Senescence: Not Just for Tumor Suppression

Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Cell (Impact Factor: 32.24). 09/2008; 134(4):562-4. DOI: 10.1016/j.cell.2008.08.003
Source: PubMed


Cellular senescence provides an intrinsic barrier to tumor development by preventing the proliferation of cells that are at risk for malignant transformation. In this issue, Krizhanovsky et al. (2008) report that senescence is an important player not only in tumor suppression but also in the response of liver tissue to injury.

Full-text preview

Available from:
  • Source
    • "As can be imagined, such state protects against the development of cancer and plays an important role in tissue repair [3]. On the other hand, senescence is involved in many other processes such as aging and neurodegenerative disease [4] [5] [6]. Recent studies show that senescent cells produce senescence-associated secretory phenotype (SASP) factors including chemokines, proteases, pro-inflammatory cytokines, growth factors, macrophage inflammatory proteins (MIPs), and granulocyte–macrophage colony-stimulating factors (GM-CSFs) [7] [8]. "

    Full-text · Article · Jan 2016 · Genomics Proteomics & Bioinformatics
  • Source
    • "Increasing evidence reveals moreover that senescent cells disrupt normal tissue structure and function (Parrinello et al., 2005), promote angiogenesis (Coppe et al., 2006), epithelial-mesenchymal transition and invasiveness (Coppe et al., 2008), and importantly, promote proliferation of premalignant and malignant cells in vitro (Krtolica et al., 2001; Liu & Hornsby, 2007), thus aiding tumor formation. Interestingly, secretory phenotypes similar to SAS have also been observed in fibroblasts adjacent to some carcinomas (Rodier et al., 2007), and senescent cells have been detected in both premalignant lesions (Campisi, 2005; Green, 2008) and around primary and secondary tumor sites (Charalambous et al., 2007). However, these studies were carried out with cancer cells for which the normal equivalent is not available, thus complicating the analysis of the molecular pathways that occur upon transformation of a normal cell to a tumor cell. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Senescent cells secrete a plethora of factors with potent paracrine signaling capacity. Strikingly, senescence, which acts as defense against cell transformation, exerts pro-tumorigenic activities through its secretome by promoting tumor-specific features, such as cellular proliferation, epithelial-mesenchymal transition and invasiveness. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has the unique activity of activating cell death exclusively in tumor cells. Given that the senescence-associated secretome (SAS) supports cell transformation, we asked whether SAS factor(s) would establish a program required for the acquisition of TRAIL sensitivity. We found that conditioned media from several types of senescent cells (CMS) efficiently sensitized pretransformed cells to TRAIL, while the same was not observed with normal or immortalized cells. Dynamic transcription profiling of CMS-exposed pretransformed cells indicated a paracrine autoregulatory loop of SAS factors and a dominant role of CMS-induced MYC. Sensitization to TRAIL coincided with and depended on MYC upregulation and massive changes in gene regulation. Senescent cell-induced MYC silenced its target gene CFLAR, encoding the apoptosis inhibitor FLIPL , thus leading to the acquisition of TRAIL sensitivity. Altogether, our results reveal that senescent cell-secreted factors exert a TRAIL-sensitizing effect on pretransformed cells by modulating the expression of MYC and CFLAR. Notably, CMS dose-dependent sensitization to TRAIL was observed with TRAIL-insensitive cancer cells and confirmed in co-culture experiments. Dissection and characterization of TRAIL-sensitizing CMS factors and the associated signaling pathway(s) will not only provide a mechanistic insight into the acquisition of TRAIL sensitivity but may lead to novel concepts for apoptogenic therapies of premalignant and TRAIL-resistant tumors.
    Full-text · Article · Mar 2014 · Aging cell

  • No preview · Article · May 2001 · Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion
Show more