHrP also increased the percentage of NHDF producing KGF. Our results indicate that PTHrP produced by keratinocytes is a potential paracrine regulator of KGF expression by dermal fibroblasts in vivo. This paracrine regulation may explain, in part, the epidermal atrophy seen in the PTHrP null mice and epidermal hyperplasia seen in transgenic mice overexpressing PTHrP in their basal keratinocytes. Our results also suggest that PTHrP is an important mediator for the healing of skin wounds and growth of neoplasms of squamous origin.
Assuntos
Fatores de Crescimento de Fibroblastos , Fibroblastos/metabolismo , Substâncias de Crescimento/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Proteínas/metabolismo , Animais , Divisão Celular , Células Cultivadas , Fator 10 de Crescimento de Fibroblastos , Fator 7 de Crescimento de Fibroblastos , Humanos , Interleucina-1/farmacologia , Camundongos , Proteína Relacionada ao Hormônio Paratireóideo , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Pele/citologia , Pele/metabolismoRESUMO
The RET/PTC1 oncogene, a rearranged form of the RET proto-oncogene, has been reported to be associated with human papillary thyroid carcinomas. We have shown that targeted expression of RET/PTC1 in the thyroid gland leads to the development of thyroid carcinomas in transgenic mice with histologic and cytologic similarities to human papillary thyroid carcinoma. To further investigate how RET/PTC1 expression contributes to the pathogenesis of papillary thyroid tumor, the time of tumor onset and the early phenotypic consequences of RET/PTC1 expression in thyrocytes were determined. All high copy transgenic mice developed bilateral thyroid tumors as early as 4 days of age. At embryological days 16-18, increased proliferation rate, distorted thyroid follicle formation and reduced radioiodide concentrating activity were identified in transgenic embryos. The reduced radioiodide concentrating activity was attributed to decreased expression of the sodium-iodide symporter. Our study showed that RET/PTC1 not only increased proliferation of thyrocytes, it also altered morphogenesis and differentiation. These findings provide a model for the role of RET/PTC1 in the formation of abnormal follicles with reduced iodide uptake ability observed in human papillary thyroid carcinoma.
Assuntos
Proteínas de Fusão Oncogênica/genética , Oncogenes , Simportadores , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Idade de Início , Animais , Proteínas de Transporte/genética , Divisão Celular , Hipotireoidismo Congênito , DNA/biossíntese , Progressão da Doença , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Expressão Gênica , Hipotireoidismo/genética , Hipotireoidismo/metabolismo , Radioisótopos do Iodo/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Morfogênese , Fenótipo , Proteínas Tirosina Quinases , Proto-Oncogene Mas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/embriologia , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/embriologia , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Tireotropina/farmacologia , Tiroxina/farmacologiaRESUMO
Parathyroid hormone-related protein is produced by many normal tissues including the skin, where it regulates growth and differentiation of keratinocytes. To define better the role of parathyroid hormone-related protein in the skin, we investigated the spatial and temporal expression of parathyroid hormone-related protein and mRNA by immunohistochemistry and in situ hybridization during the healing of skin wounds, and the effects of topical administration of a parathyroid hormone-related protein agonist [parathyroid hormone-related protein (1-36)] and a parathyroid hormone-related protein antagonist [parathyroid hormone (7-34)] on the healing rate and morphology of the wounds. Wounds were produced on the back of guinea pigs with a 4 mm punch, and wound sites were collected at different time points during the healing process. Parathyroid hormone-related protein was expressed in normal skin by all viable keratinocyte layers, hair follicles, and adnexae. Following injury, migratory keratinocytes at wound margins and the newly restored epidermis expressed increased levels of parathyroid hormone-related protein. The remodeling phase was associated with progressive restoration of the pattern of parathyroid hormone-related protein expression in normal epidermis. Granulation tissue myofibroblasts and infiltrating macrophages also expressed parathyroid hormone-related protein. In vitro studies using THP-1 cells (a promonocytic cell line) confirmed that macrophages expressed parathyroid hormone-related protein, especially after activation. Topical application of parathyroid hormone related protein (1-36) or parathyroid hormone (7-34) did not result in significant changes in the healing rate and morphology of the wounds. These findings demonstrated that, in addition to keratinocytes, myofibroblasts and macrophages also represent sources of parathyroid hormone-related protein during the healing of skin wounds. Although the data suggest a role for parathyroid hormone-related protein in the healing of skin and in the restoration of epidermal homeostasis, parathyroid hormone-related protein does not appear to be required for proper re-epithelialization in response to injury, potentially because of redundancy in epidermal growth and wound healing, as has been shown for other paracrine and autocrine growth factors of the epidermis.