The Lautenberg Center for Immunology, Institute of Medical Research, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Cancer Cell. 2013 Aug 12;24(2):242-56. doi: 10.1016/j.ccr.2013.06.005. Epub 2013 Jul 25.
Senescence, perceived as a cancer barrier, is paradoxically associated with inflammation, which promotes tumorigenesis. Here, we characterize a distinct low-grade inflammatory process in stressed epithelium that is related to para-inflammation; this process either represses or promotes tumorigenesis, depending on p53 activity. Csnk1a1 (CKIα) downregulation induces a senescence-associated inflammatory response (SIR) with growth arrest in colorectal tumors, which loses its growth control capacity in the absence of p53 and instead, accelerates growth and invasiveness. Corresponding processes occur in CKIα-deleted intestinal organoids, assuming tumorigenic transformation properties ex vivo, upon p53 loss. Treatment of organoids and mice with anti-inflammatory agents suppresses the SIR and prevents p53-deficient organoid transformation and mouse carcinogenesis. SIR/para-inflammation suppression may therefore constitute a key mechanism in the anticarcinogenic effects of nonsteroidal anti-inflammatory drugs.
衰老被认为是一种癌症障碍，但它与炎症有矛盾的联系，炎症促进了肿瘤的发生。在这里，我们描述了一种在应激上皮细胞中独特的低级别炎症过程，这种过程与副炎症有关；根据 p53 的活性，这个过程可以抑制或促进肿瘤的发生。Csnk1a1（CKIα）下调诱导结直肠肿瘤中的衰老相关炎症反应（SIR）和生长停滞，而在没有 p53 的情况下，它失去了生长控制能力，反而加速了生长和侵袭。在 CKIα 缺失的肠道类器官中，也会发生相应的过程，在 p53 缺失的情况下，类器官获得肿瘤转化特性。用抗炎药物治疗类器官和小鼠可以抑制 SIR，并防止 p53 缺失的类器官转化和小鼠致癌。因此，SIR/副炎症抑制可能是非甾体抗炎药抗癌作用的关键机制。
