Department of Medicine, Division of Endocrinology and Metabolism, Cedars Sinai Medical Center-David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90048, USA.
Mol Cell Endocrinol. 2010 Sep 15;326(1-2):55-9. doi: 10.1016/j.mce.2010.02.012. Epub 2010 Feb 12.
Despite the high prevalence of pituitary adenomas they are invariably benign, indicative of unique intrinsic mechanisms controlling pituitary cell proliferation. Cellular senescence is characterized by a largely irreversible cell cycle arrest and constitutes a strong anti-proliferative response, which can be triggered by DNA damage, chromosomal instability and aneuploidy, loss of tumor suppressive signaling or oncogene activation. In vivo senescence is an important protective mechanism against cancer. Here we discuss prospective mechanisms underlying senescence-associated molecular pathways activated in benign pituitary adenomas. Both deletion and over-expression of pituitary tumor transforming gene (Pttg) promote chromosomal instability and aneuploidy. Pttg deletion abrogates tumor development by activating p53/p21-dependent senescence pathways. Abundant PTTG in GH-secreting pituitary adenomas also triggers p21-dependent senescence. Pituitary p21 may therefore safeguard against further chromosomal instability by constraining pituitary tumor growth. These observations point to senescence as a target for effective therapy for both tumor silencing and growth restraint towards development of pituitary malignancy.
尽管垂体腺瘤的患病率很高，但它们始终是良性的，这表明控制垂体细胞增殖的独特内在机制。细胞衰老的特征是细胞周期的大部分不可逆停滞，并构成了一种强大的抗增殖反应，这种反应可以由 DNA 损伤、染色体不稳定和非整倍体、肿瘤抑制信号的丧失或致癌基因的激活来触发。在体内，衰老期是防止癌症的重要保护机制。在这里，我们讨论了良性垂体腺瘤中激活的与衰老相关的分子途径的潜在机制。垂体肿瘤转化基因 (Pttg) 的缺失和过表达都促进了染色体不稳定和非整倍体。Pttg 的缺失通过激活 p53/p21 依赖性衰老途径来阻止肿瘤的发展。在 GH 分泌性垂体腺瘤中大量的 PTTG 也会引发 p21 依赖性衰老。因此，垂体 p21 可能通过限制垂体肿瘤的生长，来防止进一步的染色体不稳定。这些观察结果表明，衰老期可能是针对肿瘤沉默和生长抑制的有效治疗靶点，以防止垂体恶性肿瘤的发展。
