DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang, Qi-En

doi:10.4331/wjbc.v6.i3.57

Cited by 69 publications

(46 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Therefore, the generation of MIC properties may be phenotypically linked to enhanced drug resistance capacities. MICs enriched with CSC-like features may benefit from resistant mechanisms of CSCs, such as a stronger DNA damage response (Wang 2015), elevated expression of efflux drug pumps (Schinkel et al 1994;Zhou et al 2001;Dean et al 2005), and ALDH detoxifying enzymes (Honoki et al 2010;Rausch et al 2010). Therefore, inhibitors of pathways involved in CSC regulation, such as antibodies against NOTCH, FZD, IL6R, and other relevant signaling pathway receptors, may also have a therapeutic impact on MICs (Brooks et al 2015).…”

Section: Drug Resistance Of Micsmentioning

confidence: 99%

Distinctive properties of metastasis-initiating cells

2016

View full text Add to dashboard Cite

Primary tumors are known to constantly shed a large number of cancer cells into systemic dissemination, yet only a tiny fraction of these cells is capable of forming overt metastases. The tremendous rate of attrition during the process of metastasis implicates the existence of a rare and unique population of metastasis-initiating cells (MICs). MICs possess advantageous traits that may originate in the primary tumor but continue to evolve during dissemination and colonization, including cellular plasticity, metabolic reprogramming, the ability to enter and exit dormancy, resistance to apoptosis, immune evasion, and co-option of other tumor and stromal cells. Better understanding of the molecular and cellular hallmarks of MICs will facilitate the development and deployment of novel therapeutic strategies.

show abstract

Section: Drug Resistance Of Micsmentioning

confidence: 99%

Distinctive properties of metastasis-initiating cells

2016

View full text Add to dashboard Cite

show abstract

“…Similar to full-length L1CAM, recombinant expression of L1-ICD in nonneuronal cell lines affects gene expression of CRABPII and ␤3-integrin (11). In addition, it was shown that nuclear L1-ICD also led to up-regulation of NBS1 (Nijmegen breakage syndrome gene) via c-Myc, which plays a role in DNA damage checkpoint responses and renders human glioblastoma stem cells chemo-and radioresistant (7,14). However, little is known about the normal role of nuclear L1-type CAMs in the nervous system.…”

mentioning

confidence: 99%

An ankyrin-binding motif regulates nuclear levels of L1-type neuroglian and expression of the oncogene Myc in Drosophila neurons

Kakad¹,

Penserga²,

Davis³

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Eric R. Fearon L1 cell adhesion molecule (L1CAM) is well-known for its importance in nervous system development and cancer progression. In addition to its role as a plasma membrane protein in cytoskeletal organization, recent in vitro studies have revealed that both transmembrane and cytosolic fragments of proteolytically cleaved vertebrate L1CAM translocate to the nucleus. In vitro studies indicate that nuclear L1CAM affects genes with functions in DNA post-replication repair, cell cycle control, and cell migration and differentiation, but its in vivo role and how its nuclear levels are regulated is less well-understood. Here, we report that mutations in the conserved ankyrin-binding domain affect nuclear levels of the sole Drosophila homolog neuroglian (Nrg) and that it also has a noncanonical role in regulating transcript levels of the oncogene Myc in the adult nervous system. We further show that altered nuclear levels of Nrg correlate with altered transcript levels of Myc in neurons, similar to what has been reported for human glioblastoma stem cells. However, whereas previous in vitro studies suggest that increased nuclear levels of L1CAM promote tumor cell survival, we found here that elevated levels of nuclear Nrg in neurons are associated with increased sensitivity to oxidative stress and reduced life span of adult animals. We therefore conclude that these findings are of potential relevance to the management of neurodegenerative diseases associated with oxidative stress and cancer.L1-type cell adhesion molecules (CAMs) 4 are single-pass transmembrane glycoproteins belonging to the immunoglobu-lin family of receptors that are highly conserved from invertebrates to vertebrates (1). The structure of L1CAM consists of extracellular immunoglobulin and fibronectin type III domains, a transmembrane domain, and a cytoplasmic tail harboring an ezrin-binding FERM domain as well as an ankyrinbinding FIGQY domain (Fig. 1A). In its unphosphorylated state, the highly conserved FIGQY domain reversibly binds to ankyrin (Fig. 1A), which couples L1-type CAMs to actin. This interaction is known to mediate neuritogenesis, synapse growth, and stability (2-4). In contrast, phosphorylation of the tyrosine in the FIGQY domain inhibits ankyrin binding (5,6).In addition to its function as a cytoskeleton-organizing protein at the plasma membrane, vertebrate L1CAM can be proteolytically cleaved with fragments translocating to the nucleus (7-11). The 200-kDa full-length L1CAM is cleaved proximal to the plasma membrane by metalloproteases to a 32-kDa fragment (12,13). The 32-kDa fragment is further cleaved by ␥-secretase/presenilin, releasing a 28-kDa cytosolic fragment containing the intracellular domain (ICD), which translocates to the nucleus (10, 11). Similar to full-length L1CAM, recombinant expression of L1-ICD in nonneuronal cell lines affects gene expression of CRABPII and ␤3-integrin (11). In addition, it was shown that nuclear L1-ICD also led to up-regulation of NBS1 (Nijmegen breakage syndrome gene) via c-Myc, w...

show abstract

“…Increased expression of major DNA repair proteins, including BRCA1, ATR and ATM, has been observed in pancreatic, breast and prostate CSCs [156][157][158]. Reduced DNA repair capacity in CSCs has also been reported (reviewed by Wang [159]). In any case, DNA-damaging therapies targeting CSCs certainly benefit from inhibition of DNA repair as well as from increasing the total DNA damage burden.…”

Section: Dna Repairmentioning

confidence: 99%

Targeting therapy-resistant cancer stem cells by hyperthermia

Oei

Vriend

Krawczyk

et al. 2017

International Journal of Hyperthermia

View full text Add to dashboard Cite

Eradication of all malignant cells is the ultimate but challenging goal of anti-cancer treatment; most traditional clinically-available approaches fail because there are cells in a tumour that either escape therapy or become therapy-resistant. A subpopulation of cancer cells, the cancer stem cells (CSCs), is considered to be of particular significance for tumour initiation, progression and metastasis. CSCs are considered in particular to be therapy-resistant and may drive disease recurrence, which positions CSCs in the focus of anti-cancer research, but successful CSC-targeting therapies are limited. Here, we argue that hyperthermia -a therapeutic approach based on local heating of a tumour -is potentially beneficial for targeting CSCs in solid tumours. First, hyperthermia has been described to target cells in hypoxic and nutrient-deprived tumour areas where CSCs reside and ionising radiation and chemotherapy are least effective. Second, hyperthermia can modify factors that are essential for tumour survival and growth, such as the microenvironment, immune responses, vascularisation and oxygen supply. Third, hyperthermia targets multiple DNA repair pathways, which are generally upregulated in CSCs and protect them from DNA-damaging agents. Addition of hyperthermia to the therapeutic armamentarium of oncologists may thus be a promising strategy to eliminate therapy-escaping and -resistant CSCs.ARTICLE HISTORY

show abstract

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Cited by 69 publications

References 64 publications

Distinctive properties of metastasis-initiating cells

Distinctive properties of metastasis-initiating cells

An ankyrin-binding motif regulates nuclear levels of L1-type neuroglian and expression of the oncogene Myc in Drosophila neurons

Targeting therapy-resistant cancer stem cells by hyperthermia

Contact Info

Product

Resources

About