Sabatino Maria Eugenia, Petiti Juan Pablo, Sosa Liliana Del Valle, Pérez Pablo Anibal, Gutiérrez Silvina, Leimgruber Carolina, Latini Alexandra, Torres Alicia Inés, De Paul Ana Lucía
Endocr Relat Cancer. 2015 Jun;22(3):299-317. doi: 10.1530/ERC-14-0333. Epub 2015 Mar 19.
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 senescence-associated 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.
尽管垂体腺瘤占颅内肿瘤的25%，但它们通常是良性的，这些肿瘤通常避免侵袭性特征和转移生长发展的机制仍不清楚。在这种情况下，细胞衰老可能是垂体腺瘤良性性质的一个合理的解释。在本研究中，我们研究了细胞衰老作为雌激素诱导的垂体肿瘤进展过程中的一种生长控制机制的出现。对雌激素处理的雄性大鼠垂体在10、20、40和60天后Ki67免疫阳性细胞的定量分析显示，在整个分析期间，有丝分裂潜能率并未持续，在雌激素暴露10天后相继下降。此外，在垂体肿瘤发展过程中，观察到细胞衰老特征的表达，如衰老相关β-半乳糖苷酶（SA-β-gal）活性、IL6、IL1β和TGFβ表达的逐渐升高。此外，肿瘤性垂体细胞还显示出核pATM表达，表明DNA损伤信号激活，同时也检测到p21表达显著增加。DNA损伤信号激活、SA-β-gal表达和p21之间的关联可能为体内垂体衰老检测提供一组可靠的衰老相关标志物组合。这些结果表明这一细胞过程在垂体细胞生长调节中起作用。因此，细胞衰老应被视为垂体腺瘤良性性质的一个促成因素，从而影响垂体避免细胞增殖失控的能力。
