Cells

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21 pages, 5163 KiB

Open AccessArticle

Disulfiram Acts as a Potent Radio-Chemo Sensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines and Transplanted Xenografts

by Wenhao Yao, Xu Qian, Sebastian Ochsenreither, Ferrone Soldano, Albert B. DeLeo, Holger Sudhoff, Felix Oppel, Andreas Kuppig, Konrad Klinghammer, Andreas M. Kaufmann and Andreas E. Albers

Cells 2021, 10(3), 517; https://doi.org/10.3390/cells10030517 - 28 Feb 2021

Cited by 19 | Viewed by 2747

Abstract

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance [...] Read more.

The poor prognosis of locally advanced and metastatic head and neck squamous cell carcinoma (HNSCC) is primarily mediated by the functional properties of cancer stem cells (CSCs) and resistance to chemoradiotherapy. We investigated whether the aldehyde dehydrogenase (ALDH) inhibitor disulfiram (DSF) can enhance the sensitivity of therapy. Cell viability was assessed by the 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and apoptosis assays, and the cell cycle and reactive oxygen species (ROS) levels were evaluated by fluorescence-activated cell sorting (FACS). The radio-sensitizing effect was measured by a colony formation assay. The synergistic effects were calculated by combination index (CI) analyses. The DSF and DSF/Cu²⁺ inhibited the cell proliferation (inhibitory concentration 50 (IC₅₀) of DSF and DSF/Cu²⁺ were 13.96 μM and 0.24 μM). DSF and cisplatin displayed a synergistic effect (CI values were <1). DSF or DSF/Cu²⁺ abolished the cisplatin-induced G2/M arrest (from 52.9% to 40.7% and 41.1%), and combining irradiation (IR) with DSF or DSF/Cu²⁺ reduced the colony formation and attenuated the G2/M arrest (from 53.6% to 40.2% and 41.9%). The combination of cisplatin, DSF or DSF/Cu²⁺, and IR enhanced the radio-chemo sensitivity by inducing apoptosis (42.04% and 32.21%) and ROS activity (46.3% and 37.4%). DSF and DSF/Cu²⁺ enhanced the sensitivity of HNSCC to cisplatin and IR. Confirming the initial data from patient-derived tumor xenograft (PDX) supported a strong rationale to repurpose DSF as a radio-chemosensitizer and to assess its therapeutic potential in a clinical setting. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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15 pages, 3658 KiB

Open AccessArticle

Gene Expression Clustering and Selected Head and Neck Cancer Gene Signatures Highlight Risk Probability Differences in Oral Premalignant Lesions

by Andrea Carenzo, Mara S. Serafini, Elisa Roca, Alberto Paderno, Davide Mattavelli, Chiara Romani, Pierre Saintigny, Senada Koljenović, Lisa Licitra, Loris De Cecco and Paolo Bossi

Cells 2020, 9(8), 1828; https://doi.org/10.3390/cells9081828 - 3 Aug 2020

Cited by 13 | Viewed by 2909

Abstract

Background: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early [...] Read more.

Background: Oral premalignant lesions (OPLs) represent the most common oral precancerous conditions. One of the major challenges in this field is the identification of OPLs at higher risk for oral squamous cell cancer (OSCC) development, by discovering molecular pathways deregulated in the early steps of malignant transformation. Analysis of deregulated levels of single genes and pathways has been successfully applied to head and neck squamous cell cancers (HNSCC) and OSCC with prognostic/predictive implications. Exploiting the availability of gene expression profile and clinical follow-up information of a well-characterized cohort of OPL patients, we aim to dissect tissue OPL gene expression to identify molecular clusters/signatures associated with oral cancer free survival (OCFS). Materials and methods: The gene expression data of 86 OPL patients were challenged with: an HNSCC specific 6 molecular subtypes model (Immune related: HPV related, Defense Response and Immunoreactive; Mesenchymal, Hypoxia and Classical); one OSCC-specific signature (13 genes); two metabolism-related signatures (3 genes and signatures raised from 6 metabolic pathways associated with prognosis in HNSCC and OSCC, respectively); a hypoxia gene signature. The molecular stratification and high versus low expression of the signatures were correlated with OCFS by Kaplan–Meier analyses. The association of gene expression profiles among the tested biological models and clinical covariates was tested through variance partition analysis. Results: Patients with Mesenchymal, Hypoxia and Classical clusters showed an higher risk of malignant transformation in comparison with immune-related ones (log-rank test, p = 0.0052) and they expressed four enriched hallmarks: “TGF beta signaling” “angiogenesis”, “unfolded protein response”, “apical junction”. Overall, 54 cases entered in the immune related clusters, while the remaining 32 cases belonged to the other clusters. No other signatures showed association with OCFS. Our variance partition analysis proved that clinical and molecular features are able to explain only 21% of gene expression data variability, while the remaining 79% refers to residuals independent of known parameters. Conclusions: Applying the existing signatures derived from HNSCC to OPL, we identified only a protective effect for immune-related signatures. Other gene expression profiles derived from overt cancers were not able to identify the risk of malignant transformation, possibly because they are linked to later stages of cancer progression. The availability of a new well-characterized set of OPL patients and further research is needed to improve the identification of adequate prognosticators in OPLs. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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14 pages, 3130 KiB

Open AccessArticle

Intrinsic Radiosensitivity Is Not the Determining Factor in Treatment Response Differences between HPV Negative and HPV Positive Head and Neck Cancers

by Paul Reid, Alexander H. Staudacher, Loredana G. Marcu, Ian Olver, Leyla Moghaddasi, Michael P. Brown, Yanrui Li and Eva Bezak

Cells 2020, 9(8), 1788; https://doi.org/10.3390/cells9081788 - 27 Jul 2020

Cited by 7 | Viewed by 2028

Abstract

Head and neck squamous cell carcinomas (HNSCC) resulting from human papillomavirus (HPV) are increasing in incidence but demonstrate significantly better treatment response than HNSCC from other causes such as tobacco and alcohol. This study sought to identify differences in HNSCC, intrinsic to HPV [...] Read more.

Head and neck squamous cell carcinomas (HNSCC) resulting from human papillomavirus (HPV) are increasing in incidence but demonstrate significantly better treatment response than HNSCC from other causes such as tobacco and alcohol. This study sought to identify differences in HNSCC, intrinsic to HPV status, in their response to radiation dose. Previously unexamined changes in radio-responsiveness following fractionated X-ray irradiation were compared between HPV positive and negative statuses of HNSCC. Six HNSCC cell lines, 3 of each HPV status, were investigated for radiosensitivity by clonogenic assay and modelled by response as a function of dose. Generational cultures of each cell line were developed to follow changes in radiosensitivity after repeated irradiations simulating fractionated radiation therapy. As a group, the HPV positive cell lines were more radiosensitive, but with changes following repeated fractions of dose, and modelling of response as a function of dose, both statuses displayed large radiobiological heterogeneity. These findings challenge current radiobiological assumptions of head and neck cancers as early responding tissue to radiation and may go some way in explaining difficulties reaching consensus in stratification of treatment by HPV status. Consequently, results from this study do not support stratifying radiation therapy by HPV status. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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12 pages, 2724 KiB

Open AccessArticle

Carbonic Anhydrase III Promotes Cell Migration and Epithelial–Mesenchymal Transition in Oral Squamous Cell Carcinoma

by Yin-Hung Chu, Chun-Wen Su, Yih-Shou Hsieh, Pei-Ni Chen, Chiao-Wen Lin and Shun-Fa Yang

Cells 2020, 9(3), 704; https://doi.org/10.3390/cells9030704 - 13 Mar 2020

Cited by 15 | Viewed by 2976

Abstract

Epithelial–mesenchymal transition (EMT) is strongly correlated with tumor metastasis and contains several protein markers, such as E-cadherin. Carbonic anhydrase III (CA III) exhibits low carbon dioxide hydratase activity in cancer. However, the detailed mechanisms of CA III and their roles in oral cancer [...] Read more.

Epithelial–mesenchymal transition (EMT) is strongly correlated with tumor metastasis and contains several protein markers, such as E-cadherin. Carbonic anhydrase III (CA III) exhibits low carbon dioxide hydratase activity in cancer. However, the detailed mechanisms of CA III and their roles in oral cancer are still unknown. This study established a CA III-overexpressed stable clone and observed the expression of CA III protein in human SCC-9 and SAS oral cancer cell lines. The migration and invasion abilities were determined using a Boyden chamber assay. Our results showed that the overexpression of CA III protein significantly increased the migration and invasion abilities in oral cancer cells. Moreover, a whole genome array analysis revealed that CA III regulated epithelial–mesenchymal transition by reducing the expression of epithelial markers. Data from the GEO database also demonstrated that CA III mRNA is negatively correlated with CDH1 mRNA. Mechanistically, CA III increased the cell motility of oral cancer cells through the FAK/Src signaling pathway. In conclusion, this suggests that CA III promotes EMT and cell migration and is potentially related to the FAK/Src signaling pathway in oral cancer. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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0 pages, 4494 KiB

Open AccessArticle

Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN)

by Yin Zhao, Yuan Lei, Shi-Wei He, Ying-Qin Li, Ya-Qin Wang, Xiao-Hong Hong, Ye-Lin Liang, Jun-Yan Li, Yang Chen, Wei-Jie Luo, Pan-Pan Zhang, Xiao-Jing Yang, Qing-Mei He, Jun Ma, Na Liu and Ling-Long Tang

Cells 2020, 9(3), 559; https://doi.org/10.3390/cells9030559 - 27 Feb 2020

Cited by 15 | Viewed by 3155 | Correction

Abstract

Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 [...] Read more.

Epigenetic regulation plays an important role in the development and progression of nasopharyngeal carcinoma (NPC), but the epigenetic mechanisms underlying NPC metastasis remain poorly understood. Here, we demonstrate that hypermethylation of the UCHL1 promoter leads to its downregulation in NPC. Restoration of UCHL1 inhibited the migration and invasion of NPC cells in vitro and in vivo, and knockdown of UCHL1 promoted NPC cell migration and invasion in vitro and in vivo. Importantly, we found that UCHL1 interacts with CTTN, and may function as a ligase promoting CTTN degradation by increasing K48-linked ubiquitination of CTTN. Additionally, restoration of CTTN in NPC cells that overexpressed UCHL1 rescued UCHL1 suppressive effects on NPC cell migration and invasion, which indicated that CTTN is a functional target of UCHL1 in NPC. Our findings revealed that UCHL1 acts as a tumor suppressor gene in NPC and thus provided a novel therapeutic target for NPC treatment. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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14 pages, 3832 KiB

Open AccessArticle

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

by Liwei Lang, Tiffany Lam, Alex Chen, Caleb Jensen, Leslie Duncan, Feng-Chong Kong, Zoya B. Kurago, Chloe Shay and Yong Teng

Cells 2020, 9(3), 533; https://doi.org/10.3390/cells9030533 - 25 Feb 2020

Cited by 21 | Viewed by 3746

Abstract

Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy [...] Read more.

Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Methods: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. Conclusions: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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Review

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30 pages, 913 KiB

Open AccessReview

HNSCC: Tumour Antigens and Their Targeting by Immunotherapy

by Adrian von Witzleben, Chuan Wang, Simon Laban, Natalia Savelyeva and Christian H. Ottensmeier

Cells 2020, 9(9), 2103; https://doi.org/10.3390/cells9092103 - 15 Sep 2020

Cited by 50 | Viewed by 6611

Abstract

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains [...] Read more.

Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of malignant tumours typically caused by alcohol and tobacco consumption, although an increasing number of HNSCC arise due to persistent infection with high-risk human papilloma virus (HPV). The treatment of HNSCC remains challenging, and the first-line setting is focused on surgery and chemoradiotherapy. A substantial proportion of HNSCC patients die from their disease, especially those with recurrent and metastatic disease. Among factors linked with good outcome, immune cell infiltration appears to have a major role. HPV-driven HNSCC are often T-cell rich, reflecting the presence of HPV antigens that are immunogenic. Tumour-associated antigens that are shared between patients or that are unique to an individual person may also induce varying degrees of immune response; studying these is important for the understanding of the interaction between the host immune system and the cancer. The resulting knowledge is critical for the design of better immunotherapies. Key questions are: Which antigens lead to an adaptive immune response in the tumour? Which of these are exploitable for immunotherapy? Here, we review the current thinking regarding tumour antigens in HNSCC and what has been learned from early phase clinical trials. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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Jump to: Research, Review

3 pages, 1493 KiB

Open AccessCorrection

Correction: Zhao et al. Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 2020, 9, 559

by Yin Zhao, Yuan Lei, Shi-Wei He, Ying-Qin Li, Ya-Qin Wang, Xiao-Hong Hong, Ye-Lin Liang, Jun-Yan Li, Yang Chen, Wei-Jie Luo, Pan-Pan Zhang, Xiao-Jing Yang, Qing-Mei He, Jun Ma, Na Liu and Ling-Long Tang

Cells 2024, 13(10), 816; https://doi.org/10.3390/cells13100816 - 10 May 2024

Viewed by 106

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Head and Neck Cancer)

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