Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas

Öngürü, Önder; Scheithauer, Bernd W.; Kovács, Kálmán; Vidal, Sergio; Jin, Long; Zhang, Shuya; Ruebel, Katharina H.; Lloyd, Ricardo V.

doi:10.1038/modpathol.3800118

Cited by 56 publications

(43 citation statements)

References 32 publications

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“…This is indicated by the presence of immunoreactivity for the phosphorylated, i.e., activated, receptor in these tumors (41,52). EGFR-expressing corticotrophinomas also had very weak or absent immunoreactivity for the cell cycle inhibitor p27 (41).…”

Section: Egfr and Corticotroph Functionmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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Cushing's disease (CD) arises from pituitary-dependent glucocorticoid excess due to an ACTH-secreting corticotroph tumor. Genetic hits in oncogenes and tumor suppressor genes that afflict other pituitary tumor subtypes are not found in corticotrophinomas. Recently, a somatic mutational hotspot was found in up to half of corticotrophinomas in the USP8 gene that encodes a protein that impairs the downregulation of the epidermal growth factor receptor (EGFR) and enables its constitutive signaling. EGF is an important regulator of corticotroph function and its receptor is highly expressed in Cushing's pituitary tumors, where it leads to increased ACTH synthesis in vitro and in vivo. The mutational hotspot found in corticotrophinomas hyper-activates USP8, enabling it to rescue EGFR from lysosomal degradation and ensure its stimulatory signaling. This review presents new developments in the study of the genetics of CD and focuses on the USP8-EGFR system as trigger and target of corticotroph tumorigenesis.

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Section: Egfr and Corticotroph Functionmentioning

confidence: 99%

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Theodoropoulou

Reincke

Faßnacht

et al. 2015

European Journal of Endocrinology

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“…Several studies have found the expression of EGF and/or EGFR in pituitary adenomas, sometimes associated with a more aggressive (invasive) phenotype (Lubke et al 1995, LeRiche et al 1996, Asa & Ezzat 2002, Onguru et al 2004, Cooper et al 2011, Fukuoka et al 2011, del Pliego et al 2013. In ACP, EGF signaling has been reported to play a role in tumor cell migration (Hölsken et al 2011).…”

Section: Dysregulation Of Egf/fgf In Pituitary Tumorigenesismentioning

confidence: 99%

Pituitary stem cell regulation: who is pulling the strings?

Cox

Roose

Vennekens

et al. 2017

Journal of Endocrinology

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The pituitary gland plays a pivotal role in the endocrine system, steering fundamental processes of growth, metabolism, reproduction and coping with stress. The adult pituitary contains resident stem cells, which are highly quiescent in homeostatic conditions. However, the cells show marked signs of activation during processes of increased cell remodeling in the gland, including maturation at neonatal age, adaptation to physiological demands, regeneration upon injury and growth of local tumors. Although functions of pituitary stem cells are slowly but gradually uncovered, their regulation largely remains virgin territory. Since postnatal stem cells in general reiterate embryonic developmental pathways, attention is first being given to regulatory networks involved in pituitary embryogenesis. Here, we give an overview of the current knowledge on the NOTCH, WNT, epithelial-mesenchymal transition, SHH and Hippo pathways in the pituitary stem/progenitor cell compartment during various (activation) conditions from embryonic over neonatal to adult age. Most information comes from expression analyses of molecular components belonging to these networks, whereas functional extrapolation is still very limited. From this overview, it emerges that the 'big five' embryonic pathways are indeed reiterated in the stem cells of the 'lazy' homeostatic postnatal pituitary, further magnified en route to activation in more energetic, physiological and pathological remodeling conditions. Increasing the knowledge on the molecular players that pull the regulatory strings of the pituitary stem cells will not only provide further fundamental insight in postnatal pituitary homeostasis and activation, but also clues toward the development of regenerative ideas for improving treatment of pituitary deficiency and tumors.

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“…9 Immunostaining for insulin, glucagon, gastrin and somatostatin was performed as previously reported.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Various studies have shown that EGFR is expressed in carcinoids and pancreatic endocrine tumors. [4][5][6][7][8] However, the activated or phosphorylated form of EGFR (P-EGFR) has been examined in only a few neuroendocrine tumors, 9 and it has not been studied in primary gastrointestinal carcinoid or pancreatic endocrine tumors.…”

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confidence: 99%

Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas

et al. 2005

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The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of many tumors. To analyze the expression of EGFR and activated EGFR in well-differentiated neuroendocrine carcinomas including primary and metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors (PET), we examined 58 gastrointestinal carcinoid tumors and 48 PET using immunohistochemistry, Western blotting, and RT-PCR. EGFR and activated EGFR (P-EGFR) were expressed by both gastrointestinal carcinoids and PET in primary and metastatic tumors, although a higher percentage of gastrointestinal carcinoid tumors expressed EGFR and activated EGFR. Western blotting detected a 170 kDa band for both EGFR and activated EGFR in three primary carcinoid tumors and two metastatic carcinoid tumors to the liver. RT-PCR analysis confirmed the expression of EGFR mRNA in both primary and metastatic carcinoid tumors. Patients with activated EGFR expression in their primary PET had a significantly worse prognosis compared to those who did not express activated-EGFR (P ¼ 0.043). These results indicate that gastrointestinal carcinoid tumors as well as PET express EGFR and activated EGFR, and that expression is more common in gastrointestinal carcinoid tumors compared to pancreatic endocrine tumors. These findings implicate the EGFR and P-EGFR signal transduction pathway in the pathogenesis of these neuroendocrine tumors and suggest that targeted therapy directed against the EGFR tyrosine kinase domain may be a useful therapeutic approach in patients with unresectable metastatic gastrointestinal carcinoid tumors and pancreatic endocrine tumors.

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Analysis of epidermal growth factor receptor and activated epidermal growth factor receptor expression in pituitary adenomas and carcinomas

Cited by 56 publications

References 32 publications

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Decoding the genetic basis of Cushing's disease: USP8 in the spotlight

Pituitary stem cell regulation: who is pulling the strings?

Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas

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