Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging
Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging
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DOI：
10.1073/pnas.211053698
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发表时间：
2001-10-09
影响因子：
11.1
通讯作者：
Campisi, J
中科院分区：
文献类型：
--
作者：
Krtolica, A;Parrinello, S;Campisi, J
哺乳动物细胞在受到损伤或应激时可进入一种生长停滞且功能改变的状态，称为细胞衰老。多项证据表明，衰老反应可抑制肿瘤发生。细胞衰老也被认为与衰老有关，但其机制尚未完全明确。我们发现，衰老的人类成纤维细胞在培养中可刺激癌前和恶性上皮细胞（但不刺激正常上皮细胞）增殖，并在小鼠体内形成肿瘤。在培养中，当衰老细胞仅占成纤维细胞群体的10%时，其生长刺激作用就很明显，而且无论衰老由复制耗竭、致癌性RAS、p14(ARF)还是过氧化氢诱导，这种刺激作用都同样显著。此外，这至少部分是由于衰老细胞分泌的可溶性和不可溶性因子所致。在小鼠体内，衰老的成纤维细胞（远比衰老前的成纤维细胞更明显）促使癌前和恶性上皮细胞形成肿瘤。我们的研究结果表明，尽管细胞衰老在生命早期抑制肿瘤发生，但在老年生物体中可能促进癌症发生，这表明它是进化拮抗多效性的一个例子。
Mammalian cells can respond to damage or stress by entering a state of arrested growth and altered function termed cellular senescence. Several lines of evidence suggest that the senescence response suppresses tumorigenesis. Cellular senescence is also thought to contribute to aging, but the mechanism is not well understood. We show that senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. in culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14(ARF), or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. our findings suggest that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy.