Developmental Biology and Cancer Programme, Birth Defects Research Centre, UCL Institute of Child Health, London, WC1N 1EH, UK.
Basic Research Department, Instituto Nacional de Geriatría, Anillo Periférico 2767, Magdalena Contreras, 10200, Mexico City, Mexico.
Nat Commun. 2017 Nov 28;8(1):1819. doi: 10.1038/s41467-017-01992-5.
Senescent cells may promote tumour progression through the activation of a senescence-associated secretory phenotype (SASP), whether these cells are capable of initiating tumourigenesis in vivo is not known. Expression of oncogenic β-catenin in Sox2+ young adult pituitary stem cells leads to formation of clusters of stem cells and induction of tumours resembling human adamantinomatous craniopharyngioma (ACP), derived from Sox2- cells in a paracrine manner. Here, we uncover the mechanisms underlying this paracrine tumourigenesis. We show that expression of oncogenic β-catenin in Hesx1+ embryonic precursors also results in stem cell clusters and paracrine tumours. We reveal that human and mouse clusters are analogous and share a common signature of senescence and SASP. Finally, we show that mice with reduced senescence and SASP responses exhibit decreased tumour-inducing potential. Together, we provide evidence that senescence and a stem cell-associated SASP drive cell transformation and tumour initiation in vivo in an age-dependent fashion.
衰老细胞可能通过激活衰老相关分泌表型（SASP）来促进肿瘤进展，目前尚不清楚这些细胞是否能够在体内引发肿瘤发生。在 Sox2+年轻成年垂体干细胞中表达致癌β-连环蛋白会导致干细胞簇的形成，并诱导类似于人类造釉细胞瘤（ACP）的肿瘤，这些肿瘤通过旁分泌方式由 Sox2-细胞衍生而来。在这里，我们揭示了这种旁分泌肿瘤发生的机制。我们表明，在 Hesx1+胚胎前体中表达致癌β-连环蛋白也会导致干细胞簇和旁分泌肿瘤的形成。我们揭示了人类和小鼠簇是类似的，并具有共同的衰老和 SASP 特征。最后，我们表明，衰老和 SASP 反应减少的小鼠表现出降低的肿瘤诱导潜力。总之，我们提供的证据表明，衰老和与干细胞相关的 SASP 以年龄依赖的方式驱动体内细胞转化和肿瘤起始。
