Embryonic NANOG Activity Defines Colorectal Cancer Stem Cells and Modulates through AP1- and TCF-dependent Mechanisms

Ibrahim, Elsayed E.; Babaei‐Jadidi, Roya; Saadeddin, Anas; Spencer‐Dene, Bradley; Hossaini, Sina; Abuzinadah, Mohammed F.; Li, Ningning; Fadhil, Wakkas; Ilyas, Mohammad; Bonnet, Dominique; Nateri, Abdolrahman S.

doi:10.1002/stem.1182

Cited by 119 publications

(126 citation statements)

References 57 publications

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“…Oct-4 and Nanog themselves are critically involved in the self-renewal of undifferentiated ES cells (23), and there is evidence that these transcriptional factors are expressed in some human cancers. For example, Oct-4 overexpression is associated with an undifferentiated tumor phenotype (24), and expression of NANOG, or its retrogene NANOGP8, can be used to identify TIC cells in several types of solid tumors, including prostate and colorectal cancer (25,26). Importantly, and relevant to the work presented here, activity of the NANOG promoter has been shown to mark a TIC-enriched population in triple-negative breast cancer (27).…”

Section: Discussionmentioning

confidence: 72%

Stress granule-associated protein G3BP2 regulates breast tumor initiation

Gupta

Badeaux

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Breast tumors contain tumorigenic cancer cells, termed “tumor-initiating cells” (TICs), which are capable of both replenishing themselves and giving rise to populations of nontumorigenic breast cancer cells (non-TICs). However, the molecular mechanisms responsible for breast tumor initiation remain poorly understood. Here we describe a chemical screening strategy to identify small molecules that enhance the effect of chemotherapeutic agents on TIC-enriched breast cancer cells. We identified proteins that interact with the lead compound C108, including the stress granule-associated protein, GTPase-activating protein (SH3 domain)-binding protein 2, G3BP2. G3BP2 regulates breast tumor initiation through the stabilization of Squamous cell carcinoma antigen recognized by T cells 3 (SART3) mRNA, which leads to increased expression of the pluripotency transcription factors Octamer-binding protein 4 (Oct-4) and Nanog Homeobox (Nanog). Our findings suggest that G3BP2 is important for the process of breast cancer initiation. Furthermore, these data suggest a possible connection between stress granule formation and tumor initiation in breast cancer cells.

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Section: Discussionmentioning

confidence: 72%

Stress granule-associated protein G3BP2 regulates breast tumor initiation

Gupta

Badeaux

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, Nanog colocalizes with endogenous nuclear b-catenin in colorectal cancer cells and defines colon CSCs. 40 It is known that b-catenin inhibits Tcf3-mediated repression of Nanog and activates targets together with Tcf1 to collectively facilitate embryonic stem cell self-renewal. 41 Additionally, b-catenin interacts with and stabilizes Oct4 in a TCF-independent manner as an alternative strategy to enhance the pluripotent stem cell state.…”

Section: Discussionmentioning

confidence: 99%

RARα2 expression confers myeloma stem cell features

Yang

Shi

Tolomelli

et al. 2013

Blood

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Key Points• RARa2 activates Wnt and hedgehog pathways in maintaining myeloma stem cell features and drug resistance.We previously demonstrated that RARa2 expression is increased in CD138 selected plasma cells of relapsed multiple myelomas (MMs), and increased expression was linked to poor prognosis in newly diagnosed MM patients. In the present study, we demonstrate that increased RARa2 confers myeloma stem cell features. Higher expression of RARa2 was identified in the multiple myeloma stem cell (MMSC) fraction. Overexpression of RARa2 in bulk MM cell lines resulted in: 1) increased drug resistance; 2) increased clonogenic potential; 3) activation of both Wnt and Hedgehog (Hh) pathways; 4) increased side population and aldehyde dehydrogenase levels; and 5) increased expression of embryonic stem cell genes. The opposite effects were seen with RARa2 knockdown. We demonstrate that RARa2 induces drug resistance by activating the drug efflux pump gene ABCC3 and anti-apoptotic Bcl-2 family members. Inhibition of Wnt signaling or ABCC3 function could overcome drug resistance in RARa2 overexpressing MM cells. We also showed that in the 5TGM1 mouse model, targeting of the Wnt and Hh pathways using CAY10404, cyclopamine, or itraconazole significantly reduced the myeloma tumor burden and increased survival. Targeting RARa2 or its downstream signaling pathways provides a potential strategy to eliminate

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“…26,27 As few as 100 cells with these molecular characteristics grew rapidly and extensively in vitro and generated new tumors in vivo. 26 Recently, extensive research has identified CSCs in different types of solid tumors, including brain, 28 colon, 29 head and neck, 30 liver, 31 lung, 32,33 and other cancers. 34 CSCs are typically resistant to various chemotherapeutic drugs [13][14][15] and radiation therapies.…”

Section: Cancer Stem Cells: Implications For Tumorigenesis Identificamentioning

confidence: 99%

Targeting cancer stem cells by using the nanoparticles

Hong

Jang

Lee

et al. 2015

IJN

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Cancer stem cells (CSCs) have been shown to be markedly resistant to conventional cancer treatments such as chemotherapy and radiation therapy. Therefore, therapeutic strategies that selectively target CSCs will ultimately lead to better cancer treatments. Currently, accessible conventional therapeutic agents mainly eliminate the bulk tumor but do not eliminate CSCs. Therefore, the discovery and improvement of CSC-targeting therapeutic agents are necessary. Nanoparticles effectively inhibit multiple types of CSCs by targeting specific signaling pathways (Wnt/β-catenin, Notch, transforming growth factor-β, and hedgehog signaling) and/or specific markers (aldehyde dehydrogenases, CD44, CD90, and CD133) critically involved in CSC function and maintenance. In this review article, we summarized a number of findings to provide current information about their therapeutic potential of nanoparticles in various cancer cell types and CSCs.

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Embryonic NANOG Activity Defines Colorectal Cancer Stem Cells and Modulates through AP1- and TCF-dependent Mechanisms

Cited by 119 publications

References 57 publications

Stress granule-associated protein G3BP2 regulates breast tumor initiation

Stress granule-associated protein G3BP2 regulates breast tumor initiation

RARα2 expression confers myeloma stem cell features

Targeting cancer stem cells by using the nanoparticles

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