Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

Moore, N.; Lyle, Stephen

doi:10.1155/2011/396076

Cited by 307 publications

(248 citation statements)

References 82 publications

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“…On the one hand, ATR inhibitors may protect normal, non-replicating cells in various organs and tissues from some of the adverse effects of DNA damaging cancer chemotherapies. However, it is also possible that non-cycling cancer stem cells or other slowly proliferating cells within tumors (81,82) may be less prone to undergo apoptosis during cancer treatments that utilize an ATR inhibitor. Such treatments could give rise to additional mutations and ultimately to new tumors that may be associated with cancer recurrence.…”

Section: Discussionmentioning

confidence: 99%

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Kemp

Sancar

2016

Journal of Biological Chemistry

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ATR (ataxia telangiectasia and Rad-3-related) is a protein kinase that maintains genome stability and halts cell cycle phase transitions in response to DNA lesions that block DNA polymerase movement. These DNA replication-associated features of ATR function have led to the emergence of ATR kinase inhibitors as potential adjuvants for DNA-damaging cancer chemotherapeutics. However, whether ATR affects the genotoxic stress response in non-replicating, non-cycling cells is currently unknown. We therefore used chemical inhibition of ATR kinase activity to examine the role of ATR in quiescent human cells. Although ATR inhibition had no obvious effects on the viability of non-cycling cells, inhibition of ATR partially protected nonreplicating cells from the lethal effects of UV and UV mimetics. Analyses of various DNA damage response signaling pathways demonstrated that ATR inhibition reduced the activation of apoptotic signaling by these agents in non-cycling cells. The pro-apoptosis/cell death function of ATR is likely due to transcription stress because the lethal effects of compounds that block RNA polymerase movement were reduced in the presence of an ATR inhibitor. These results therefore suggest that whereas DNA polymerase stalling at DNA lesions activates ATR to protect cell viability and prevent apoptosis, the stalling of RNA polymerases instead activates ATR to induce an apoptotic form of cell death in non-cycling cells. These results have important implications regarding the use of ATR inhibitors in cancer chemotherapy regimens.Ultraviolet (UV) photoproducts and other bulky DNA lesions block the progression of DNA and RNA polymerases and lead to the activation of various DNA damage responses that are regulated by the action of the ataxia telangiectasia and Rad-3-related (ATR) 3 protein kinase. For example, in response to DNA polymerase stalling and uncoupling from DNA helicase activity (1), ATR is thought to be recruited to singlestranded regions of DNA where it promotes a number of DNA metabolic processes that maintain genomic integrity (2-6), including replication fork stabilization, DNA synthesis and lesion bypass, homologous recombination, replication origin firing, and cell cycle delay. The importance of ATR kinase activity in these responses in replicating cells is evidenced by the fate of cells in which the catalytic activity of ATR has been genetically or pharmacologically inhibited following replication stress, which include apoptosis and entry into catastrophic mitoses (7-10). Thus, ATR helps replicating cells cope with DNA damage and replication stress by facilitating cellular processes that maintain genomic stability and avoid cell death. Given these features of ATR, there has been great interest in the development and use of selective small-molecule inhibitors of ATR kinase activity in cancer chemotherapy regimens in conjunction with compounds that damage DNA and generate replication stress (11-13). For example, several studies have shown that ATR inhibition sensitizes cancer cells to cell kill...

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Section: Discussionmentioning

confidence: 99%

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Kemp

Sancar

2016

Journal of Biological Chemistry

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“…24 Quiescence is a common feature of drug-resistant cells and has been associated with stem cell traits in several tumors. 22 In glioblastoma, quiescent CSCs have been demonstrated to selectively resist temozolomide treatment and to regenerate the tumor after chemotherapy. 25 Interestingly, quiescent CSC populations in leukemias have been recently shown to express high levels of Bcl-2 and to rely on this factor for oxidative phosporylation, which represents their main energy-generating pathway.…”

Section: Discussionmentioning

confidence: 99%

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

et al. 2014

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Lung cancer is the most common cause of cancer-related mortality worldwide, urging the discovery of novel molecular targets and therapeutic strategies. Stem cells have been recently isolated from non-small cell lung cancer (NSCLC), thus allowing the investigation of molecular pathways specifically active in the tumorigenic population. We have found that Bcl-X L is constantly expressed by lung cancer stem cells (LCSCs) and has a prominent role in regulating LCSC survival. Whereas chemotherapeutic agents were scarcely effective against LCSC, the small molecule Bcl-2/Bcl-X L inhibitor ABT-737, but not the selective Bcl-2 inhibitor ABT-199, induced LCSC death at nanomolar concentrations. Differently from gemcitabine, which preferentially eliminated proliferating LCSC, ABT-737 had an increased cytotoxic activity in vitro towards quiescent/slow-proliferating LCSC, which expressed high levels of Bcl-X L . In vivo, ABT-737 as a single agent was able to inhibit the growth of LCSC-derived xenografts and to reduce cancer stem cell content in treated tumors. Altogether, these results indicate that quiescent/ slow-proliferating LCSC strongly depend on Bcl-X L for their survival and indicate Bcl-X L inhibition as a potential therapeutic avenue in NSCLC. Cell Death and Differentiation (2014) 21, 1877-1888; doi:10.1038/cdd.2014.105; published online 18 July 2014Lung cancer is the leading cause of cancer-related death in men and is expected to become the main cause of cancer death for women in the near future. 1,2 There is increasing evidence that cancer stem cells (CSCs) have a key role in drug resistance, tumor progression and metastasis in multiple tumor types, including lung cancer. 3 Lung cancer stem cells (LCSCs) have been previously identified through different criteria including surface expression of CD133, c-kit or through functional properties such as selective drug survival, elevated aldehyde dehydrogenase (ALDH) activity, increased glycolysis and glycine/serine metabolism or low concentrations of reactive oxygen species and ATP. 4-9 Importantly, when inoculated into immunocompromised mice, LCSCs give rise to xenografts that histologically reproduce the tumor of origin, thus representing an improved model for in vivo testing of new targeted therapies. 10 Several tumors express elevated levels of anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl-X L and Mcl-1, which affect the apoptotic threshold of neoplastic cells contributing to chemotherapy resistance. 11 Inhibition of anti-apoptotic Bcl-2 family members has been for long time regarded as a promising strategy to induce cancer cell death through approaches of increasing specificity. BH3 mimetics such as ABT-737, the related orally available ABT-263 (navitoclax) and the recently developed Bcl-2-selective inhibitor ABT-199 have been shown to exert an antitumor effect in preclinical and clinical settings either as single agents or in combination with conventional or targeted drugs. 12 Recently, a new role for Bcl-2 has emerged in acute myeloid leukemia (AML), whe...

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“…It has been proposed that most cancers originate from a small population of cells, mostly quiescent yet capable of undergoing self-replication and generating actively replicating cancer cells. 47,48 These so-called cancer stem cells are thought to be responsible for relapses following cancer therapy, as most therapeutic agents target actively growing cells and would thus spare cancer stem cells in their dormant phase. 48,49 The origin of cancer stem cells is still debated, but one prevalent hypothesis is that they may originate from adult stem cells having undergone carcinogenic transformation.…”

Section: Potential Role In Generation Of Cancer Stem Cells?mentioning

confidence: 99%

Nucleotide excision repair and B lymphoma: Somatic hypermutation is not the only culprit

Hyka‐Nouspikel

Nouspikel²

2011

Cell Cycle

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Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

Cited by 307 publications

References 82 publications

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

ATR Kinase Inhibition Protects Non-cycling Cells from the Lethal Effects of DNA Damage and Transcription Stress

Elimination of quiescent/slow-proliferating cancer stem cells by Bcl-XL inhibition in non-small cell lung cancer

Nucleotide excision repair and B lymphoma: Somatic hypermutation is not the only culprit

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