Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

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Evaluation of the immunogenicity of aldhhigh human head and neck squamous cell carcinoma cancer stem cells in vitro

Journal for ImmunoTherapy of Cancer ◽

10.1186/2051-1426-3-s2-p28 ◽

2015 ◽

Vol 3 (S2) ◽

Author(s):

Qiao Li ◽

Mark Prince

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Human Head ◽

Neck Squamous Cell Carcinoma

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Cancer stem cells in oesophageal squamous cell carcinoma: Identification, prognostic and treatment perspectives

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2015.04.007 ◽

2015 ◽

Vol 96 (1) ◽

pp. 9-19 ◽

Cited By ~ 37

Author(s):

Farhadul Islam ◽

Vinod Gopalan ◽

Riajul Wahab ◽

Robert A. Smith ◽

Alfred K.-Y. Lam

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Squamous Cell ◽

Oesophageal Squamous Cell Carcinoma

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Inhibition of cell growth and up-regulation of MAD2 in human oesophageal squamous cell carcinoma after treatment with the Src/Abl inhibitor dasatinib

Clinical Science ◽

10.1042/cs20110230 ◽

2011 ◽

Vol 122 (1) ◽

pp. 13-24 ◽

Cited By ~ 2

Author(s):

Li Wang ◽

Bin Guo ◽

Ruwen Wang ◽

Yaoguang Jiang ◽

Shukui Qin ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Cell Lines ◽

Squamous Cell ◽

Carcinoma Cell ◽

Oesophageal Carcinoma ◽

Oesophageal Squamous Cell Carcinoma ◽

Cycle Arrest ◽

Carcinoma Cell Lines

Aberrant expression and/or activity of the non-receptor protein tyrosine kinase SFK (Src family kinase) members are commonly observed in progressive stages of human tumours. The aim of the present study was to investigate whether Src is a potential drug target for treating oesophageal squamous cell carcinoma. Compared with the human immortalized oesophageal epithelial cell line SHEE, oesophageal squamous cell carcinoma cells have increased tyrosine phosphorylation activities. We have explored the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, for the treatment of oesophageal squamous cell carcinoma. We examined that the effects of dasatinib on proliferation, invasion, apoptosis, spindle checkpoint, cell-cycle arrest and kinase activity in vitro using three human oesophageal carcinoma cell lines KYSE30, KYSE180 and EC109. In nude mouse models, dasatinib treatment effectively inhibited the expression of activated Src, resulting in the inhibition of tumour growth. Multiple drug effect isobologram analysis was used to study interactions with the chemotherapeutic drug docetaxel. As expected, the three oesophageal carcinoma cell lines were highly sensitive to dasatinib, but SHEE cells were not sensitive to this drug. Concentration-dependent anti-proliferative effects of dasatinib were observed in the three oesophageal carcinoma cell lines. Dasatinib significantly inhibited oesophageal carcinoma cell invasion and up-regulation of MAD2 (mitotic arrest-deficient 2), as well as inducing cell apoptosis and cell-cycle arrest. Additive and synergistic interactions were observed for the combination of dasatinib and docetaxel. Therefore it was concluded that dasatinib blocks the G1/S transition and inhibits cell growth. These results provided a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in oesophageal squamous cell carcinoma. Moreover, we have shown in vitro and in vivo that dasatinib might have therapeutic benefit for patients with oesophageal squamous cell carcinoma who are not eligible for surgery.

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Cytotoxic Effects of 5-Azacytidine on Primary Tumour Cells and Cancer Stem Cells from Oral Squamous Cell Carcinoma: An In Vitro FTIRM Analysis

Cells ◽

10.3390/cells10082127 ◽

2021 ◽

Vol 10 (8) ◽

pp. 2127

Author(s):

Valentina Notarstefano ◽

Alessia Belloni ◽

Simona Sabbatini ◽

Chiara Pro ◽

Giulia Orilisi ◽

...

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Conformational Transition ◽

Primary Tumour ◽

Cytotoxic Effects

In the present study, the cytotoxic effects of 5-azacytidine on primary Oral Squamous Cell Carcinoma cells (OSCCs) from human biopsies, and on Cancer Stem Cells (CSCs) from the same samples, were investigated by an in vitro Fourier Transform InfraRed Microscospectroscopy (FTIRM) approach coupled with multivariate analysis. OSCC is an aggressive tumoral lesion of the epithelium, accounting for ~90% of all oral cancers. It is usually diagnosed in advanced stages, and this causes a poor prognosis with low success rates of surgical, as well as radiation and chemotherapy treatments. OSCC is frequently characterised by recurrence after chemotherapy and by the development of a refractoriness to some employed drugs, which is probably ascribable to the presence of CSCs niches, responsible for cancer growth, chemoresistance and metastasis. The spectral information from FTIRM was correlated with the outcomes of cytotoxicity tests and image-based cytometry, and specific spectral signatures attributable to 5-azacytidine treatment were identified, allowing us to hypothesise the demethylation of DNA and, hence, an increase in the transcriptional activity, together with a conformational transition of DNA, and a triggering of cell death by an apoptosis mechanism. Moreover, a different mechanism of action between OSSC and CSC cells was highlighted, probably due to possible differences between OSCCs and CSCs response.

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Evaluation of the immunogenicity of ALDHhigh human head and neck squamous cell carcinoma cancer stem cells in vitro

Oral Oncology ◽

10.1016/j.oraloncology.2016.05.013 ◽

2016 ◽

Vol 59 ◽

pp. 30-42 ◽

Cited By ~ 6

Author(s):

Mark E.P. Prince ◽

Li Zhou ◽

Jeffrey S. Moyer ◽

Huimin Tao ◽

Lin Lu ◽

...

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Human Head ◽

Neck Squamous Cell Carcinoma

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EXPRESSION OF CANCER STEM CELLS SURFACE MARKERS IN TONGUE SQUAMOUS CELL CARCINOMA CELL LINES

Oral Surgery Oral Medicine Oral Pathology and Oral Radiology ◽

10.1016/j.oooo.2019.06.731 ◽

2020 ◽

Vol 129 (1) ◽

pp. e171-e172

Author(s):

FLORENCE JUANA MARIA CUADRA ◽

IARA AQUINO ◽

RICARDO D. COLETTA ◽

DEBORA CAMPANELLA BASTOS ◽

EDGARD GRANER

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Cell Lines ◽

Squamous Cell ◽

Carcinoma Cell ◽

Surface Markers ◽

Squamous Cell Carcinoma Cell ◽

Carcinoma Cell Lines

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Identification and Characterization of Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma Cell Lines

Cellular Physiology and Biochemistry ◽

10.1159/000430138 ◽

2015 ◽

Vol 36 (2) ◽

pp. 784-798 ◽

Cited By ~ 38

Author(s):

Valentina Pozzi ◽

Davide Sartini ◽

Romina Rocchetti ◽

Andrea Santarelli ◽

Corrado Rubini ◽

...

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Head And Neck ◽

Cell Line ◽

Cell Lines ◽

Squamous Cell

Background/Aims: Head and neck squamous cell carcinoma (HNSCC) ranks sixth worldwide for tumor-related mortality. A subpopulation of tumor cells, termed cancer stem cells (CSCs), has the ability to support cancer growth. Therefore, profiling CSC-enriched populations could be a reliable tool to study cancer biology. Methods: We performed phenotypic characterization of 7 HNSCC cell lines and evaluated the presence of CSCs. CSCs from Hep-2 cell line and HNSCC primary cultures were enriched through sphere formation and sphere-forming cells have been characterized both in vitro and in vivo. In addition, we investigated the expression levels of Nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed in several malignancies. Results: CSC markers were markedly expressed in Hep-2 cell line, which was found to be highly tumorigenic. CSC-enriched populations displayed increased expression of CSC markers and a strong capability to form tumors in vivo. We also found an overexpression of CSC markers in tumor formed by CSC-enriched populations. Interestingly, NNMT levels were significantly higher in CSC-enriched populations compared with parental cells. Conclusion: Our study provides an useful procedure for CSC identification and enrichment in HNSCC. Moreover, results obtained seem to suggest that CSCs may represent a promising target for an anticancer therapy.

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Different Aspects of Head and Neck Squamous Cell Carcinoma: Cancer Stem Cells, Their Niche and Targeted Therapy

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200921163326 ◽

2020 ◽

Vol 15 ◽

Author(s):

Meriç Bilgiç Küçükgüven ◽

Betül Çelebi-Saltik

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Targeted Therapy ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Head And Neck ◽

Squamous Cell ◽

Crucial Role ◽

Tumor Therapy ◽

Neck Squamous Cell Carcinoma

: Head and Neck Squamous Cell Carcinoma (HNSCC) is categorized as the sixth most common cancer worldwide, with an incidence of more than 830,000 cases per year and a mortality rate of 50%. Tobacco use, alcohol consumption, and Human Papillomavirus infection are the prominent risks for HNSCC. Despite significant developments in the treatment of HNSCC, a high rate of recurrences makes the clinical situation worse and results in poor survival rates. Recent perspectives demonstrate that whereas epithelial transformation plays a crucial role in cancer development, tumor surrounding microenvironment takes part in progression of cancer as well. Cancer Stem Cells (CSCs), which harbor unlimited self-renewal capacity, have a crucial role in the growth of HNSCC and this cell population is responsible for tumor recurrence unless eliminated by targeted therapy. CSCs are not only a promising target for tumor therapy, but also a crucial biomarker to determine the patients at high risk for undetermined results and disease development. Just as the bone marrow which is the niche of hematopoietic and mesenchymal stem cells, is important for stem cells maintenance. Similarly, the concept of microenvironment is also important for the maintenance of CSCs. Apart from the cell-cell interactions, there are many parameters in the cancer microenvironment that affect the development of cancer, such as extracellular regulation, vascularization, microbial flora, pH and oxygenation. The purpose of this review is to introduce HNSCC, explain the role of CSCs and their microenvironment and refer to the conventional and novel targeted therapy for HNSCC and CSCs.

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Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Gut ◽

10.1136/gutjnl-2020-323276 ◽

2021 ◽

pp. gutjnl-2020-323276

Author(s):

Jin Zhou ◽

Zhong Wu ◽

Zhouwei Zhang ◽

Louisa Goss ◽

James McFarland ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Large Scale ◽

Cell Cancer ◽

Oesophageal Squamous Cell Carcinoma ◽

Squamous Cancer ◽

Striking Success

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

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