Targeting Cancer Stemness in the Clinic: From Hype to Hope

Saygin, Caner; Matei, Daniela; Majeti, Ravindra; Reizes, Ofer; Lathia, Justin D.

doi:10.1016/j.stem.2018.11.017

Cited by 428 publications

(360 citation statements)

References 131 publications

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“…We impaired MYC activity through inhibition of BET bromodomain proteins -an intervention that slows progression of MLL-driven leukemia -finding that this inhibitor blocked the conversion of CD34to CD34 + cells (Bardini et al, 2018;Dawson et al, 2011;Delmore et al, 2011). Together, our findings reinforce the notion that LICs are plastic and adaptable, providing possible explanations as to why therapies targeting LICs have yet to prove widespread efficacy despite being the object of intense investigation for over two decades (Pollyea and Jordan, 2017;Saygin et al, 2019). Although aspects of LICs in…”

Section: Discussionsupporting

confidence: 63%

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Morris

Marion

Hughes

et al. 2020

Preprint

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Leukemia initiating cells (LICs) fuel leukemic growth and spark relapse. Previously thought to be primitive and rare, the LIC state may actually be heterogeneous and dynamic, enabling evasion of therapies. Here, we use single-cell transcriptomics to dissect the ontogeny of MLL-rearranged B-lymphoblastic leukemia (MLL-r B-ALL).Although we identify rare transcriptionally and phenotypically primitive LICs, we also observe LICs emerging from more differentiated populations with the capability to replenish the full cellular diversity of MLL-r B-ALL. We find that activation of MYC-driven oxidative phosphorylation controls this process of LIC state conversion.

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Section: Discussionsupporting

confidence: 63%

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Morris

Marion

Hughes

et al. 2020

Preprint

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“…Venetoclax, a BCL-2 inhibitor, was initially approved by the FDA recently and shows good tolerance and activity for AML patients with adverse reactions. 627 Two arachidonate 5-lipoxygenase inhibitors, VIA-2291 and GSK2190915, might be potent agents for targeting LSCs in CML, 628 as shown in Table 3.…”

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,307

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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“…Moreover, E-M plasticity has long been shown to regulate tumor-or metastasis-initiating characteristics of tumor cells [216][217][218]. Interestingly, cancer stemness has also been documented to contribute to resistance to anti-cancer drugs [219,220]. FN is one of most studied genes that are upregulated in tumor cells bearing E-M plasticity and often employed as a biomarker for the mesenchymal phenotype [221,222].…”

Section: Hypoxia-induced Reexpression Of Fn In Tumor Cells and Cancermentioning

confidence: 99%

Fibronectin in Cancer: Friend or Foe

Lin

Yang

et al. 2019

Cells

143

117

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The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Figure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). On the contrary, Among 46 publications after 2000, 7 (15.2%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 25 (54.4%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 14 (30.4%) papers are related to the role of stromal FN in promoting early tumor progression but not late metastasis (in dark green boxes). Abbreviations in boxes are referred to the context of this article. (C) Percentages of articles for the three various roles of FN (the same colors as depicted in (B) before 2000 and after 2000. Numbers in the parenthesis represent article numbers. The Pathobiology of CancerFigure 1. (A) The structure of fibronectin (FN) containing three types of repeats and three alternative splicing regions (EDA, EDB, and IIICS) with several well-known binding sites for extracellular matrix (ECM) components (fibrin, heparin, collagen, and gelatin), polymeric assembly (FN-FN), cell adhesion (integrin α5β1), DPP IV, and two C-terminal disulfide bonds for dimeric FN. (B) Publications in recent some forty years regarding the roles of cancerous FN and stromal FN in ECM in tumor progression as represented in a time-line pattern. Among 26 publications before 2000, 15 (57.7%) papers are related to the role of cancerous FN in tumor suppression (in light green boxes), 3 (11.5%) papers are related to the role of cancerous FN in metastasis promotion (in orange boxes), and 8 (30.8%) papers are related to the r...

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Targeting Cancer Stemness in the Clinic: From Hype to Hope

Cited by 428 publications

References 131 publications

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Single-cell analysis uncovers mechanisms of plasticity in leukemia initiating cells

Targeting cancer stem cell pathways for cancer therapy

Fibronectin in Cancer: Friend or Foe

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