Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
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DOI：
10.1371/journal.pbio.0060301
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发表时间：
2008-12-02
期刊：
影响因子：
9.8
通讯作者：
Campisi J
中科院分区：
文献类型：
--
作者：
Coppé JP;Patil CK;Rodier F;Sun Y;Muñoz DP;Goldstein J;Nelson PS;Desprez PY;Campisi J
细胞衰老通过基本上永久地阻止细胞增殖来抑制癌症，以响应致癌刺激，包括基因毒性应激。我们修改了抗体阵列的使用，以对衰老细胞分泌的因子进行定量评估。我们发现，通过基因毒性应激诱导衰老的人类细胞会分泌多种与炎症和恶性肿瘤相关的因子。这种与衰老相关的分泌表型（SASP）在几天内缓慢发展，并且仅在 DNA 损伤达到足以诱导衰老的程度后才形成。在培养物中受到基因毒性应激后，在正常成纤维细胞、正常上皮细胞和上皮肿瘤细胞中，以及在用DNA损伤性化疗治疗前列腺癌患者后的体内上皮肿瘤细胞中，都出现了非常相似的SASP。在培养的癌前上皮细胞中，SASP 通过很大程度上依赖于 SASP 因子白细胞介素 (IL)-6 和 IL-8 的旁分泌机制，诱导上皮间质转变和侵袭性，这是恶性肿瘤的标志。引人注目的是，两种操作显着放大并加速了 SASP 的发育：致癌 RAS 表达（导致正常细胞的基因毒性应激和衰老）和 p53 肿瘤抑制蛋白的功能丧失。 p53 的缺失和致癌 RAS 的增加也加剧了 SASP 的恶性旁分泌活性。我们的研究结果定义了基因毒性应激诱导衰老的一个核心特征。此外，他们提出了一种细胞非自主机制，通过改变组织微环境，p53 可以抑制年龄相关癌症的发展，而致癌 RAS 可以促进与年龄相关的癌症的发展。 DNA 受损的细胞有变成癌性肿瘤的风险。虽然“细胞衰老”可以通过阻止癌症生长的细胞分裂来抑制受损细胞形成肿瘤，但它也与促进癌症和其他与年龄相关的疾病有关。为了了解这种情况是如何发生的，我们测量了衰老的人类细胞分泌到其局部环境中的蛋白质，并发现了许多与炎症和癌症发展相关的因素。不同类型的细胞在衰老时会分泌一组共同的蛋白质。这种衰老相关的分泌表型 (SASP) 不仅发生在培养细胞中，而且还发生在体内对 DNA 损伤性化疗的反应中。获得高活性 RAS 蛋白突变体（已知该蛋白有助于肿瘤生长）的正常细胞会经历细胞衰老，并产生非常强烈的 SASP，并分泌更高水平的蛋白。同样，当细胞失去肿瘤抑制因子 p53 的功能时，SASP 会更加强烈。衰老细胞会促进附近癌前细胞或癌细胞的生长和侵袭性，而具有更强 SASP 的细胞会更有效地发挥作用。我们的研究结果支持这样的观点，即细胞衰老既可以有益于防止受损细胞分裂，也可以通过影响邻近细胞而有害。这种效应平衡是由衰老进化理论预测的。通过控制受损细胞如何改变其周围组织环境，抑癌基因可以抑制癌症的发展，而癌基因可以促进癌症的发展。
Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial–mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment. Cells with damaged DNA are at risk of becoming cancerous tumors. Although “cellular senescence” can suppress tumor formation from damaged cells by blocking the cell division that underlies cancer growth, it has also been implicated in promoting cancer and other age-related diseases. To understand how this might happen, we measured proteins that senescent human cells secrete into their local environment and found many factors associated with inflammation and cancer development. Different types of cells secrete a common set of proteins when they senesce. This senescence-associated secretory phenotype (SASP) occurs not only in cultured cells, but also in vivo in response to DNA-damaging chemotherapy. Normal cells that acquire a highly active mutant version of the RAS protein, which is known to contribute to tumor growth, undergo cellular senescence, and develop a very intense SASP, with higher levels of proteins secreted. Likewise, the SASP is more intense when cells lose the functions of the tumor suppressor p53. Senescent cells promote the growth and aggressiveness of nearby precancerous or cancer cells, and cells with a more intense SASP do so more efficiently. Our findings support the idea that cellular senescence can be both beneficial, in preventing damaged cells from dividing, and deleterious, by having effects on neighboring cells; this balance of effects is predicted by an evolutionary theory of aging. By controlling how damaged cells modify their surrounding tissue environment, a tumor suppressor gene can restrain, and an oncogene can promote, the development of cancer.
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影响因子：
11.2
作者：
Bavik, C;Coleman, I;Nelson, PS
通讯作者：
Nelson, PS
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
64.8
作者：
Di Micco, Raffaella;Fumagalli, Marzia;di Fagagna, Fabrizio d'Adda
通讯作者：
di Fagagna, Fabrizio d'Adda
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
15.9
作者：
Ben-Porath, I;Weinberg, RA
通讯作者：
Weinberg, RA