Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Peitzsch, Claudia; Nathansen, Jacqueline; Schniewind, Iñaki; Schwarz, Frank; Dubrovska, Anna

doi:10.3390/cancers11050616

Cited by 71 publications

(62 citation statements)

References 191 publications

(286 reference statements)

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“…Accumulating evidence indicates that just as the presence of cancer stem cells (CSCs) contributes to tumor initiation, progression, and development of resistance [1,2], so also does the tumor microenvironment (TME) where tumor cells and diverse stromal cells cohabitate, facilitating a favourable niche for promoting tumorigenesis [3,4]. There is evidence that stromal cells, such as cancer-associated fibroblasts (CAFs), promote and maintain the generation of CSCs [5]; however, regardless of whether the reverse is possible, the probable underlying mechanism remains unclear, thus necessitating the unraveling of complex cellular interactions and signaling cascades between CSCs and stromal cells, thereby enabling the discovery of druggable targets and/or signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

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Oral squamous cell carcinoma (OSCC) is among the most commonly diagnosed malignancies in the world. Patients with OSCC often develop treatment resistance, resulting in a poor prognosis. Mounting evidence indicates that interactions between cancerous cells and other components of the tumor microenvironment (TME) determine their response to treatment. Herein, we examined the role of cancer stem cell-derived extracellular vesicles (CSC_EVs) generated from CAL27 and SCC-15 OSCC cells in the development of cisplatin (CDDP) resistance. We demonstrated that CSC_EVs enhance CDDP resistance, clonogenicity, and the tumorsphere formation potential of OSCC cells. Our bioinformatics analyses revealed that OSCC_EVs are enriched with microRNA (miR)-21-5p and are associated with increased metastasis, stemness, chemoresistance, and poor survival in patients with OSCC. Mechanistically, enhanced activity of CSC_EVs was positively correlated with upregulated Cancers 2020, 12, 56 2 of 16 β-catenin, phosphatidylinositol-3 kinase (PI3K), signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and transforming growth factor (TGF)-β1 messenger (m)RNA and protein expression levels. CSC_EVs also conferred a cancer-associated fibroblast (CAF) phenotype on normal gingival fibroblasts (NGFs), with the resultant CAFs enhancing the oncogenicity of OSCC cells. Interestingly, treatment with ovatodiolide (OV), the bioactive component of Anisomeles indica, suppressed OSCC tumorigenesis by reducing the cargo content of EVs derived from CSCs, suppressing self-renewal, and inhibiting the NGF-CAF transformation by disrupting EV-TME interactions. Moreover, by suppressing miR-21-5p, STAT3, and mTOR expressions in CSC_EVs, OV re-sensitized CSCs to CDDP and suppressed OSCC tumorigenesis. In vivo, treatment with OV alone or in combination with CDDP significantly reduced the tumor sphere-forming ability and decreased EV cargos containing mTOR, PI3K, STAT3, β-catenin, and miR-21-5p. In summary, our findings provide further strong evidence of OV's therapeutic effect in OSCC.

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Section: Introductionmentioning

confidence: 99%

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Chen

Bamodu

et al. 2019

Cancers

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“…The identification of new markers in cancer is crucial to develop better forecasts on prognosis and to find new therapy options [5,7,19,32]. In this field of research, CSC markers are very prominent, although some are linked to a better and some to a worse prognosis, whereas the literature is controversial for some markers [12,13,33,34].…”

mentioning

confidence: 99%

Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC

et al. 2020

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Purpose Cancer stem cells (CSCs) are held accountable for the progress of head and neck squamous cell carcinoma (HNSCC). In the presented study, the authors evaluated the prognostic value of CSC markers in two particular HNSCC cohorts. Methods This two cohort study consisted of 85 patients with advanced stage HNSCC, treated with primary radio(chemo)therapy (pRCT), and 95 patients with HNSCC, treated with surgery and partially adjuvant radio(chemo)therapy. Overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) were assessed. Samples were assessed for the expression of different molecular stem cell markers (ALDH1, BCL11B, BMI-1, and CD44). Results In the pRCT cohort, none of the baseline patient and tumor features exhibited a statistically significant relation with survival in either the cohort or the human papillomavirus (HPV)-stratified subcohorts. High expression of BMI-1 significantly decreased OS and DFS, while high expression of CD44 decreased all modes of survival. Multivariate analysis showed significant prognostic influence for all tested CSC markers, with high BMI-1 and CD44 decreasing survival (BMI-1: OS, DFS, DSS; CD44: OS, DFS) and high ALDH1 and BCL11B showing a beneficial effect on survival (ALDH1: OS, DFS; BCL11B: OS, DSS). In the surgical cohort, classical prognosticators such as HPV status, R1 resection, and nodal status in HPV-negative HNSCC played a significant role, but the tested CSC markers showed no significant effect on prognosis. Conclusion Although validation in independent cohorts is still needed, testing for CSC markers in patients with advanced or late stage HNSCC might be beneficial, especially if many comorbidities exist or disease is irresectable. The findings might guide the development and earlier use of targeted therapies in the future.

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“…This study supports the theory according to which CSCs originate from differentiated cells by being reprogrammed during EMT [ 125 ]. A role for EMT in the formation of CSCs and resistance to antitumor therapy and the metastatic progression associated with these processes has also been shown in pancreatic cancer [ 243 , 244 ], prostate cancer [ 245 ], squamous cell carcinoma of the head and neck [ 158 , 246 , 247 ], stomach cancer [ 248 , 249 ], melanoma [ 250 ], glioblastoma [ 251 ], and colorectal cancer [ 252 , 253 ].…”

Section: Emt and Resistance To Antitumor Therapy: Role In The Formatimentioning

confidence: 99%

Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment

et al. 2020

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About 90% of all malignant tumors are of epithelial nature. The epithelial tissue is characterized by a close interconnection between cells through cellcell interactions, as well as a tight connection with the basement membrane, which is responsible for cell polarity. These interactions strictly determine the location of epithelial cells within the body and are seemingly in conflict with the metastatic potential that many cancers possess (the main criteria for highly malignant tumors). Tumor dissemination into vital organs is one of the primary causes of death in patients with cancer. Tumor dissemination is based on the so-called epithelialmesenchymal transition (EMT), a process when epithelial cells are transformed into mesenchymal cells possessing high mobility and migration potential. More and more studies elucidating the role of the EMT in metastasis and other aspects of tumor progression are published each year, thus forming a promising field of cancer research. In this review, we examine the most recent data on the intracellular and extracellular molecular mechanisms that activate EMT and the role they play in various aspects of tumor progression, such as metastasis, apoptotic resistance, and immune evasion, aspects that have usually been attributed exclusively to cancer stem cells (CSCs). In conclusion, we provide a detailed review of the approved and promising drugs for cancer therapy that target the components of the EMT signaling pathways.

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Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: Identification, Characterization and Clinical Implications

Cited by 71 publications

References 191 publications

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Ovatodiolide Suppresses Oral Cancer Malignancy by Down-Regulating Exosomal Mir-21/STAT3/β-Catenin Cargo and Preventing Oncogenic Transformation of Normal Gingival Fibroblasts

Role of cancer stem cell markers ALDH1, BCL11B, BMI-1, and CD44 in the prognosis of advanced HNSCC

Epithelial–mesenchymal transition: role in cancer progression and the perspectives of antitumor treatment

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