Targeting Head and Neck Cancer Stem Cells

Birkeland, Andrew C.; Owen, Jennifer C.; Prince, Mark E.

doi:10.1177/0022034515601960

Cited by 21 publications

(10 citation statements)

References 63 publications

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“…Similar with other malignancies, HNSCC is characterized by a histologically heterogeneous population of cancer cells as evidenced that very small fraction of cells serves as CSCs or tumor-initiating cells that are critical for cancer initiation, recurrence, metastatic spreading and therapeutic resistance 9,10,12 . Dysfunctional Hippo signaling pathway has been increasingly recognized as a central mediator for tumorigenesis, as well as a potential therapeutic target in diverse cancer contexts 21 .…”

Section: Discussionmentioning

confidence: 99%

“…These cells sustain tumor overgrowth and drive recurrence and metastatic dissemination 7,8 . Moreover, these unique characteristics have enabled CSCs as attractive and yet challenging therapeutic targets as evidenced by the facts that targeting key regulators or molecular pathways responsible for CSCs properties has yielded remarkable anti-cancer effects with promising translational potentials 9 . Previous pioneering work has documented several surface or functional markers for HNSCC CSCs including CD44, CD133, Bmi1, SOX2 and ALDH1 10–12 .…”

Section: Introductionmentioning

confidence: 99%

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The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

Jin

et al. 2019

Cell Death Dis

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The Hippo-TAZ signaling has emerged as a fundamental regulator underlying cancer stem cells (CSCs) stemness which intricately associates with local recurrence and metastatic spreading in head neck squamous cell carcinoma (HNSCC). However, the precise downstream targets of TAZ responsible for HNSCC CSCs maintenance remain largely underexplored. Here, we identified Sex determining region Y box 2 (SOX2) as a putative downstream target of TAZ to promote CSCs maintenance and tumorigenicity in HNSCC. Both TAZ and SOX2 were significantly enriched in CSCs subpopulation (CD44 + CD133 + ) isolated from Cal27 and Fadu cells via fluorescence-activated cell sorting. TAZ knockdown significantly reduced expression of SOX2 at both mRNA and protein levels, whereas its ectopic overexpression markedly increased its abundance in HNSCC cells. Moreover, reintroduction of ectopic SOX2 abolished, at least in part, the reduced tumorsphere formation and tumorigenicity in vivo induced by TAZ knockdown. Mechanistically, transcriptional complex formed by TAZ and TEAD4 was recruited to two binding sites in SOX2 promoter, which in turn facilitated transcription of SOX2 in HNSCC cells. In addition, the abundance of TAZ and SOX2 was positively correlated in HNSCC clinical samples, and both upregulations of TAZ and SOX2 associated with the worst survival. Taken together, our data reveal a previously unknown mechanistic linkage between TAZ and SOX2 and identify SOX2 as a direct downstream target of TAZ in modulating CSCs self-renewal and maintenance in HNSCC. These findings suggest that targeting TAZ-SOX2 axis might be a promising therapeutic strategy for HNSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

Jin

et al. 2019

Cell Death Dis

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“…In addition, most stem cell markers currently used to identify CSCs in basic science research are not sufficiently specific and would be poor targets for direct therapy. Investigations into targeting CSCs vary, including targeting CSC markers and pathways, using epigenetic modulators, immunotherapy agents, and increasing CSC sensitivity to ChT and RT ( 100 ).…”

Section: Discussionmentioning

confidence: 99%

Cancer Stem Cells in Oral Cavity Squamous Cell Carcinoma: A Review

2017

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Cancer stem cells (CSCs) have been identified in oral cavity squamous cell carcinoma (OCSCC). CSCs possess the ability for perpetual self-renewal and proliferation, producing downstream progenitor cells and cancer cells that drive tumor growth. Studies of many cancer types including OCSCC have identified CSCs using specific markers, but it is still unclear as to where in the stem cell hierarchy these markers fall. This is compounded further by the presence of multiple CSC subtypes within OCSCC, making investigation reliant on the use of multiple markers. This review examines the current knowledge in CSC markers OCT4, SOX2, NANOG, ALDH1, phosphorylated STAT3, CD44, CD24, CD133, and Musashi-1, specifically focusing on their use and validity in OCSCC CSC research and how they may be organized into the CSC hierarchy. OCSCC CSCs also express components of the renin–angiotensin system (RAS), which suggests CSCs may be novel therapeutic targets by modulation of the RAS using existing medications.

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“…Heterogeneity of cells within tumors exist with a subset of cells, called tumor-initiating cells, having increased potential of self-renewal, invasion and resistance to chemoradiotherapy (2–8). Contrary to the physiological EMT process which allows cells to change morphology and lose polarity to become motile, EMT involved in cancer confers tumor cells with the ability to leave the primary site, enter blood or lymphatic vessels, and migrate to distant sites.…”

Section: Introductionmentioning

confidence: 99%

CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma through the Upregulation of Slug

Chung

Jung

Lee

et al. 2018

Clinical Cancer Research

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Head and neck squamous cell carcinoma (HNSCC) is comprised of heterogeneous populations of cells, and CD271 (NGFR; p75NTR) has been associated with a tumor-initiating cell subpopulation. This study assessed the role of CD271 in modulating metastatic behavior in HNSCC. CD271 was overexpressed in murine and human oral squamous cell carcinoma cells to assess the impact of CD271 activation on the invasive and metastatic phenotype of these cells, using and orthotopic modeling. Treatment with human nerve growth factor (NGF) to activate CD271, as well as shRNA knockdown of the CD271-upregulated expression, was used to assess the mechanism of the CD271-induced invasive phenotype. Relevance of CD271 expression in human HNSCC was evaluated in patient-derived xenografts (PDX) and primary human oral cancers, annotated with clinical behavior characteristics and survival data. Forced expression of CD271 resulted in a more invasive and metastatic phenotype. Slug, an epithelial-to-mesenchymal transition (EMT)-related transcription factor, encoded by , was highly expressed in MOC2-CD271 and HSC3-CD271, compared with respective parental cells. CD271 activation by NGF conferred enhanced invasiveness in CD271-overexpressing cells, which was abrogated by knockdown. In PDXs and primary human HNSCC, CD271 expression correlated with higher expression, greater nodal metastasis, and shorter disease-free survival. Activation of CD271 results in upregulation of /Slug, which, in turn, results in a more invasive phenotype and an enhanced capacity for metastasis to regional lymph nodes. These findings point to CD271 as a promising, therapeutic target for oral cancer metastasis..

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Targeting Head and Neck Cancer Stem Cells

Cited by 21 publications

References 63 publications

The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma

Cancer Stem Cells in Oral Cavity Squamous Cell Carcinoma: A Review

CD271 Confers an Invasive and Metastatic Phenotype of Head and Neck Squamous Cell Carcinoma through the Upregulation of Slug

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