Oncogene-induced senescence in pituitary adenomas and carcinomas

Alexandraki, Krystallenia Ι.; Khan, Mohammed Munayem; Chahal, Harvinder; Dalantaeva, Nadezhda; Trivellin, Giampaolo; Berney, Dan; Caron, Philippe; Popović, Vera; Pfeifer, Marija; Jordan, Suzanne; Korbonits, M; Grossman, Ashley

doi:10.14310/horm.2002.1358

Cited by 34 publications

(29 citation statements)

References 32 publications

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“…In agreement, Chesnokova et al (2008) have described senescence taking place predominantly in GH-secreting tumors, and to a lesser extent in PRL-secreting tumors. In addition, Alexandraki et al (2012) showed that SA-b-gal is overexpressed only in nonfunctional pituitary adenomas and GH-secreting tumors, and that in the context of senescence, these adenomas behave differently compared with ACTH-and PRL-secreting adenomas. Finally, as the great majority of pituitary carcinomas are derived from these latter types of adenoma, we might speculate that the lack or bypass of senescence in lactotrophs may permit the occasional prolactinoma to develop into a carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…Cellular senescence may constitute a plausible explanation for the benign nature of pituitary adenomas through the existence of an intrinsic predisposition of pituitary cells to limit uncontrolled proliferation through this cellular program. Some recent studies on pituitary tumorigenesis in transgenic mice (Chesnokova et al 2007(Chesnokova et al , 2008 and SA-b-gal in human pituitary tumor (Chesnokova et al 2011, Alexandraki et al 2012 have suggested that cellular senescence could be a significant mediator of growth cessation in these tumors. However, it still remains uncertain whether this cellular response takes place in the absence of direct genetic manipulation or during the development of pituitary proliferative injuries, indicating a possible physiological role for cellular senescence in the modulation of pituitary cell growth.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

Sabatino

Petiti

Sosa

et al. 2015

Endocrine-Related Cancer

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Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67-immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescenceassociated b-galactosidase (SA-b-gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

Sabatino

Petiti

Sosa

et al. 2015

Endocrine-Related Cancer

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“…OIS has been implicated in the arrest of pituitary tumors as in several other types of benign tumors. It has been shown in human and murine melanocytic nevi (Michaloglou et al 2005, Goel et Alexandraki et al 2012, Sapochnik et al 2016), but not in malignant adenocarcinomas. Cell senescence has a functional relevance in vivo, as a physiological mechanism limiting tumorigenesis in many diseases.…”

Section: Pathophysiological Role Of Il-6 In the Pituitarymentioning

confidence: 96%

Programmed cell senescence: role of IL-6 in the pituitary

Sapochnik

Fuertes

Arzt

2017

Journal of Molecular Endocrinology

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IL-6 is a pleiotropic cytokine with multiple pathophysiological functions. As a key factor of the senescence secretome, it can not only promote tumorigenesis and cell proliferation but also exert tumor suppressive functions, depending on the cellular context. IL-6, as do other cytokines, plays important roles in the function, growth and neuroendocrine responses of the anterior pituitary gland. The multiple actions of IL-6 on normal and adenomatous pituitary function, cell proliferation, angiogenesis and extracellular matrix remodeling indicate its importance in the regulation of the anterior pituitary. Pituitary tumors are mostly benign adenomas with low mitotic index and rarely became malignant. Premature senescence occurs in slow-growing benign tumors, like pituitary adenomas. The dual role of IL-6 in senescence and tumorigenesis is well represented in pituitary tumor development, as it has been demonstrated that effects of paracrine IL-6 may allow initial pituitary cell growth, whereas autocrine IL-6 in the same tumor triggers senescence and restrains aggressive growth and malignant transformation. IL-6 is instrumental in promotion and maintenance of the senescence program in pituitary adenomas.

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“…Senescent cells show altered cell morphology, including increased lysosomal breakage, causing the lysosomal enzyme β-galactosidase to enter into the cytoplasm [54]. In a recent study, it has been suggested that the senescence pathway, as assessed by β-galactosidase IHC, is more activated in GH-secreting and nonfunctioning pituitary adenomas (NFPAs) [55]. Moreover, a negative correlation was found between Ki67 LI and cytoplasmic staining for both p16 and p21.…”

Section: Evolving Biomarkers Of Pituitary Tumor Aggressivenessmentioning

confidence: 99%

Aggressive Pituitary Tumors

et al. 2015

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Pituitary adenomas are common intracranial tumors that are mainly considered as benign. Rarely, these tumors can exhibit an aggressive behavior, characterized by gross invasion of the surrounding tissues, resistance to conventional treatment leading to early and frequent recurrences. Even more rarely, pituitary tumors can give rise to cerebrospinal or systemic metastases qualifying as pituitary carcinomas according to the latest WHO definition. In the same classification, a subset of tumors with relatively distinct histopathological features was identified and defined as atypical adenomas designated to follow a more aggressive clinical course. This classification, although clinically useful, does not provide an accurate correlation between histopathological findings and the clinical behavior of these tumors, neither is it adequate to convey the precise features of ‘aggressive' tumors. Thus, ‘aggressive' pituitary adenomas need to be properly defined with clinical, radiological, histological and molecular markers in order to identify patients at increased risk of early recurrence or subsequent tumor progression. At present, no single marker or classification system of pituitary tumor aggressiveness exists, and clinically useful information in the literature is insufficient to guide diagnostic and therapeutic decisions. Treatment of patients with aggressive pituitary tumors is challenging since conventional treatments often fail, necessitating multiple surgical procedures with additional radiotherapy. Although traditional chemotherapy applied in other neuroendocrine tumors has not been shown to be efficacious, newer agents, particularly temozolomide, have shown promising results and are currently used despite the lack of data from a randomized prospective trial. Molecular targeted therapies such as mTOR and epidermal growth factor inhibitors have also been applied and might prove to be useful in the management of these patients. In the present review, we provide information regarding the epidemiology and clinical, histopathological and molecular features of aggressive pituitary tumors using recent employed definitions. In addition, we review currently employed therapeutic means providing a therapeutic algorithm and highlight the need to identify more specific disease-related and prognostic markers and the necessity for central registration of these tumors.

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Oncogene-induced senescence in pituitary adenomas and carcinomas

Cited by 34 publications

References 32 publications

Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

Programmed cell senescence: role of IL-6 in the pituitary

Aggressive Pituitary Tumors

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