Hallmarks of senescence in carcinogenesis and cancer therapy

Shay, Jerry W.; Roninson, Igor B.

doi:10.1038/sj.onc.1207518

Cited by 459 publications

(383 citation statements)

References 156 publications

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“…Here we report that CD28-null,CD56ϩ T cells have nil capacity for proliferation, consistent with cells that are approaching the end stages of senescence (32). CD56ϩ T cell lines generated in vitro ( Figure 1B) or fresh CD56ϩ T cells (Figure 4) exhibit nil cell division.…”

Section: Discussionsupporting

confidence: 78%

“…The in vitro chronic activation system showed that gain of CD56 was associated with nil capacity for proliferation ( Figure 1B), a characteristic of cells in advanced stages of senescence (26,32). We therefore evaluated the proliferative capacity of CD56ϩ T cells derived directly from patients.…”

Section: Cd56؉ T Cells Are Oligoclonal Lymphocytes Oligoclonal Cd28-mentioning

confidence: 99%

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CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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Objective. T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.Methods. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.Results. Chronic stimulation of CD28؉ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56؉,CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56؉,CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56؉ T cells had skewed T cell receptor (TCR) ␣/␤-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56؉ T cells were components of cellular infiltrates in RAassociated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.Conclusion. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56؉ T cells in RA contributes to maladaptive immune responses and that CD56؉ T cells are potential targets for therapy.

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Section: Discussionsupporting

confidence: 78%

Section: Cd56؉ T Cells Are Oligoclonal Lymphocytes Oligoclonal Cd28-mentioning

confidence: 99%

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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“…In such case, a more refined FISH scoring system with reproducible criteria to identify clinically and biologically valid hTERT gene amplification would need to be developed. Since hTERT reactivation is a mechanism for cancer cells to avoid senescence (Shay and Roninson, 2004) and the latter could be induced by chemotherapy, the predictive value of hTERT amplification for benefit to adjuvant chemotherapy also needs evaluation (Winton et al, 2005). Recently, telomerase has been intensively studied as a target for novel cancer gene therapy and therapeutics (reviewed in Shay and Wright, 2002;Keith et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer

et al. 2006

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Telomerase reactivation is a hallmark of human carcinogenesis. Increased telomerase activity may result from gene amplification and/or overexpression. This study evaluates the prognostic value of hTERT gene amplification and mRNA overexpression in 144 resectable non-small-cell lung cancer (NSCLC) specimens. The hTERT gene copy number was assessed by quantitative polymerase chain reaction (qPCR) on laser-capture microdissected tumour cells of 81 tumours, and by fluorescence in situ hybridisation (FISH) on a subset of 59 tumours. hTERT mRNA level was determined by reverse transcription (RT) -qPCR in 130 tumours. In total, 57% of (46 out of 81) primary NSCLC specimens demonstrated hTERT amplification, which was significantly more common (Po0.001) in adenocarcinoma (30 out of 40) than in squamous cell carcinoma (13 out of 37). The hTERT mRNA overexpression was noted in 74% (94 out of 130) of tumours; it was more frequent in squamous cell than in adenocarcinoma (87 vs 68%, P ¼ 0.03). Overexpression was significantly associated with amplification (P ¼ 0.03), especially in adenocarcinoma. The hTERT gene amplification was prognostic for shorter recurrence-free survival (hazard ratio ¼ 2.16, P ¼ 0.03). These data indicate that gene amplification is an important mechanism for hTERT overexpression in lung adenocarcinoma and is an independent poor prognostic marker for disease-free survival in NSCLC.

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“…The process of carcinogenesis involves dysregulated, unlimited proliferation and an ability to bypass the senescence program. Treatment of tumor cells with many conventional cancer therapies activates DNA damage signaling pathways, which induce apoptosis in some cells and senescence in others (Shay and Roninson, 2004). Thus, a deep understanding of the molecular mechanisms of differentiation and therapy-induced senescence of cancer-initiating cells might provide selective and targeted molecules for novel antitumor strategies.…”

Section: Introductionmentioning

confidence: 99%

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

et al. 2011

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Glioblastoma multiforme is one of the most devastating cancers and presents unique challenges to therapy because of its aggressive behavior. Cancer-initiating or progenitor cells have been described to be the only cell population with tumorigenic capacity in glioblastoma. Therefore, effective therapeutic strategies targeting these cells or the early precursors may be beneficial. We have established different cultures of glioblastoma-initiating cells (GICs) derived from surgical specimens and found that, after induction of differentiation, the NFjB transcriptional pathway was activated, as determined by analyzing key proteins such as p65 and IjB and the upregulation of a number of target genes. We also showed that blockade of nuclear factor (NF)jB signaling in differentiating GICs by different genetic strategies or treatment with smallmolecule inhibitors, promoted replication arrest and senescence. This effect was partly mediated by reduced levels of the NFjB target gene cyclin D1, because its downregulation by RNA interference reproduced a similar phenotype. Furthermore, these results were confirmed in a xenograft model. Intravenous treatment of immunodeficient mice bearing human GIC-derived tumors with a novel smallmolecule inhibitor of the NFjB pathway induced senescence of tumor cells but no ultrastructural alterations of the brain parenchyma were detected. These findings reveal that activation of NFjB may keep differentiating GICs from acquiring a mature postmitotic phenotype, thus allowing cell proliferation, and support the rationale for therapeutic strategies aimed to promote premature senescence of differentiating GICs by blocking key factors within the NFjB pathway.

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Hallmarks of senescence in carcinogenesis and cancer therapy

Cited by 459 publications

References 156 publications

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Amplification of telomerase (hTERT) gene is a poor prognostic marker in non-small-cell lung cancer

Blockade of the NFκB pathway drives differentiating glioblastoma-initiating cells into senescence both in vitro and in vivo

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