Explore the vast range of titles available.

Key Points Genomic instability is a characteristic of most cancers. Insight into the possible mechanisms leading to genomic instability can be gained by reviewing the recent high-throughput sequencing studies of human cancers. In hereditary cancers, characterized either by microsatellite instability or chromosomal instability, the underlying basis for the genomic instability is mutations in DNA repair genes. In sporadic (non-hereditary) cancers, genomic instability, at least at the early stages of cancer development, is not due to mutations in DNA repair genes or mitotic checkpoint genes. The pattern of mutations in sporadic human cancers suggests that the selective pressure for tumour suppressor p53 ( TP53 ) mutations is linked to DNA damage, rather than p14ARF activation. Genomic instability in sporadic human cancers may be linked to oncogene-induced DNA damage. Analysis of the recent high-throughput sequencing studies of human cancers suggests that genomic instability can be added to the original hallmarks of cancer, and that two previously distinct hallmarks, self-sufficiency in growth signals and insensitivity to anti-growth signals, can be consolidated into one. Genomic instability in hereditary cancers results from mutations in DNA repair genes, as predicted by the mutator hypothesis. However, high-throughput sequencing studies show that mutations in DNA repair genes are infrequent in non-hereditary cancers, leaving open the possibility that genomic instability in these cancers may be related to oncogene-induced DNA damage. Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated ( ATM ) and cyclin-dependent kinase inhibitor 2A ( CDKN2A ; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

TP53 mutants (mutp53) are involved in the pathogenesis of most human cancers. Specific mutp53 proteins gain oncogenic functions (GOFs) distinct from the tumor suppressor activity of the wild-type protein. Tumor-associated macrophages (TAMs), a hallmark of solid tumors, are typically correlated with poor prognosis. Here, we report a non-cell-autonomous mechanism, whereby human mutp53 cancer cells reprogram macrophages to a tumor supportive and anti-inflammatory state. The colon cancer cells harboring GOF mutp53 selectively shed miR-1246-enriched exosomes. Uptake of these exosomes by neighboring macrophages triggers their miR-1246-dependent reprogramming into a cancer-promoting state. Mutp53-reprogammed TAMs favor anti-inflammatory immunosuppression with increased activity of TGF-β. These findings, associated with poor survival in colon cancer patients, strongly support a microenvironmental GOF role for mutp53 in actively engaging the immune system to promote cancer progression and metastasis. p53 gain of function mutants (mutp53) are involved in the pathogenesis of most human cancers. Here, the authors show that mutp53 regulates the tumor microenvironment by inducing the release of specific exosomes containing miR-1246 that once received by macrophages turns them into tumor supportive macrophages.

Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.

Rejuvenation of elementary immune system components has emerged as a promising strategy to deal with increased susceptibility to infections, cancers, autoimmune disorders, and low efficacy to vaccines, frequently accompanying aging. In this context, the thymus has gained significant attention. A recent study by Santamaria et al. reveals that the receptor activator of nuclear factor‐κB (RANK)–RANK ligand (RANKL) axis is altered during age related thymic involution, compromising immune responses. Based on their findings, authors propose exogenous RANKL administration as a therapeutic strategy to reinvigorate thymic function and improve T‐cell immunity during aging. Rejuvenation of the immune system has gained significant attention to alleviate age‐related disorders and to slow down aging. Strategies toward this direction either focus on lymphatic organs such as the thymus or follow systematic trajectories. Among the latter, recently emerging ones preventing, reversing or even removing immune senescence by exploiting innovative platforms, pave the way for effective future interventions.

Cellular senescence refers to a stress response aiming to preserve cellular and, therefore, organismal homeostasis. Importantly, deregulation of mitochondrial homeostatic mechanisms, manifested as impaired mitochondrial biogenesis, metabolism and dynamics, has emerged as a hallmark of cellular senescence. On the other hand, impaired mitostasis has been suggested to induce cellular senescence. This review aims to provide an overview of homeostatic mechanisms operating within mitochondria and a comprehensive insight into the interplay between cellular senescence and mitochondrial dysfunction.

Summary Cellular senescence contributes to organismal development, aging, and diverse pathologies, yet available assays to detect senescent cells remain unsatisfactory. Here, we designed and synthesized a lipophilic, biotin-linked Sudan Black B (SBB) analogue suitable for sensitive and specific, antibody-enhanced detection of lipofuscin-containing senescent cells in any biological material. This new hybrid histo-/immunochemical method is easy to perform, reliable, and universally applicable to assess senescence in biomedicine, from cancer research to gerontology.

There is strong evidence that COVID-19 pathophysiology is mainly driven by a spatiotemporal immune deregulation. Both its phenotypic heterogeneity, spanning from asymptomatic to severe disease/death, and its associated mortality, are dictated by and linked to maladaptive innate and adaptive immune responses against SARS-CoV-2, the etiologic factor of the disease. Deregulated interferon and cytokine responses, with the contribution of immune and cellular stress-response mediators (like cellular senescence or uncontrolled inflammatory cell death), result in innate and adaptive immune system malfunction, endothelial activation and inflammation (endothelitis), as well as immunothrombosis (with enhanced platelet activation, NET production/release and complement hyper-activation). All these factors play key roles in the development of severe COVID-19. Interestingly, another consequence of this immune deregulation, is the production of autoantibodies and the subsequent development of autoimmune phenomena observed in some COVID-19 patients with severe disease. These new aspects of the disease that are now emerging (like autoimmunity and cellular senescence), could offer us new opportunities in the field of disease prevention and treatment. Simultaneously, lessons already learned from the immunobiology of COVID-19 could offer new insights, not only for this disease, but also for a variety of chronic inflammatory responses observed in autoimmune and (auto)inflammatory diseases.

Ageing is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying ageing. Several stressors associated with ageing and MS pathology such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of CS. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with ageing and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness. Yet, the link between mutant p53 and colorectal CSCs is not well-established. In the present study, we set to examine whether oncogenic mutant p53 proteins may augment colorectal CSCs phenotype. By genetic manipulation of mutant p53 in several cellular systems, we demonstrated that mutant p53 enhances colorectal tumorigenesis. Moreover, mutant p53-expressing cell lines harbor larger sub-populations of cells highly expressing the known colorectal CSCs markers: CD44, Lgr5, and ALDH. This elevated expression is mediated by mutant p53 binding to CD44, Lgr5, and ALDH1A1 promoter sequences. Furthermore, ALDH1 was found to be involved in mutant p53-dependent chemotherapy resistance. Finally, analysis of ALDH1 and CD44 in human CRC biopsies indicated a positive correlation between their expression and the presence of oncogenic p53 missense mutations. These findings suggest novel insights pertaining the mechanism by which mutant p53 enhances CRC development, which involves the expansion of CSCs sub-populations within CRC tumors, and underscore the importance of targeting these sub-populations for CRC therapy.