Nickoloff Brian J, Lingen Mark W, Chang Bey-Dih, Shen Mei, Swift Mari, Curry Jonathan, Bacon Patricia, Bodner Barbara, Roninson Igor B
Department of Pathology, Loyola University Medical Center, Maywood, Illinois 60153, USA.
Cancer Res. 2004 May 1;64(9):2956-61. doi: 10.1158/0008-5472.can-03-2388.
Cell senescence is a physiological program of terminal growth arrest, which is believed to play an important role in cancer prevention. Senescent cells secrete multiple growth-regulatory proteins, some of which can affect tumor growth, survival, invasion, or angiogenesis. Changes in expression of different senescence-associated genes were analyzed in cultured human skin keratinocytes (KCs) that underwent replicative senescence or confluence-induced accelerated senescence. Senescent KC cultures showed a strong increase in mRNA and protein expression of maspin, a member of serine protease inhibitor family and an epithelial cell tumor suppressor with anti-invasive and antiangiogenic activities. Immunohistochemical analysis of 14 normal human skin samples (age range from 3 months to 84 years) showed that maspin is expressed by KCs in vivo and that the extent and intensity of maspin expression in the skin is significantly (P = 0.01) correlated with chronological age. Antiangiogenic activity of maspin secreted by senescent KCs was investigated in vitro by testing the effect of conditioned media from different KC cultures on endothelial cell migration in the presence or absence of several angiogenic factors. Media conditioned by senescent cultures (undergoing replicative or accelerated senescence), but not by proliferating KCs, strongly inhibited the stimulation of endothelial cell migration by all of the tested angiogenic factors. Neutralizing antibody against maspin abrogated this effect of conditioned media. These findings indicate that senescent KCs exert a paracrine antiangiogenic activity, and maspin is the principal contributor to this potentially tumor-suppressive effect of cellular senescence.
细胞衰老一种终末生长停滞的生理程序，被认为在癌症预防中发挥重要作用。衰老细胞分泌多种生长调节蛋白，其中一些可影响肿瘤生长、存活、侵袭或血管生成。在经历复制性衰老或汇合诱导加速衰老的培养人皮肤角质形成细胞（KC）中，分析了不同衰老相关基因的表达变化。衰老的KC培养物显示丝氨酸蛋白酶抑制剂家族成员、具有抗侵袭和抗血管生成活性的上皮细胞肿瘤抑制因子maspin的mRNA和蛋白表达显著增加。对14份正常人类皮肤样本（年龄范围从3个月到84岁）进行免疫组织化学分析，结果显示maspin在体内由KC表达，且皮肤中maspin表达的程度和强度与实际年龄显著相关（P = 0.01）。通过检测来自不同KC培养物的条件培养基在存在或不存在几种血管生成因子的情况下对内皮细胞迁移的影响，在体外研究了衰老KC分泌的maspin的抗血管生成活性。由衰老培养物（经历复制性或加速衰老）而非增殖性KC条件化的培养基，强烈抑制了所有测试血管生成因子对内皮细胞迁移的刺激。针对maspin的中和抗体消除了条件培养基的这种作用。这些发现表明，衰老的KC发挥旁分泌抗血管生成活性，而maspin是细胞衰老这种潜在肿瘤抑制作用的主要贡献者。
