The Hidden Link of Exosomes to Head and Neck Cancer

Teng, Yong; Gao, Lixia; Loveless, Reid; Rodrigo, Juan P.; Strojan, Primož; Willems, Stefan M.; Nathan, Cherie‐Ann; Mäkitie, Antti; Saba, Nabil F.; Ferlito, Alfio

doi:10.3390/cancers13225802

Cited by 17 publications

(27 citation statements)

References 80 publications

(99 reference statements)

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“…HNSCC is highly aggressive and multi-factorial disease in the upper aerodigestive tract and uncontrolled proliferation is the main cause of death in HNSCC patients [1,2]. Therefore, elucidating the mechanisms underpinning uncontrolled cancer cell proliferation will provide new theoretical platforms and potential therapeutic targets for the treatment of HNSCC.…”

Section: Discussionmentioning

confidence: 99%

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Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Gao

Yang

Tang

et al. 2023

J Exp Clin Cancer Res

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Background Enolase 2 (ENO2) is a crucial glycolytic enzyme in cancer metabolic process and acts as a “moonlighting” protein to play various functions in diverse cellular processes unrelated to glycolysis. ENO2 is highly expressed in head and neck squamous cell carcinoma (HNSCC) tissues relative to normal tissues; however, its impact and underlying regulatory mechanisms in HNSCC malignancy remain unclear. Methods Molecular alterations were examined by bioinformatics, qRT-PCR, western blotting, immunofluorescence, immunohistochemistry, immunoprecipitation, and ChIP-PCR assays. Metabolic changes were assessed by intracellular levels of ATP and glucose. Animal study was used to evaluate the therapeutic efficacy of the ENO inhibitor. Results ENO2 is required for HNSCC cell proliferation and glycolysis, which, surprisingly, is partially achieved by controlling PKM2 protein stability and its nuclear translocation. Mechanistically, loss of ENO2 expression promotes PKM2 protein degradation via the ubiquitin-proteasome pathway and prevents the switch of cytoplasmic PKM2 to the nucleus by inactivating AKT signaling, leading to a blockade in PKM2-mediated glycolytic flux and CCND1-associated cell cycle progression. In addition, treatment with the ENO inhibitor AP-III-a4 significantly induces HNSCC remission in a preclinical mouse model. Conclusion Our work elucidates the signaling basis underlying ENO2-dependent HNSCC development, providing evidence to establish a novel ENO2-targeted therapy for treating HNSCC.

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Section: Discussionmentioning

confidence: 99%

“…Head and neck squamous cell carcinoma (HNSCC) develops from the mucosal epithelium in the oral cavity, pharynx and larynx and are on the rise, with annual rates increasing from 4% to as much as 10% in recent years [1,2]. Alcohol, tobacco, and human papillomavirus (HPV) infection are well known causative factors for HNSCC.…”

Section: Introductionmentioning

confidence: 99%

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Gao

Yang

Tang

et al. 2023

J Exp Clin Cancer Res

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“…Exosomes act as the communication channels, encouraging crosstalk between cancer and non-cancerous cells. They are associated with the increased invasiveness and drug resistance in head and neck cancer, indicative of an attractive therapeutic target [ 154 ]. Activation of the Akt pathway is one of the mechanisms involved in resistance to radiotherapy, an effective treatment modality for HNSCC [ 155 ].…”

Section: Discussionmentioning

confidence: 99%

Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration

Alzawi

Iftikhar

Shalgm

et al. 2022

Cancers

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This review aims to provide evidence for the role of the tumour microenvironment in cancer progression, including invasion and metastasis. The tumour microenvironment is complex and consists of tumour cells and stromal-derived cells, in addition to a modified extracellular matrix. The cellular components synthesise growth factors such as EGF, TGFα and β, VEGF, and NGF, which have been shown to initiate paracrine signalling in head and neck cancer cells by binding to cell surface receptors. One example is the phosphorylation, and hence activation, of the signalling protein Akt, which can ultimately induce oral cancer cell migration in vitro. Blocking of Akt activation by an inhibitor, MK2206, leads to a significant decrease, in vitro, of cancer-derived cell migration, visualised in both wound healing and scatter assays. Signalling pathways have therefore been popular targets for the design of chemotherapeutic agents, but drug resistance has been observed and is related to direct tumour–tumour cell communication, the tumour–extracellular matrix interface, and tumour–stromal cell interactions. Translation of this knowledge to patient care is reliant upon a comprehensive understanding of the complex relationships present in the tumour microenvironment and could ultimately lead to the design of efficacious treatment regimens such as targeted therapy or novel therapeutic combinations.

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“…Exosomes have been intensively studied for disease progression, aggressiveness and therapeutic monitoring in OSCC (19). Moreover, the presence of exosomes in biological fluids such as saliva, cerebrospinal fluid, urine, and blood is providing a new source for biomarkers for OSCC (20, 21). However, until now no standard method has been established for isolation and characterisation of exosomes.…”

Section: Discussionmentioning

confidence: 99%

Salivary exosomal miR-1307-5p predicts disease aggressiveness and poor prognosis in oral squamous cell carcinoma patients

Patel¹,

Patel²,

Patel³

et al. 2022

Preprint

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Background: Salivary exosomal miRNAs as biomarkers facilitate repeated sampling, real-time disease monitoring and assessment of therapeutic response. This study identifies a single salivary exosomal miRNA prognosticator that will aid in improved patient outcome using a liquid biopsy approach. Method: Small RNA and transcriptome sequencing profiles of tumour tissues and salivary exosomes from oral cancer patients were compared to their non-cancerous counterparts. We validated these results using the Cancer Genome Atlas database and performing Real-time PCR on a larger patient cohort. Potential target genes, miRNA-mRNA networks and enriched biological pathways regulated by this microRNA were identified using computational tools. Results: Salivary exosomes (size: 30-50nm) demonstrated a strong expression of CD47 and detectable expression of tetraspanins CD63, CD81 and CD9 by flow cytometry. miR-1307-5p was exclusively overexpressed in tissues and salivary exosomes of oral cancer patients compared to their non-cancerous counterparts. Enhanced expression of miR-1307-5p clinically correlated with poor patient survival, disease progression, aggressiveness and chemo-resistance in these patients. Transcriptome analysis suggested that miRNA-1307-5p could promote oral cancer progression by suppressing THOP1, EHF, RNF4, GET4, and RNF114. Conclusion: Salivary exosomal miRNA-1307-5p is a potential prognosticator for predicting poor survival and poor patient outcome in oral cancers.

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The Hidden Link of Exosomes to Head and Neck Cancer

Cited by 17 publications

References 80 publications

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Mediation of PKM2-dependent glycolytic and non-glycolytic pathways by ENO2 in head and neck cancer development

Receptor, Signal, Nucleus, Action: Signals That Pass through Akt on the Road to Head and Neck Cancer Cell Migration

Salivary exosomal miR-1307-5p predicts disease aggressiveness and poor prognosis in oral squamous cell carcinoma patients

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