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Mesenchymal stem cells are enriched in head neck squamous cell carcinoma, correlates with tumour size and inhibit T-cell proliferation.

ABSTRACT: Cancer is a multifactorial disease not only restricted to transformed epithelium, but also involving cells of the immune system and cells of mesenchymal origin, particularly mesenchymal stem cells (MSCs). Mesenchymal stem cells contribute to blood- and lymph- neoangiogenesis, generate myofibroblasts, with pro-invasive activity and may suppress anti-tumour immunity.In this paper, we evaluated the presence and features of MSCs isolated from human head neck squamous cell carcinoma (HNSCC).Fresh specimens of HNSCC showed higher proportions of CD90+ cells compared with normal tissue; these cells co-expressed CD29, CD105, and CD73, but not CD31, CD45, CD133, and human epithelial antigen similarly to bone marrow-derived MSCs (BM-MSCs). Adherent stromal cells isolated from tumour shared also differentiation potential with BM-MSCs, thus we named them as tumour-MSCs. Interestingly, tumour-MSCs showed a clear immunosuppressive activity on in vitro stimulated T lymphocytes, mainly mediated by indoelamine 2,3 dioxygenase activity, like BM-MSCs. To evaluate their possible role in tumour growth in vivo, we correlated tumour-MSC proportions with neoplasm size. Tumour-MSCs frequency directly correlated with tumour volume and inversely with the frequency of tumour-infiltrating leukocytes.These data support the concept that tumour-MSCs may favour tumour growth not only through their effect on stromal development, but also by inhibiting the anti-tumour immune response.

SUBMITTER: Liotta F

PROVIDER: S-EPMC4333504 | biostudies-other | 2015 Feb

REPOSITORIES: biostudies-other

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Tumour-suppressive microRNA-29s inhibit cancer cell migration and invasion by targeting laminin-integrin signalling in head and neck squamous cell carcinoma.

Project description:BACKGROUND:Our recent studies of microRNA (miRNA) expression signatures demonstrated that microRNA-29s (miR-29s; miR-29a/b/c) were significantly downregulated in head and neck squamous cell carcinoma (HNSCC) and were putative tumour-suppressive miRNAs in human cancers. Our aim in this study was to investigate the functional significance of miR-29s in cancer cells and to identify novel miR-29s-mediated cancer pathways and responsible genes in HNSCC oncogenesis and metastasis. METHODS:Gain-of-function studies using mature miR-29s were performed to investigate cell proliferation, migration and invasion in two HNSCC cell lines (SAS and FaDu). To identify miR-29s-mediated molecular pathways and targets, we utilised gene expression analysis and in silico database analysis. Loss-of-function assays were performed to investigate the functional significance of miR-29s target genes. RESULTS:Restoration of miR-29s in SAS and FaDu cell lines revealed significant inhibition of cancer cell migration and invasion. Gene expression data and in silico analysis demonstrated that miR-29s modulated the focal adhesion pathway. Moreover, laminin ?2 (LAMC2) and ?6 integrin (ITGA6) genes were candidate targets of the regulation of miR-29s. Luciferase reporter assays showed that miR-29s directly regulated LAMC2 and ITGA6. Silencing of LAMC2 and ITGA6 genes significantly inhibited cell migration and invasion in cancer cells. CONCLUSION:Downregulation of miR-29s was a frequent event in HNSCC. The miR-29s acted as tumour suppressors and directly targeted laminin-integrin signalling. Recognition of tumour-suppressive miRNA-mediated cancer pathways provides new insights into the potential mechanisms of HNSCC oncogenesis and metastasis and suggests novel therapeutic strategies for the disease.

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Loss of HOP tumour suppressor expression in head and neck squamous cell carcinoma.

Project description:We report that homeodomain-only protein (HOP) is expressed in the suprabasal layer of normal upper aerodigestive tract epithelium and expression strongly decreases in hypopharyngeal carcinoma. Interestingly, HOP has very recently been shown to be a tumour suppressor involved in differentiation, suggesting that HOP may have a similar role in head and neck squamous cell carcinoma (HNSSC).

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Head and neck squamous cell carcinoma

Project description:Quantitative (iTRAQ 4-plex) proteomic analysis of progressive head and neck cancers

2022-03-01 | PXD001438 | Pride

HPV, tumour metabolism and novel target identification in head and neck squamous cell carcinoma.

Project description:BackgroundMetabolic changes in tumour cells are used in clinical imaging and may provide potential therapeutic targets. Human papillomavirus (HPV) status is important in classifying head and neck cancers (HNSCC), identifying a distinct clinical phenotype; metabolic differences between these HNSCC subtypes remain poorly understood.MethodsWe used RNA sequencing to classify the metabolic expression profiles of HPV+ve and HPV-ve HNSCC, performed a meta-analysis on FDG-PET imaging characteristics and correlated results with in vitro extracellular flux analysis of HPV-ve and HPV+ve HNSCC cell lines. The monocarboxylic acid transporter-1 (MCT1) was identified as a potential metabolic target and tested in functional assays.ResultsSpecific metabolic profiles were associated with HPV status, not limited to carbohydrate metabolism. There was dominance of all energy pathways in HPV-negative disease, with elevated expression of genes associated with glycolysis and oxidative phosphorylation. In vitro analysis confirmed comparative increased rates of oxidative phosphorylation and glycolysis in HPV-negative cell lines. PET SUV(max) scores however were unable to reliably differentiate between HPV-positive and HPV-negative tumours. MCT1 expression was significantly increased in HPV-negative tumours, and inhibition suppressed tumour cell invasion, colony formation and promoted radiosensitivity.ConclusionHPV-positive and negative HNSCC have different metabolic profiles which may have potential therapeutic applications.

| S-EPMC6353968 | biostudies-literature

Epithelial-Mesenchymal Transition Associated with Head and Neck Squamous Cell Carcinomas: A Review.

Project description:Head and neck squamous cell carcinomas (HNSCCs) are aggressive, recurrent, and metastatic neoplasms with a high occurrence around the world and can lead to death when not treated appropriately. Several molecules and signaling pathways are involved in the malignant conversion process. Epithelial-mesenchymal transition (EMT) has been described in HNSCCs, a major type of aggressive carcinoma. EMT describes the development of epithelial cells into mesenchymal cells, which depends on several molecular interactions and signaling pathways that facilitate mesenchymal conversion. This is related to interactions with the microenvironment of the tumor, hypoxia, growth factors, matrix metalloproteinases, and the presence of viral infections. In this review, we focus on the main molecules related to EMT, their interactions with the tumor microenvironment, plasticity phenomena, epigenetic regulation, hypoxia, inflammation, their relationship with immune cells, and the inhibition of EMT in the context of HNSCCs.

| S-EPMC8234594 | biostudies-literature

Epithelial-to-Mesenchymal Transition-Derived Heterogeneity in Head and Neck Squamous Cell Carcinomas.

Project description:Head and neck squamous cell carcinomas (HNSCC) are common tumors with a poor overall prognosis. Poor survival is resulting from limited response to multi-modal therapy, high incidence of metastasis, and local recurrence. Treatment includes surgery, radio(chemo)therapy, and targeted therapy specific for EGFR and immune checkpoint inhibition. The understanding of the molecular basis for the poor outcome of HNSCC was improved using multi-OMICs approaches, which revealed a strong degree of inter- and intratumor heterogeneity (ITH) at the level of DNA mutations, transcriptome, and (phospho)proteome. Single-cell RNA-sequencing (scRNA-seq) identified RNA-expression signatures related to cell cycle, cell stress, hypoxia, epithelial differentiation, and a partial epithelial-to-mesenchymal transition (pEMT). The latter signature was correlated to nodal involvement and adverse clinical features. Mechanistically, shifts towards a mesenchymal phenotype equips tumor cells with migratory and invasive capacities and with an enhanced resistance to standard therapy. Hence, gradual variations of EMT as observed in HNSCC represent a potent driver of tumor progression that could open new paths to improve the stratification of patients and to innovate approaches to break therapy resistance. These aspects of molecular heterogeneity will be discussed in the present review.

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Overexpression of TWIST2 correlates with poor prognosis in head and neck squamous cell carcinomas.

Project description:Head and neck squamous cell carcinomas (HNSCC) are a heterogeneous group of tumors with variable presentation and clinical behavior. Despite improvements in surgical and radiation therapy techniques, the 5-year survival rate has not improved significantly over the past decades. Thus, there is an urgent need to identify novel markers that may allow for the development of personalized therapeutic approaches. In the present study we evaluated the prognostic role of the expression of genes related to the induction of epithelial mesenchymal transition (EMT). To this aim, a consecutive series of 69 HNSCC were analyzed for the expression of TWIST1, TWIST2, SNAI1, SNAI2, E-Cadherin, N-Cadherin and Vimentin.TWIST1, TWIST2, SNAI1 and SNAI2 were significantly overexpressed in HNSCC, with TWIST2, SNAI1 and SNAI2 being more markedly increased in tumors compared to normal mucosae. The expression of TWIST1 and SNAI2 was associated with upregulation of mesenchymal markers, but failed to correlate with pathological parameters or clinical behaviour. In contrast, we found that upregulation of TWIST2, which was independent of the activation of a mesenchymal differentiation program, correlated with poor differentiation grade (p=0.016) and shorter survival (p=0.025), and identifies a subset of node-positive oral cavity/pharynx cancer patients with very poor prognosis (p less than 0.001). Overall our study suggests that the assessment of TWIST2 expression might help to stratify HNSCC patients for risk of disease progression, pointing to TWIST2 as a potential prognostic marker.

| S-EPMC3282075 | biostudies-literature

Immunogenomic correlates of response to cetuximab monotherapy in head and neck squamous cell carcinoma.

Project description:BACKGROUND:Mechanisms of resistance to immune-modulating cancer treatments are poorly understood. Using a novel cohort of patients with head and neck squamous cell carcinoma (HNSCC), we investigated mechanisms of immune escape from epidermal growth factor receptor-specific monoclonal antibody (mAb) therapy. METHODS:HNSCC tumors (n = 20) from a prospective trial of neoadjuvant cetuximab monotherapy underwent whole-exome sequencing. Expression of killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen-C (HLA-C) and the effect of KIR blockade were assessed in HNSCC cell lines. RESULTS:Nonresponders to cetuximab had an increased rate of mutations in HLA-C compared to responders and HNSCC tumors (n = 528) in The Cancer Genome Atlas (P < 0.00001). In vitro, cetuximab-activated natural killer (NK) cells induced upregulation of HLA-C on HNSCC cells (P < 0.01) via interferon gamma. Treatment of NK cells with the anti-KIR mAb lirilumab increased killing of HNSCC cells (P < 0.001). CONCLUSIONS:Alterations in HLA-C may provide a mechanism of immune evasion through disruption of NK activation.

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Head and neck squamous cell carcinoma.

Project description:Most head and neck cancers are derived from the mucosal epithelium in the oral cavity, pharynx and larynx and are known collectively as head and neck squamous cell carcinoma (HNSCC). Oral cavity and larynx cancers are generally associated with tobacco consumption, alcohol abuse or both, whereas pharynx cancers are increasingly attributed to infection with human papillomavirus (HPV), primarily HPV-16. Thus, HNSCC can be separated into HPV-negative and HPV-positive HNSCC. Despite evidence of histological progression from cellular atypia through various degrees of dysplasia, ultimately leading to invasive HNSCC, most patients are diagnosed with late-stage HNSCC without a clinically evident antecedent pre-malignant lesion. Traditional staging of HNSCC using the tumour-node-metastasis system has been supplemented by the 2017 AJCC/UICC staging system, which incorporates additional information relevant to HPV-positive disease. Treatment is generally multimodal, consisting of surgery followed by chemoradiotherapy (CRT) for oral cavity cancers and primary CRT for pharynx and larynx cancers. The EGFR monoclonal antibody cetuximab is generally used in combination with radiation in HPV-negative HNSCC where comorbidities prevent the use of cytotoxic chemotherapy. The FDA approved the immune checkpoint inhibitors pembrolizumab and nivolumab for treatment of recurrent or metastatic HNSCC and pembrolizumab as primary treatment for unresectable disease. Elucidation of the molecular genetic landscape of HNSCC over the past decade has revealed new opportunities for therapeutic intervention. Ongoing efforts aim to integrate our understanding of HNSCC biology and immunobiology to identify predictive biomarkers that will enable delivery of the most effective, least-toxic therapies.

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Tumour-specific PI3K inhibition via nanoparticle-targeted delivery in head and neck squamous cell carcinoma.

Project description:Alterations in PIK3CA, the gene encoding the p110α subunit of phosphatidylinositol 3-kinase (PI3Kα), are frequent in head and neck squamous cell carcinomas. Inhibitors of PI3Kα show promising activity in various cancer types, but their use is curtailed by dose-limiting side effects such as hyperglycaemia. In the present study, we explore the efficacy, specificity and safety of the targeted delivery of BYL719, a PI3Kα inhibitor currently in clinical development in solid tumours. By encapsulating BYL719 into P-selectin-targeted nanoparticles, we achieve specific accumulation of BYL719 in the tumour milieu. This results in tumour growth inhibition and radiosensitization despite the use of a sevenfold lower dose of BYL719 compared with oral administration. Furthermore, the nanoparticles abrogate acute and chronic metabolic side effects normally observed after BYL719 treatment. These findings offer a novel strategy that could potentially enhance the efficacy of PI3Kα inhibitors while mitigating dose-limiting toxicity in patients with head and neck squamous cell carcinomas.

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