iNOS promotes CD24
            <sup>+</sup>
            CD133
            <sup>+</sup>
            liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway

Wang, Ronghua; Li, Yawen; Tsung, Allan; Huang, Hai; Du, Qiang; Yang, Minwei; Deng, Meihong; Xiong, Si; Wang, Xiju; Zhang, Liyong; Geller, David A.; Cheng, Bin; Billiar, Timothy R.

doi:10.1073/pnas.1722100115

Cited by 126 publications

(109 citation statements)

References 43 publications

(63 reference statements)

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“…197 Inducible nitric oxide synthase promotes the self-renewal capacity of CD24 + CD133 + liver CSCs through TACE/ ADAM17 activation to regulate Notch1 signaling. 198 Moreover, tumor necrosis factor-α (TNFα) enhances the CSC-like phenotype by activating Notch1 signaling in oral SCC cells. 199 Overexpression of PER3 decreases the expression of Notch1 and Jagged 1 in colorectal CSCs.…”

Section: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

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: Major Signaling Pathways In Cscsmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,113

998

View full text Add to dashboard Cite

show abstract

“…In particular, ADAM17 is a potential source of deregulation in the tumor microenvironment and adds an additional level of complexity to the manipulation of these natural systems, which also results in the resistance to chemo-/radiotherapy via the targeted signaling activation (45,46). ADAM17 can be considered as the therapeutic targeting when over activated in the tumor cells either alone or in combination with other treatment, including chemotherapy and radiotherapy (47,48). On the other hand, ADAM17 was discovered as a crucial mediator of resistance to radiotherapy, which can be considered as a therapeutic target when it overexpresses in tumor cells either alone or in combination with other immune modulating treatment.…”

Section: Discussionmentioning

confidence: 99%

Combination of pembrolizumab and 125I attenuates the aggressiveness of non‑small cell lung cancer

et al. 2020

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-associated mortality. Therapies targeting programmed cell death 1 ligand 1 (PD1L1) have promising effects on NSCLC. However, resistance to targeted therapy has become the main problem and the underling molecular mechanism remains unclear. In the present study, the expression of PD1L1 in NSCLC was determined and the association with clinicopathological characteristics was analyzed. A combination therapy was also constructed, including pembrolizumab (Pem) and iodine-125 ( 125 I), which represented an efficient strategy for the treatment of NSCLC. The expression of PD1L1 was upregulated in NSCLC tissues and positively correlated with the Ki-67 index, pathological subtypes and risk stages. A higher level of PD1L1 expression was associated with poorer survival in patients with NSCLC, which could be used as a prognostic indicator. When NSCLC cells were cultured in the presence of Pem and 125 I seeds, the combination treatment significantly abrogated the tumor proliferation and aggressiveness through the inhibition of matrix metalloproteinase-2 and -9 secretion. Flow cytometry analysis revealed pembrolizumab combined with 125 I contributed to a higher rate of apoptosis and cell cycle arrest, indicating that the combination treatment improved the resistance to immunotherapy. Furthermore, the associated molecular mechanism was the dysregulation of ADAM metallopeptidase domain 17. The findings from the present study revealed that PD1L1 could be used as a predictive biomarker, and the application of combination treatment of pembrolizumab and 125 I showed promising effects on NSCLC.Abbreviations: PD1L1, programmed cell death 1 ligand 1; ADAM17, ADAM metallopeptidase domain 17; RT-qPCR, reverse transcriptase-quantitative polymerase chain reaction; PI, propidium iodide; MMP, matrix metalloproteinase; FCM, flow cytometry Key words: non-small cell lung cancer, programmed cell death 1 ligand 1, iodine-125, targeted therapy

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“…More precisely, regulation of stemness properties was dependent on STAT3 signaling (81). The abundance of the stem cell markers CD24 and CD133 in tumors of HCC patients correlated with increased inducible nitric oxide synthase (iNOS) expression, promoting Notch1 signaling and subsequent development of stemness traits, as well as accelerated HCC initiation in the mouse xenograft tumor model (82).…”

Section: Markers To Identify Lcscsmentioning

confidence: 99%

Cellular Origin of Hepatocellular Carcinoma

Schneller

Angel

2019

Hepatocellular Carcinoma

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Molecular features of hepatocellular carcinoma affect patient prognosis and treatment efficiency. This chapter provides an overview of the relevant studies conducted to identify the cell of origin of hepatocellular carcinoma with a special focus on the controversy of hepatocytes versus hepatic progenitors as the main tumor-initiating cell. Furthermore, we introduce the concept of cancer stem cells (CSCs) and highlight recent publications covering this topic in relation to liver cancer. More precisely, we concentrate on the origin of CSCs, discuss accepted markers and the need to define a consistent combination of them that can be utilized to clearly define this heterogeneous cell type, summarize important signaling pathways that govern the stemness, and describe state-of-the-art assays to isolate and evaluate CSCs. We focus on their contributions to oncogenesis and tumor heterogeneity, as well as their feature to resist chemo-and radiotherapy. Finally, the potential of using CSC markers for diagnostic purposes and therapeutic approaches targeting these cells is addressed.

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iNOS promotes CD24 ⁺ CD133 ⁺ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway

Cited by 126 publications

References 43 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Combination of pembrolizumab and 125I attenuates the aggressiveness of non‑small cell lung cancer

Cellular Origin of Hepatocellular Carcinoma

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iNOS promotes CD24 + CD133 + liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway

Cited by 126 publications

References 43 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Combination of pembrolizumab and 125I attenuates the aggressiveness of non‑small cell lung cancer

Cellular Origin of Hepatocellular Carcinoma

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Product

Resources

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iNOS promotes CD24 ⁺ CD133 ⁺ liver cancer stem cell phenotype through a TACE/ADAM17-dependent Notch signaling pathway