Animal models of Cushing's disease

Kemppainen, Robert J.; Peterson, Mark E.

doi:10.1016/1043-2760(94)90117-1

Cited by 23 publications

(12 citation statements)

References 28 publications

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“…Canine pituitary-dependent hyperadrenocorticism (PDH) largely recapitulates Cushing disease in humans and is commonly encountered. Clinical signs are mostly similar to the human disease, including central obesity, ravenous appetite, polyuria, polydipsia, thin skin, distinctive "potbelly" appearance, and loss of hair (31). In the present study, inhibition of EGFR kinase activity in canine tumor cell cultures suppressed 80% of POMC expression and 75% of ACTH secretion.…”

Section: Discussionmentioning

confidence: 66%

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Fukuoka

Cooper²,

Ben-Shlomo³

et al. 2011

J. Clin. Invest.

235

169

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Cushing disease is a condition in which the pituitary gland releases excessive adrenocorticotropic hormone (ACTH) as a result of an adenoma arising from the ACTH-secreting cells in the anterior pituitary. ACTH-secreting pituitary adenomas lead to hypercortisolemia and cause significant morbidity and mortality. Pituitarydirected medications are mostly ineffective, and new treatment options are needed. As these tumors express EGFR, we tested whether EGFR might provide a therapeutic target for Cushing disease. Here, we show that in surgically resected human and canine corticotroph cultured tumors, blocking EGFR suppressed expression of proopiomelanocortin (POMC), the ACTH precursor. In mouse corticotroph EGFR transfectants, ACTH secretion was enhanced, and EGF increased Pomc promoter activity, an effect that was dependent on MAPK. Blocking EGFR activity with gefitinib, an EGFR tyrosine kinase inhibitor, attenuated Pomc expression, inhibited corticotroph tumor cell proliferation, and induced apoptosis. As predominantly nuclear EGFR expression was observed in canine and human corticotroph tumors, we preferentially targeted EGFR to mouse corticotroph cell nuclei, which resulted in higher Pomc expression and ACTH secretion, both of which were inhibited by gefitinib. In athymic nude mice, EGFR overexpression enhanced the growth of explanted ACTH-secreting tumors and further elevated serum corticosterone levels. Gefitinib treatment decreased both tumor size and corticosterone levels; it also reversed signs of hypercortisolemia, including elevated glucose levels and excess omental fat. These results indicate that inhibiting EGFR signaling may be a novel strategy for treating Cushing disease.

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Section: Discussionmentioning

confidence: 66%

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Fukuoka

Cooper²,

Ben-Shlomo³

et al. 2011

J. Clin. Invest.

235

169

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“…In approximately 70% of the dogs with PDH, hyper¬ adrenocorticism originates from the anterior lobe of the pituitary, and in 30% it arises from either the A cells or the cells of the pars intermedia (Peterson et al 1986, Kemppainen & Peterson 1994. Also in man, it has been suggested that there might be two types of pituitary corticotroph adenomas, one originating from the anterior lobe and the other from remnants of the fetal intermediate lobe (Lamberts 1987 Rijnberk et al (19886) concluded in their study that high plasma a-MSH concentrations and dexamethasone resistance in dogs with PDH were not unambiguously associated with the theoretically expected characteristics of pars intermedia disease.…”

Section: Discussionmentioning

confidence: 99%

Correlation between impairment of glucocorticoid feedback and the size of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism

Kooistra¹,

Voorhout²,

Mol³

et al. 1997

Journal of Endocrinology

127

145

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Under the assumption that the impaired inhibitory effect of glucocorticoids on cell division is an important determinant in the progression of corticotrophic adenomas, it is postulated that the magnitude of proliferation and the resistance to glucocorticoids are correlated. To test this hypothesis, 67 dogs with pituitary-dependent hyperadrenocorticism were studied to determine whether a correlation could be demonstrated between the effect of dexamethasone administration on the activity of the pituitary-adrenocortical axis and the size of the pituitary gland as estimated by computed tomography. The volumes of the pituitary glands as calculated from summations of subsequent images of pituitary areas, ranged from 11.8 to 3238.6 mm3. Among the three dimensions, the height of the pituitary was the most sensitive indicator of enlargement. Calculation of the pituitary height/brain area ratio (P/B ratio) allowed correction for the size of the dog. The P/B ratio had the highest discriminatory power in distinguishing enlarged (n = 41) from non-enlarged (n = 26) pituitaries. The effects of dexamethasone (0.1 mg/kg) on the plasma concentrations of cortisol and ACTH and on the urinary corticoid/creatinine (C/C) ratios were expressed as percentage changes from the initial values. For ACTH, cortisol and C/C ratios these figures for resistance to dexamethasone were significantly correlated with the dimensions of the pituitary, particularly the height, volume and P/B ratio. It is concluded that the magnitude of the expansion of pituitary corticotrophic adenomas is dependent upon the loss of restraint by glucocorticoids, i.e. the degree of insensitivity to glucocorticoid feedback.

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“…Here we report on the effects of CRH, AVP and IGF-I on the proliferation of and adrenocorticotrophin (ACTH) secretion by normal pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism (PDH), which is generally regarded to be a valuable model for pathogenetic studies (27). The sensitivity to inhibition by cortisol was analysed under various conditions.…”

Section: Introductionmentioning

confidence: 99%

Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro

Wijk

Rijnberk²,

Croughs³

et al. 1998

European Journal of Endocrinology

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Extrinsic factors such as hypothalamic hormones or intrapituitary growth factors may stimulate clonal expansion of a genomically altered cell and therefore play a role in pituitary tumorigenesis. Here we report on the effects of the hypophysiotrophic hormones corticotrophin-releasing hormone (CRH) and vasopressin (AVP) and the intrapituitary growth factor insulin-like growth factor-I (IGF-I) on the proliferation of, as measured by the bromodeoxyuridine labelling index, and ACTH secretion by normal canine pituitary cells and corticotrophic adenoma cells of dogs with pituitary-dependent hyperadrenocorticism. The sensitivity to inhibition by cortisol was analysed under various conditions.Under basal conditions, no signi®cant differences were found in the bromodeoxyuridine labelling indices between control cells and tumour cells. CRH, AVP, IGF-I and cortisol had no effect on the proliferation of canine pituitary cells or canine corticotrophic adenoma cells. In contrast with normal pituitary cells, the proliferation of corticotrophic adenoma cells was stimulated by fetal calf serum (FCS). This FCS-induced proliferation was not inhibited by cortisol.The CRH-induced ACTH secretion by corticotrophic adenoma cells was signi®cantly (P < 0.05) lower than that by normal pituitary cells after 4 h incubation with CRH. Incubation with cortisol for 24 h resulted in reduced ACTH secretion under basal and AVP-or IGF-I-stimulated conditions. The relative inhibition was, however, signi®cantly (P < 0.05) lower in ACTH-producing tumour cells than in normal pituitary cells. Cortisol did not inhibit the CRH-induced ACTH secretion in normal pituitary cells after 24 h.In conclusion, canine corticotrophic adenomas are less sensitive to stimulation by CRH and less sensitive to inhibition by glucocorticoids. These tumours have an aberrant sensitivity to a growthpromoting factor present in FCS. This factor may have an important role in the growth promotion of canine corticotrophic tumours. European Journal of Endocrinology 138 309±315

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Animal models of Cushing's disease

Cited by 23 publications

References 28 publications

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas

Correlation between impairment of glucocorticoid feedback and the size of the pituitary gland in dogs with pituitary-dependent hyperadrenocorticism

Effects of corticotrophin-releasing hormone, vasopressin and insulin-like growth factor-I on proliferation of and adrenocorticotrophic hormone secretion by canine corticotrophic adenoma cells in vitro

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