Induction of autophagy represents an effective survival strategy for nutrient-deprived or stressed cancer cells. Autophagy contributes to the modulation of communication within the tumor microenvironment. Here, we conducted a study of the metabolic and signaling implications associated with autophagy induced by glutamine (Gln) and serum starvation and PI3K/mTOR inhibitor and autophagy inducer NVP-BEZ235 (BEZ) in the head and neck squamous cell carcinoma (HNSCC) cell line FaDu. We compared the effect of these different types of autophagy induction on ATP production, lipid peroxidation, mitophagy, RNA cargo of extracellular vesicles (EVs), and EVs-associated cytokine secretome of cancer cells. Both BEZ and starvation resulted in a decline in ATP production. Simultaneously, Gln starvation enhanced oxidative damage of cancer cells by lipid peroxidation. In starved cells, there was a discernible fragmentation of the mitochondrial network coupled with an increase in the presence of tumor susceptibility gene 101 (TSG101) on the mitochondrial membrane, indicative of the sorting of mitochondrial cargo into EVs. Consequently, the abundance of mitochondrial RNAs (mtRNAs) in EVs released by FaDu cells was enhanced. Notably, mtRNAs were also detectable in EVs isolated from the serum of both HNSCC patients and healthy controls. Starvation and BEZ reduced the production of EVs by cancer cells, yet the characteristic molecular profile of these EVs remained unchanged. We also found that alterations in the release of inflammatory cytokines constitute a principal response to autophagy induction. Importantly, the specific mechanism driving autophagy induction significantly influenced the composition of the EVs-associated cytokine secretome.
- MeSH
- adenosintrifosfát * metabolismus MeSH
- autofagie * účinky léků MeSH
- dlaždicobuněčné karcinomy hlavy a krku metabolismus genetika patologie MeSH
- extracelulární vezikuly * metabolismus účinky léků MeSH
- glutamin * metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus MeSH
- nádorové buněčné linie MeSH
- nádory hlavy a krku metabolismus patologie genetika MeSH
- oxidační stres * MeSH
- RNA mitochondriální * metabolismus genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Classification of head and neck tumors has evolved in recent decades including a widespread application of molecular testing in tumors of the salivary glands, sinonasal tract, oropharynx, nasopharynx, and soft tissue. Availability of new molecular techniques allowed for the definition of multiple novel tumor types unique to head and neck sites. Moreover, the expanding spectrum of immunohistochemical markers facilitates a rapid identification of diagnostic molecular abnormalities. As such, it is currently possible for head and neck pathologists to benefit from a molecularly defined classifications, while making diagnoses that are still based largely on histopathology and immunohistochemistry. This review highlights some principal molecular alterations in head and neck neoplasms presently available to assist pathologists in the practice of diagnosis, prognostication and prediction of response to treatment.
- MeSH
- imunohistochemie MeSH
- lidé MeSH
- molekulární patologie * MeSH
- nádory hlavy a krku * diagnóza genetika MeSH
- patologové MeSH
- slinné žlázy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Human papillomaviruses (HPVs) induce a subset of head and neck squamous cell carcinomas (HNSCC) and anogenital cancers, particularly cervical cancer (CC). The major viral proteins that contribute to tumorigenesis are the E6 and E7 oncoproteins, whose expression is usually enhanced after the integration of viral DNA into the host genome. Recently, an alternative tumorigenesis pathway has been suggested in approximately half of HNSCC and CC cases associated with HPV infection. This pathway is characterized by extrachromosomal HPV persistence and increased expression of the viral E2, E4, and E5 genes. The E6, E7, E5, and E2 proteins have been shown to modify the expression of numerous cellular immune-related genes. The antitumor immune response is a critical factor in the prognosis of HPV-driven cancers, and its characterization may contribute to the prediction and personalization of the increasingly used cancer immunotherapy. METHODS: We analyzed the immune characteristics of HPV-dependent tumors and their association with carcinogenesis types. Transcriptomic HNSCC and CC datasets from The Cancer Genome Atlas were used for this analysis. RESULTS: Clustering with immune-related genes resulted in two clusters of HPV16-positive squamous cell carcinomas in both tumor types: cluster 1 had higher activation of immune responses, including stimulation of the antigen processing and presentation pathway, which was associated with higher immune cell infiltration and better overall survival, and cluster 2 was characterized by keratinization. In CC, the distribution of tumor samples into clusters 1 and 2 did not depend on the level of E2/E5 expression, but in HNSCC, most E2/E5-high tumors were localized in cluster 1 and E2/E5-low tumors in cluster 2. Further analysis did not reveal any association between the E2/E5 levels and the expression of immune-related genes. CONCLUSIONS: Our results suggest that while the detection of immune responses associated with preserved expression of genes encoding components of antigen processing and presentation machinery in HPV-driven tumors may be markers of better prognosis and an important factor in therapy selection, the type of carcinogenesis does not seem to play a decisive role in the induction of antitumor immunity.
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku komplikace MeSH
- infekce papilomavirem * komplikace MeSH
- karcinogeneze genetika MeSH
- lidé MeSH
- lidské papilomaviry MeSH
- nádory děložního čípku * MeSH
- nádory hlavy a krku * genetika komplikace MeSH
- onkogenní proteiny virové * genetika metabolismus MeSH
- Papillomavirus E7 - proteiny genetika MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: Head and neck squamous cell carcinomas (HNSCCs) are a molecularly, histologically, and clinically heterogeneous set of tumors originating from the mucosal epithelium of the oral cavity, pharynx, and larynx. This heterogeneous nature of HNSCC is one of the main contributing factors to the lack of prognostic markers for personalized treatment. The aim of this study was to develop and identify multi-omics markers capable of improved risk stratification in this highly heterogeneous patient population. METHODS: In this retrospective study, we approached this issue by establishing radiogenomics markers to identify high-risk individuals in a cohort of 127 HNSCC patients. Hybrid in vivo imaging and whole-exome sequencing were employed to identify quantitative imaging markers as well as genetic markers on pathway-level prognostic in HNSCC. We investigated the deductibility of the prognostic genetic markers using anatomical and metabolic imaging using positron emission tomography combined with computed tomography. Moreover, we used statistical and machine learning modeling to investigate whether a multi-omics approach can be used to derive prognostic markers for HNSCC. RESULTS: Radiogenomic analysis revealed a significant influence of genetic pathway alterations on imaging markers. A highly prognostic radiogenomic marker based on cellular senescence was identified. Furthermore, the radiogenomic biomarkers designed in this study vastly outperformed the prognostic value of markers derived from genetics and imaging alone. CONCLUSION: Using the identified markers, a clinically meaningful stratification of patients is possible, guiding the identification of high-risk patients and potentially aiding in the development of effective targeted therapies.
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku diagnostické zobrazování genetika MeSH
- genetické markery MeSH
- hodnocení rizik MeSH
- lidé MeSH
- nádory hlavy a krku * diagnostické zobrazování genetika MeSH
- prognóza MeSH
- retrospektivní studie MeSH
- spinocelulární karcinom * patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- komentáře MeSH
Head and neck squamous cell carcinoma (HNSCC) presents a significant global health problem with variable geographic distribution and risk factors, including tobacco and alcohol abuse, human papillomavirus infections, and genetic predisposition. While the majority of cases are sporadic, several well-defined hereditary syndromes have been associated with a higher risk of developing HNSCC including Li-Fraumeni syndrome, Fanconi anaemia, Bloom syndrome, familial atypical multiple mole melanoma, and dyskeratosis congenita. There is also evidence of familial clusters of HNSCC, suggesting a genetic component in the development of the disease. Germ-line genetic testing in HNSCC using next-generation sequencing has revealed a wide range of germline variants, some of which were not anticipated based on standard guidelines. These variants may influence treatment decisions and have the potential to be targeted with precision medicine in the future. Despite these advances, routine germline genetic testing for HNSCC is not currently recommended and remains reserved for HNSCC cases with early onset or strong family cancer history. However, the increasing availability of germline genetic testing warrants development of more comprehensive and standardized testing protocols. Germline genetic testing also has the potential to influence precision-guided treatment in HNSCC patients carrying germline pathogenic variants.
- MeSH
- lidé MeSH
- nádory hlavy a krku * diagnóza genetika MeSH
- spinocelulární karcinom * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Patients with squamous cell carcinoma of the head and neck (SCCHN) have a high-risk of recurrence. We aimed to develop machine learning methods to identify transcriptomic and proteomic features that provide accurate classification models for predicting risk of early recurrence in SCCHN patients. METHODS: Clinical, genomic, transcriptomic and proteomic features distinguishing recurrence risk were examined in SCCHN patients from The Cancer Genome Atlas (TCGA). Recurrence within one year after treatment was classified as high-risk and no recurrence as low-risk. RESULTS: No significant differences in individual clinicopathological characteristics, mutation profiles or mRNA expression patterns were seen between the groups using conventional statistical analysis. Using the machine learning algorithm, extreme gradient boosting (XGBoost), ten proteins (RAD50, 4E-BP1, MYH11, MAP2K1, BECN1, NF2, RAB25, ERRFI1, KDR, SERPINE1) and five mRNAs (PLAUR, DKK1, AXIN2, ANG and VEGFA) made the greatest contribution to classification. These features were used to build improved models in XGBoost, achieving the best discrimination performance when combining transcriptomic and proteomic data, providing an accuracy of 0.939 and an Area Under the ROC Curve (AUC) of 0.951. CONCLUSIONS: This study highlights machine learning to identify transcriptomic and proteomic factors that play important roles in predicting risk of recurrence in patients with SCCHN and to develop such models by iterative cycles to enhance their accuracy, thereby aiding the introduction of personalized treatment regimens.
- MeSH
- dlaždicobuněčné karcinomy hlavy a krku genetika MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- nádory hlavy a krku * genetika MeSH
- proteomika MeSH
- rab proteiny vázající GTP genetika MeSH
- spinocelulární karcinom * genetika MeSH
- transkriptom genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Solitary fibrous tumor (SFT) is a rare fibroblastic neoplasm with potentially malignant behavior that may develop in any anatomic site and may involve the head and neck (H&N) region as well. Although typical SFT has a relatively characteristic morphology, its morphologic spectrum is extraordinarily broad and also includes rare cases with dedifferentiation or transdifferentiation which result in aberrant morphologic and/or immunohistochemical features. However, since virtually all cases are molecularly characterized by NAB2::STAT6 gene fusions, molecular genetic methods or STAT6 immunohistochemistry can be effectively used in confirming the diagnosis. Herein, we report 3 diagnostically challenging H&N SFT cases with an unusual morphology and/or phenotypes closely mimicking other well-known H&N entities. The tumors originated in the oral minor salivary glands, the base of the tongue, and sinonasal tract and closely resembled hyalinizing clear cell carcinoma of the salivary gland, adenocarcinoma not otherwise specified and biphenotypic sinonasal sarcoma, respectively. All cases were positive for cytokeratins, variably expressed S100 protein, showed diffuse nuclear STAT6 positivity, and harbored NAB2::STAT6 gene fusions.
- MeSH
- fenotyp MeSH
- lidé MeSH
- nádorové biomarkery genetika MeSH
- nádory hlavy a krku * genetika MeSH
- represorové proteiny genetika MeSH
- solitární fibrózní tumory * chemie genetika MeSH
- transdiferenciace buněk MeSH
- transkripční faktor STAT6 genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium. METHODS: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test. RESULTS: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls. CONCLUSIONS: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status. IMPACT: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis.
- MeSH
- cirkulující mikroRNA * MeSH
- lidé MeSH
- mikro RNA * genetika MeSH
- nádorové biomarkery genetika MeSH
- nádory hlavy a krku * diagnóza genetika MeSH
- průřezové studie MeSH
- stanovení celkové genové exprese MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
Recently, an increasing incidence of HPV-induced oropharyngeal squamous cell carcinoma (OPSCC) has been observed. Moreover, locoregionally advanced stages require a combined modal approach, and the prognosis is poor. Therefore, it is essential to find early diagnostic and prognostic biomarkers. DNA methylation changes play a crucial role in the process of carcinogenesis and are often investigated as promising biomarkers in many types of cancer. For analysis of DNA methylation levels of selected tumour suppressor genes in HPV-positive and HPV-negative samples (including primary tumours and corresponding metastases of metastasizing OPSCCs, primary tumours of non-metastasizing OPSCCs, and control samples), methylation-specific MLPA and methylation-specific high-resolution melting analyses were used. A significant difference in methylation between OPSCCs and the control group was observed in WT1, PAX6 (P < 0.01) and CADM1, RARβ (P < 0.05) genes. CADM1 and WT1 hypermethylation was detected mostly in HPV-positive samples; all but one HPV-negative samples were unmethylated. Moreover, hypermethylation of PAX5 gene was observed in metastases compared with control samples and was also associated with shorter overall survival of all patients (P < 0.05). Associations described herein between promoter methylation of selected genes and clinicopathological data could benefit OPSCC patients in the future by improvement in screening, early detection, and prognosis of the disease.
- MeSH
- aktivátorový protein specifický pro B-buňky genetika MeSH
- Alphapapillomavirus * MeSH
- buněčná adhezní molekula 1 genetika metabolismus MeSH
- dlaždicobuněčné karcinomy hlavy a krku genetika MeSH
- DNA metabolismus MeSH
- infekce papilomavirem * komplikace MeSH
- lidé MeSH
- metylace DNA MeSH
- nádory hlavy a krku * genetika MeSH
- nádory orofaryngu * patologie MeSH
- Papillomaviridae MeSH
- prognóza MeSH
- proteiny WT1 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
