Volatilomic insight of head and neck cancer via the effects observed on saliva metabolites.
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ABSTRACT:
SUBMITTER: Taware R
PROVIDER: S-EPMC6286361 | biostudies-literature | 2018 Dec
REPOSITORIES: biostudies-literature
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Volatilomic insight of head and neck cancer via the effects observed on saliva metabolites.
Taware Ravindra R Taunk Khushman K Pereira Jorge A M JAM Shirolkar Amey A Soneji Dharmesh D Câmara José S JS Nagarajaram H A HA Rapole Srikanth S
Scientific reports 20181207 1
Head and neck cancer (HNC) is a heterogeneous malignant disease with distinct global distribution. Metabolic adaptations of HNC are significantly gaining clinical interests nowadays. Here, we investigated effects of HNC on differential expression of volatile metabolites in human saliva. We applied headspace solid phase microextraction coupled with gas chromatography-mass spectrometry analysis of saliva samples collected from 59 human subjects (HNC - 32, Control - 27). We identified and quantifie ...[more]
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Project description:Head and neck cancer (HNC) is a heterogeneous malignant disease with distinct global distribution. Metabolic adaptations of HNC are significantly gaining clinical interests nowadays. Here, we investigated effects of HNC on differential expression of volatile metabolites in human saliva. We applied headspace solid phase microextraction coupled with gas chromatography-mass spectrometry analysis of saliva samples collected from 59 human subjects (HNC - 32, Control - 27). We identified and quantified 48 volatile organic metabolites (VOMs) and observed profound effects of HNC on these metabolites. These effects were VOM specific and significantly differed in the biologically comparable healthy controls. HNC induced changes in salivary VOM composition were well attributed to in vivo metabolic effects. A panel of 15 VOMs with variable importance in projection (VIP) score >1, false discovery rate (FDR) corrected p-value < 0.05 and log2 fold change (log2 FC) value of ≥0.58/≤-0.58 were regarded as discriminatory metabolites of pathophysiological importance. Afterwards, receiver operator characteristic curve (ROC) projected certain VOMs viz., 1,4-dichlorobenzene, 1,2-decanediol, 2,5-bis1,1-dimethylethylphenol and E-3-decen-2-ol with profound metabolic effects of HNC and highest class segregation potential. Moreover, metabolic pathways analysis portrayed several dysregulated pathways in HNC, which enhanced our basic understanding on salivary VOM changes. Our observations could redefine several known/already investigated systemic phenomenons (e.g. biochemical pathways). These findings will inspire further research in this direction and may open unconventional avenues for non-invasive monitoring of HNC and its therapy in the future.
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Project description:Oral mucositis (OM) is a common, painful and often treatment-limiting side effect of radiotherapy (RT) for head and neck cancer (HNC) patients. Unstimulated saliva was collected before the first radiotherapy application in 50 HNC patients. 41 out of 50 patients developed OM (grade III) during radiotherapy, of which 14 patients even displayed an early OM (grade III) at low radiation dose of 30 Gy. Nine patients did not develop OM (grade III). Using an LC-MS/MS approach 5,323 tryptic peptides were assigned to 487 distinct proteins (≥2 peptides) in the data set. The levels of 48 proteins differed significantly (p<0.05) between patients developing OM or not. 17 proteins displayed increased levels (≥1.3-fold) and 31 proteins decreased in level in OM, respectively. Furthermore, using partial least square analysis proteins patterns could be used to distinguish subjects which did not develop grade III OM even after 70 Gy total dose (n=9) and those displaying early OM (grade III at <30 Gy total dose, n=14). Using leave one out cross validation 37 of 41 patients (90%) developing OM could be correctly assigned indicating that prognostic proteome signatures may help to identify patients that should be specifically monitored to increase overall effectiveness of RT treatment.
2016-07-04 | PXD003230 | Pride
Project description:ObjectiveApproximately one-third of advanced head and neck squamous cell carcinomas (HNSCCs) recur within 2 years of treatment. Due to ease of collection, saliva is of interest to monitor changes that correlate with treatment. Previously this was a challenge due to xerostomia after conventional radiation. The emergence of gland-sparing radiation has made it possible to collect saliva post-treatment. This study investigated changes in cytokines in saliva pre- and post-treatment to provide foundational knowledge for future studies exploring the use of saliva to monitor treatment response.Study designPre- and post-treatment saliva was evaluated for 8 cytokines by multiplex assay and enzyme-linked immunosorbent assay.ResultsIn oropharyngeal HNSCC, secretion of epidermal growth factor (EGF), GROα (Growth-regulated protein alpha), interleukin (IL)-1α, IL-β, IL-6, IL-8, tumor necrosis factor-α, and vascular endothelial growth factor increased significantly post-treatment. In additional patients, significant increases of GR-α and IL-6 were validated, but EGF showed no change.ConclusionsThe uniqueness of this study is its comparison of salivary cytokines from HNSCC patients pre- and post-treatment.
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Project description:Small extracellular vesicles from saliva (SEVs) have high potential as biomarkers in Head and Neck cancer (HNC). However, there is no common consensus on the ideal method for their isolation. This study compared different ultracentrifugation (UC) methods (durations and + /- additional purification) with size exclusion chromatography (SEC) and investigated the potential of SEVs as diagnostic biomarkers and their biological activity on NK and CD8+ T cells. SEVs from 19 HNC patients and 8 healthy donors (HDs) were thoroughly characterized. Transmission electron microscopy confirmed the isolation of vesicles by all methods. The average size determined via nanoparticle-tracking analysis was smaller for SEVs isolated by SEC than UC. The highest particle-to-protein yield was achieved by UC (3 h + 3 h) (UCopt) and SEC. However, SEC yielded considerably fewer SEVs. Comparing the surface marker cargo, SEVs isolated by UCopt from HNC patients carried more PD-L1, FasL, and TGF-β than SEVs from HDs. These levels correlated with tumor stage and HPV status. SEVs downregulated NKG2D expression on primary NK cells. HNC SEVs accelerated CD8+ T cell death compared to HD SEVs. This study suggests that UCopt is preferable when isolation of a high particle-to-protein load is required. Especially PD-L1 and FasL on SEVs hold substantial potential as diagnostic biomarkers.
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Project description:BackgroundTo analyse over time changes in stimulated whole saliva regarding total protein, Immunoglobulin A (IgA), and mucin type O-glycans (mostly MUC5B and MUC7) in head and neck cancer patients.Methods29 dentate patients (20 men and 9 women, 59 ± 8 years) treated with curative radiation therapy and chemotherapy for cancer of the head and neck region were included. The stimulated whole salivary secretion rate was determined and saliva collected at four time-points: at pretreatment, and at 6 months, 1 and 2 years post treatment. The total protein concentration was determined spectrophotometrically by using Bicinchoninic Acid assay and Immunoglobulin A (IgA) by using ELISA technique. Glycosylation pattern of salivary mucins was determined in samples collected pre- and post treatment by using LC/MS electrospray and mucin content quantified using SDS-AgPAGE gels and PAS staining.ResultsCompared with pretreatment, the total protein concentration was increased already at 6 months post treatment (p < 0.01), and continued to increase up to 2 years post treatment (p < 0.001). During that period no significant changes in IgA concentration was detected. At pretreatment, the output/min of both total protein and IgA was significantly higher than at all time-points post treatment. Saliva from the cancer patients showed a low abundance/no detectable MUC7, while the MUC5B level remained, compared to saliva from a healthy control. The glycomic analysis showed that the percentage of core 2 O-glycans was increased as core 1, 3 and 4 O-glycans were decreased. The level of sialylation was higher at 6 months post treatment, while sulfation was lower.ConclusionA decreased output per minute of proteins at decreased salivary secretion rate, as well as reduced sulfation of MUC5B at 6 months post treatment tended to correlate with the patients' experience of sticky saliva and oral dryness. At 2 years post treatment, the decreased amount of IgA combined with a lowered salivary secretion rate indicate a reduced oral defense with increased risk of oral infections.
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Project description:Saliva, a biological fluid, is a promising candidate for novel approaches to prognosis, clinical diagnosis, monitoring and management of patients with both oral and systemic diseases. However, to date, saliva has not been widely investigated as a biomarker for radiation exposure. Since white blood cells are also present in saliva, it should theoretically be possible to investigate the transcriptional biomarkers of radiation exposure classically studied in whole blood. Therefore, we collected whole blood and saliva samples from eight head and neck cancer patients before the start of radiation treatment, at mid-treatment and after treatment. We then used a panel of five genes: BAX, BBC3, CDKN1A, DDB2 and MDM2, designated for assessing radiation dose in whole blood to evaluate gene expression changes that can occur during radiotherapy. The results revealed that the expression of the five genes did not change in whole blood. However, in saliva, CDKN1A and DDB2 were significantly overexpressed at the end, compared to the start, of radiotherapy, and MDM2 was significantly underexpressed between mid-treatment and at the end of treatment. Interestingly, CDKN1A and DDB2 expressions also showed an increasing monotonic relationship with total radiation dose received during radiotherapy. To our knowledge, these results show for the first time the ability to detect gene expression changes in saliva after head and neck cancer radiotherapy, and pave the way for further promising studies validating saliva as a minimally invasive means of biofluid collection to directly measure radiation dose escalation during treatment.
| S-EPMC5552048 | biostudies-literature
Project description:BackgroundExosomes contribute to immunosuppression in head and neck squamous cell carcinoma (HNSCC), a tumor entity which lacks specific tumor biomarkers. Plasma-derived exosomes from HNSCC patients correlate with clinical parameters and have potential as liquid biopsy. Here, we investigate the cargo and functional profile of saliva-derived exosomes from HNSCC patients and their potential as non-invasive biomarkers for disease detection and immunomodulation.MethodsExosomes were isolated from saliva of HNSCC patients (n = 21) and healthy donors (HD, n = 12) by differential ultracentrifugation. Surface values of immune checkpoints and tumor associated antigens on saliva-derived exosomes were analyzed by bead-based flow cytometry using CD63 capture. Upon co-incubation with saliva-derived exosomes, activity and proliferation of T cells were assessed by flow cytometry (CD69 expression, CFSE assay). Adenosine levels were measured by mass spectrometry after incubation of saliva-derived exosomes with exogenous ATP. miRNA profiling of saliva-derived exosomes was performed using the nCounter® SPRINT system.ResultsSaliva-derived, CD63-captured exosomes from HNSCC patients carried high amounts of CD44v3, PDL1 and CD39. Compared to plasma, saliva was rich in tumor-derived, CD44v3+ exosomes and poor in hematopoietic cell-derived, CD45+ exosomes. CD8+ T cell activity was attenuated by saliva-derived exosomes from HNSCC patients, while proliferation of CD4+ T cells was not affected. Further, saliva-derived exosomes produced high levels of immunosuppressive adenosine. 62 HD- and 31 HNSCC-exclusive miRNAs were identified. Samples were grouped in "Healthy" and "Cancer" based on their saliva-derived exosomal miRNA profile, which was further found to be involved in RAS/MAPK, NF-κB complex, Smad2/3, and IFN-α signaling.ConclusionsSaliva-derived exosomes from HNSCC patients were enriched in tumor-derived exosomes whose cargo and functional profile reflected an immunosuppressive TME. Surface values of CD44v3, PDL1 and CD39 on CD63-captured exosomes, adenosine production and the miRNA cargo of saliva-derived exosomes emerged as discriminators of disease and emphasized their potential as liquid biomarkers specific for HNSCC.
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Project description:BackgroundSOX11 is a transcription factor that plays an important role in mantle cell lymphoma development. However, its functional role in head and neck squamous cell carcinoma (HNSCC) remains unknown.MethodsProtein expression was measured with Western blotting, immunohistochemistry or quantitative proteomics, and gene expression was measured with quantitative RT-PCR. Functional role of SOX11 in HNSCC was evaluated with MTS/apoptosis, migration, invasion assays and a xenograft model. A SOX11-targeting gene, SDCCAG8, was confirmed with chromatin immunoprecipitation (ChIP), luciferase reporter and rescue assays.ResultsSOX11 was up-regulated in recurrent versus primary HNSCC and in highly invasive versus low invasive HNSCC cell lines. Silencing SOX11 in HNSCC cell lines significantly inhibited the cell proliferation, migration, invasion and resistance to Cisplatin, and vice versa. Quantitative proteomic analysis of SOX11-silencing HNSCC cells revealed a number of differentially expressed proteins, including a down-regulated tumor antigen SDCCAG8. Silencing of SDCCAG8 in HNSCC cells also significantly inhibited the cell proliferation, migration and invasion, and vice versa. ChIP assays demonstrated that endogenous SOX11 strongly bound to Sdccag8 gene promoter in highly invasive HNSCC cells. When over-expressed in low invasive HNSCC cells, wild type SOX11 but not mutant SOX11 induced the promoter activity of Sdccag8 and significantly induced the expression of SDCCAG8. However, exogenous mutant SOX11 abolished the expression of SDCCAG8 in highly invasive HNSCC cells. In addition, the inhibitory effects of SOX11 knockdown were partially rescued by over-expression of SDCCAG8 in HNSCC cells.ConclusionCollectively, our findings indicate SOX11 promotes HNSCC progression via the regulation of SDCCAG8.
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Project description:Head and Neck Squamous Cell Carcinoma (HNSCC) is the fifth most common cancer, annually affecting over half a million people worldwide. Presently, there are no accepted biomarkers for clinical detection and surveillance of HNSCC. In this work, a comprehensive genome-wide analysis of epigenetic alterations in primary HNSCC tumors was employed in conjunction with cancer-specific outlier statistics to define novel biomarker genes which are differentially methylated in HNSCC. The 37 identified biomarker candidates were top-scoring outlier genes with prominent differential methylation in tumors, but with no signal in normal tissues. These putative candidates were validated in independent HNSCC cohorts from our institution and TCGA (The Cancer Genome Atlas). Using the top candidates, ZNF14, ZNF160, and ZNF420, an assay was developed for detection of HNSCC cancer in primary tissue and saliva samples with 100% specificity when compared to normal control samples. Given the high detection specificity, the analysis of ZNF DNA methylation in combination with other DNA methylation biomarkers may be useful in the clinical setting for HNSCC detection and surveillance, particularly in high-risk patients. Several additional candidates identified through this work can be further investigated toward future development of a multi-gene panel of biomarkers for the surveillance and detection of HNSCC.
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