Keeping your senescent cells under control

摘要: Cellular senescence is a stable form of cell-cycle arrest which thought to limit the proliferative potential premalignant cells [1]. The phenotype was initially described by Hayflick and Moorhead in 1961 on human fibroblasts undergoing replicative exhaustion culture [2]. It has been shown that can be triggered different cell types response diverse forms cellular damage or stress (for review see [1]). Importantly, while denounced as tissue phenomenon for many years, recent vivo studies demonstrated represents potent failsafe mechanism against tumorigenesis contributes cytotoxicity certain anticancer agents (see example [3-7]). Interestingly, senescent have also observed aged damaged tissues there growing evidence checkpoints affect regenerative reserve organismal aging [8-11]. However, may positive effects organ maintenance limiting pathological responses acute injury such fibrotic scarring chemical induced liver [12]. Over past years it communicate with their environment secreting myriad cytokines growth factors. this "senescence associated secretory (SASP)" seems double edged sword regarding tumor initiation maintenance: i)    On one hand, SASP pro-tumorigenic effects. In an experimental system mesenchymal enhance tumorigenicity surrounding breast cancer [13]. ii)    Similarly, possible enhances selection transformed clones systems. loss competition non-transformed accelerate leukemogenesis [14]. remains seen whether aberrant secretion factors accelerated process chronically iii)    contrast its aspect, could anti-tumor A study showed mosaic mouse model activation p53 senescence, upregulation inflammatory cytokines, innate immune leading tumour clearance [15]. iv)    further support activities, series papers components stabilize cycle via autoregulatory feedback loop [16,17] induces apoptosis [18]. In addition tumorigenesis, influence aging. Studies telomere dysfunctional mice provided direct dysfunction [19]. provoked alterations stem differentiation (skewing hematopoiesis towards reduction lymphopoiesis enhancement myelopoiesis) are characteristic signs Figure 1. Different stresses induce including shortening, DNA damage, oncogene activation. Senescence ... In light roles o carcinogenesis, appears utmost importance decipher regulatory pathways controlling SASP. current publication, Bhaumik et al. identified 2 microRNAs (miR-146a/b) negatively regulate IL-6 IL-8 - two [20]. authors show these up-regulated at late stages days after permanent established. inhibitory miRs most strongly lines strong but not characterized weak propose new concept indicating 146a b function negative preventing over-activation cells. present some initial data suggesting involves IL-1 receptor, IRAK-1, NFκB signalling up-regulation miRs-146a b. proof proposed suppresses future studies. blockage IL-1-receptor prevents both well Il-6 secretion. To confirm concept, would important selective results The work places mir-146a/b central players control expression within MicroRNAs emerging therapeutic targets because levels effectively modulated use antagomirs [21]). Also, increasing microRNA expression, delivered into cellsin [22]). Therefore, will interesting functionally test impact mir-146 inhibition relevant models. Such particular interest, initiating maintaining senescene autocrine [17]. miR-146 increase cells, should program reduce risk malignant transformation. Furthermore, speculated a/b NfκB IRAK1. As modulating various inflammation genes, lead increased system. mentioned secreted act mitogen thus potentially transformation [13,17]. Besides modulation, reported target mRNAs BRCA1 BRCA2 suppressors. G C polymorphism miR-146, leads processing release mature microRNA, predict early onset [23]. Taken together, opens research area dealing gene mechanisms Given progression, surveillance stabilization itself, great interest analyse during cancer.