To wake up cancer stem cells, or to let them sleep, that is the question

Takeishi, Shoichiro; Nakayama, Keiichi I.

doi:10.1111/cas.12958

Cited by 87 publications

(72 citation statements)

References 52 publications

(130 reference statements)

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“…Sixth, whether CSCs should be activated or arrested is an open question in cancer therapy. 652 Seventh, novel signaling and more regulatory levels, such as RNA editing, 653 epigenetics, 654 and cellular metabolism, 655 should be considered in cancer therapy because they also contribute to the stemness of CSCs. Eighth, some inhibitors that target CSC signaling are not very specific, and so new inhibitors need to be designed.…”

Section: Discussionmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Discussionmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

View full text Add to dashboard Cite

show abstract

“…We recently reported a role for MERTK in formation of prostate cancer stem-like cells (CSCs) Shiozawa et al, 2016]. However, the proliferative rate of CSCs was not examined in these studies and other literature reports that CSCs can be either slowly or rapidly cycling [Sharma et al, 2016;Takeishi and Nakayama, 2016]. Additionally, others identified MERTK in an unbiased screen of over 100 kinases as a stimulator of prostate cancer metastasis.…”

Section: Discussionmentioning

confidence: 99%

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Cackowski

Eber

Rhee

et al. 2016

J of Cellular Biochemistry

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Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knock down of MERTK in PCa cells increased metastasis free survival in an intra-cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates prostate cancer dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation.

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“…Long-lived HSCs are relatively quiescent, infrequently entering cell cycle to maintain homeostasis but more frequently upon injury to repair damaged tissue. Similarly, LSCs appear to be generally quiescent (18). The same signaling pathways involved in regulating LSCs (i.e., Wnt, Notch, Hedeghog, TGFβ/BMP, JAK/Stat, Hippo, MAPK/PI3K) are also involved in the regulation of HSCs (19;20) and multiple points of intersection and crosstalk, including feedback and feedforward loops, connect the various signaling cascades that modulate “stemness”.…”

Section: Hematopoietic Stem Cells Versus Leukemic Stem Cells; Morementioning

confidence: 99%

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

Kim

Gang

Kahn

2017

Experimental Hematology

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Cancer Stem Cells (CSCs) including Leukemia Stem Cells (LSCs) exhibit self-renewal capacity and differentiation potential, and have the capacity to maintain or renew and propagate a tumor/leukemia. The initial isolation of CSCs/LSCs was in adult myelogenous leukemia, although more recently, the existence of CSCs in a wide variety of other cancers has been demonstrated. CSCs in general, and LSCs specifically in regards to this review, are responsible for initiation of disease, therapeutic resistance and ultimately disease relapse. One key focus in cancer research over the past decade has been to develop therapies to safely eliminate the LSC/CSC population. One major obstacle to this goal is the identification of key mechanisms that distinguish LSCs from normal endogenous hematopoietic stem cells. An additional daunting feature that has recently come to light with advances in next generation sequencing and single cell sequencing is the heterogeneity within leukemias/tumors, with multiple combinations of mutations, gain and loss of function of genes, etc. being capable of driving disease, even within the CSC/LSC population. The focus of this review/perspective will be on our work in identifying and validating in both CML and ALL, a safe and efficacious mechanism to target an evolutionarily conserved signaling nexus, which constitutes a common “Achilles Heel” for LSC/CSC, utilizing small molecule specific CBP/catenin antagonists.

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To wake up cancer stem cells, or to let them sleep, that is the question

Cited by 87 publications

References 52 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

CBP/Catenin antagonists: Targeting LSCs’ Achilles heel

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