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Acromegaly has traditionally been regarded as a monomorphous disorder resulting from a benign pituitary adenoma. Increasing evidence, however, is highlighting that this disorder is associated with a spectrum of morphologically distinct pituitary tumors with variable clinical, biochemical and radiologic features and differing therapeutic outcomes that are attributed to different genetic and epigenetic changes. These data underscore the need for developing a more refined clinicopathological risk stratification system and implementing personalized targeted therapeutic approaches.
Department of Pathology, Servicio de Endocrinología, Department of Medicine, University Health Network and the Ontario Cancer Institute, 200 Elizabeth Street, 11th Floor, Toronto, Ontario, Canada M5G 2C4
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Thyroid cancer exhibits a spectrum from relatively indolent tumors to tumors that are invasive, metastatic, or progress to poorly differentiated carcinoma. Microarray expression analysis of thyroid cancer cell lines has implicated a member of the melanoma-associated (MAGE) family of cancer–testis antigens in thyroid cancer development and progression. We performed this study to validate the role of MAGE in human thyroid cancers. A tissue microarray (TMA) of samples from 375 patients with thyroid cancer was analyzed with immunohistochemistry (IHC) to localize MAGE. Western blotting of fractionated proteins from MAGE-transfected cells was used to confirm intracellular localization of proteins. Automated analysis of TMA samples was evaluated and subjected to statistical analysis. MAGE immunoreactivity was identified in nuclear and cytoplasmic compartments of normal and malignant tissues. Specificity of staining was proved by fractionation studies that confirmed MAGE expression in nucleus and cytoplasm. Normal thyroid tissue exhibited weak cytoplasmic and strong nuclear MAGE reactivity. Tumors exhibited an increase in cytoplasmic MAGE scores that correlated with clinical behavior: larger tumors had higher MAGE scores, and there was a positive and significant correlation between MAGE cytoplasmic score and the number of histologically proven lymph node metastases. There was a statistically significant negative correlation between cytoplasmic MAGE and the percentage of p53-positive nuclei. Our data confirm gene-profiling evidence that members of the MAGE family play a role in thyroid cancer progression. The use of TMA analyses identifies IHC techniques that are translatable to the clinical setting for prognostic assessment of patients with thyroid cancer.
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The proteoglycan neuron-glial antigen 2 (NG2) is expressed by oligodendrocyte progenitors, pericytes, and some cancerous cells where it is implicated in tumor development. We examined mice with NG2-driven pRb inactivation. Unexpectedly, NG2-Cre:pRb flox/flox mice developed pituitary tumors with high penetrance. Adenohypophysial neoplasms developed initially as multifocal lesions; by 1 year, large tumors showed brain invasion. Immunohistochemistry identified these as Pit1-lineage neoplasms, with variable immunoreactivity for growth hormone, prolactin, thyrotropin, and α-subunit of glycoprotein hormones. Other than modest hyperprolactinemia, circulating hormone levels were not elevated. To determine the role of NG2 in the pituitary, we investigated NG2 expression. Immunoreactivity was identified in anterior and posterior lobes but not in the intermediate lobe of the mouse pituitary; in the adenohypophysis, folliculostellate cells had the strongest NG2 immunoreactivity but showed no proliferation in response to Rb inactivation. Pit1-positive adenohypophysial cells were positive for NG2, but corticotroph and gonadotroph cells were negative. RT-PCR revealed NG2 expression in normal human pituitary and human pituitary tumors; immunohistochemistry localized NG2 in nontumorous human adenohypophysis with strongest positivity in folliculostellate cells, and in tumors of all types except corticotrophs. Functional studies in GH4 mammosomatotrophs showed that NG2 increases prolactin (PRL), reduces growth hormone (GH) expression, and enhances cell adhesion without influencing proliferation. In conclusion, NG2-driven pRb inactivation results in pituitary tumors that mimic endocrinologically inactive Pit1-lineage human pituitary tumors. This model identifies a role for NG2 in pituitary cell-type-specific functions and unmasks a protective role from Rb inactivation in folliculostellate cells; it can be used for further research, including preclinical testing of novel therapies.
Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
Institute of Medical Science
Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
Institute of Medical Science
Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
Institute of Medical Science
Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
Institute of Medical Science
Department of Medical Biophysics University of Toronto, Toronto, Ontario, Canada
Division of Neurosurgery Toronto Western Hospital, 399 Bathurst Street, 4W-439, Toronto, Ontario, Canada M5T 2S8
Ontario Cancer Institute Princess Margaret Hospital, Toronto, Ontario, Canada
Endocrine Oncology Site Group Princess Margaret Hospital, Toronto, Ontario, Canada
Department of Laboratory Medicine and Pathobiology University of Toronto, Toronto, Ontario, Canada
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Pituitary adenomas are common intracranial neoplasms. Patients with these tumors exhibit a wide range of clinically challenging problems, stemming either from results of sellar mass effect in pituitary macroadenoma or the diverse effects of aberrant hormone production by adenoma cells. While some patients are cured/controlled by surgical resection and/or medical therapy, a proportion of patients exhibit tumors that are refractory to current modalities. New therapeutic approaches are needed for these patients. Activation of the AKT/phophotidylinositide-3-kinase pathway, including mTOR activation, is common in human neoplasia, and a number of therapeutic approaches are being employed to neutralize activation of this pathway in human cancer. This review examines the role of this pathway in pituitary tumors with respect to tumor biology and its potential role as a therapeutic target.
2The Royal Free Hospital, London, UK
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2The Royal Free Hospital, London, UK
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2The Royal Free Hospital, London, UK
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2The Royal Free Hospital, London, UK
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