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

Human extracellular 6-O-endosulfatases Sulf-1 and Sulf-2 are the only enzymes that post-synthetically alter the 6-O sulfation of heparan sulfate proteoglycans (HSPG), which regulates interactions of HSPG with many proteins. Oncogenicity of Sulf-2 in different cancers has been documented, and we have shown that Sulf-2 is associated with poor survival outcomes in head and neck squamous cell carcinoma (HNSCC). Despite its importance, limited information is available on direct protein-protein interactions of the Sulf-2 protein in the tumor microenvironment. In this study, we used monoclonal antibody (mAb) affinity purification and mass spectrometry to identify galectin-3-binding protein (LG3BP) as a highly specific binding partner of Sulf-2 in the conditioned media of HNSCC cell lines. We validated their direct interaction in vitro using recombinant proteins and have shown that the chondroitin sulfate (CS) covalently bound to the Sulf-2 influences the binding to LG3BP. We confirmed the importance of the CS chain for the interaction by generating a mutant Sulf-2 protein that lacks the CS. Importantly, we have shown that the LG3BP inhibits Sulf-2 activity in vitro in a concentration-dependent manner. As a consequence, the addition of LG3BP to a spheroid cell culture inhibited the invasion of the HNSCC cells into Matrigel. Thus, Sulf-2 interaction with LG3BP may regulate the physiological activity of the Sulf-2 enzyme as well as its activity in the tumor microenvironment.

• MeSH
• antigeny nádorové MeSH
• chondroitinsulfáty metabolismus   MeSH
• dlaždicobuněčné karcinomy hlavy a krku metabolismus   patologie   MeSH
• heparansulfát proteoglykany metabolismus   MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí MeSH
• nádory hlavy a krku metabolismus   patologie   MeSH
• pohyb buněk účinky léků   MeSH
• spinocelulární karcinom metabolismus   patologie   MeSH
• sulfatasy metabolismus   MeSH
• sulfotransferasy * metabolismus   MeSH
• vazba proteinů * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Cancer-associated fibroblasts (CAFs) are involved in critical aspects of head and neck squamous cell carcinoma (HNSCC) pathogenesis, such as the formation of a tumor-permissive extracellular matrix structure, angiogenesis, or immune and metabolic reprogramming of the tumor microenvironment (TME), with implications for metastasis and resistance to radiotherapy and chemotherapy. The pleiotropic effect of CAFs in TME is likely to reflect the heterogeneity and plasticity of their population, with context-dependent effects on carcinogenesis. The specific properties of CAFs provide many targetable molecules that could play an important role in the future therapy of HNSCC. In this review article, we will focus on the role of CAFs in the TME of HNSCC tumors. We will also discuss clinically relevant agents targeting CAFs, their signals, and signaling pathways, which are activated by CAFs in cancer cells, with the potential for repurposing for HNSCC therapy.

• MeSH
• dlaždicobuněčné karcinomy hlavy a krku metabolismus   MeSH
• fibroblasty asociované s nádorem * metabolismus   MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory hlavy a krku * metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Head and neck cancer is the sixth most common cancer across the globe. This is generally associated with tobacco and alcohol consumption. Cancer in the pharynx majorly arises through human papillomavirus (HPV) infection, thus classifying head and neck squamous cell carcinoma (HNSCC) into HPV-positive and HPV-negative HNSCCs. Aberrant, mesenchymal-epithelial transition factor (c-MET) signal transduction favors HNSCC progression by stimulating proliferation, motility, invasiveness, morphogenesis, and angiogenesis. c-MET upregulation can be found in the majority of head and neck squamous cell carcinomas. c-MET pathway acts on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K), alpha serine/threonine-protein kinase (Akt), mitogen-activated protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. c-MET also establishes a crosstalk pathway with epidermal growth factor receptor (EGFR) and contributes towards chemoresistance in HNSCC. In recent years, the signaling communications of c-MET/HGF in metabolic dysregulation, tumor-microenvironment and immune modulation in HNSCC have emerged. Several clinical trials have been established against c-MET/ hepatocyte growth factor (HGF) signaling network to bring up targeted and effective therapeutic strategies against HNSCC. In this review, we discuss the molecular mechanism(s) and current understanding of c-MET/HGF signaling and its effect on HNSCC.

• MeSH
• chemorezistence genetika   MeSH
• energetický metabolismus MeSH
• hepatocytární růstový faktor metabolismus   MeSH
• imunita MeSH
• lidé MeSH
• management nemoci MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery MeSH
• nádorové mikroprostředí genetika   imunologie   MeSH
• nádory hlavy a krku etiologie   metabolismus   patologie   terapie   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• protoonkogenní proteiny c-met metabolismus   MeSH
• signální transdukce * MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Many cancer therapies aim to trigger apoptosis in cancer cells. Nevertheless, the presence of oncogenic alterations in these cells and distorted composition of tumour microenvironment largely limit the clinical efficacy of this type of therapy. Luckily, scientific consensus describes about 10 different cell death subroutines with different regulatory pathways and cancer cells are probably not able to avoid all of cell death types at once. Therefore, a focused and individualised therapy is needed to address the specific advantages and disadvantages of individual tumours. Although much is known about apoptosis, therapeutic opportunities of other cell death pathways are often neglected. Molecular heterogeneity of head and neck squamous cell carcinomas (HNSCC) causing unpredictability of the clinical response represents a grave challenge for oncologists and seems to be a critical component of treatment response. The large proportion of this clinical heterogeneity probably lies in alterations of cell death pathways. How exactly cells die is very important because the predominant type of cell death can have multiple impacts on the therapeutic response as cell death itself acts as a second messenger. In this review, we discuss the different types of programmed cell death (PCD), their connection with HNSCC pathogenesis and possible therapeutic windows that result from specific sensitivity to some form of PCD in some clinically relevant subgroups of HNSCC.

• MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• chemorezistence MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• ferroptóza účinky léků   MeSH
• genetická heterogenita MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory hlavy a krku farmakoterapie   genetika   metabolismus   patologie   MeSH
• nekroptóza účinky léků   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyroptóza účinky léků   MeSH
• regulovaná buněčná smrt účinky léků   MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different "sensitizing ratio". Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.

• MeSH
• chemorezistence účinky léků   MeSH
• cisplatina farmakologie   MeSH
• dlaždicobuněčné karcinomy hlavy a krku metabolismus   patologie   MeSH
• fibroblasty asociované s nádorem účinky léků   metabolismus   MeSH
• kokultivační techniky MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• nádory hlavy a krku metabolismus   patologie   MeSH
• parakrinní signalizace účinky léků   MeSH
• protinádorové látky farmakologie   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• testy nádorových kmenových buněk MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

ABSTRACT: Sebaceous neoplasms occur sporadically or in the setting of Muir-Torre syndrome. The data regarding the correlation of pathologic features and DNA mismatch repair (MMR) staining pattern in sebaceous tumors of the skin are very scanty and based on relatively small series of patients. The goal of this study was to correlate MMR staining pattern with selected morphological features in a series of 145 sebaceous neoplasms (sebaceous adenoma, sebaceoma, and extraocular sebaceous carcinoma) from 136 patients. Cystic change, intratumoral mucin deposits, squamous metaplasia in the absence of keratoacanthoma-like changes, ulceration, intratumoral and peritumoral lymphocytes (in cases without epidermal ulceration), and intertumoral heterogeneity proved to be significantly associated with MMR deficiency. Identification of any of these changes, alone or in combination, should prompt further investigation of the patient to exclude Muir-Torre Syndrome. Our study also confirms the previously published observation that the diagnosis and tumor location are significantly associated with MMR deficiency.

• MeSH
• adenom metabolismus   patologie   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• dospělí MeSH
• homolog 2 proteinu MutS metabolismus   MeSH
• imunohistochemie MeSH
• karcinom metabolismus   patologie   MeSH
• končetiny MeSH
• lidé středního věku MeSH
• lidé MeSH
• mismatch repair endonukleáza PMS2 metabolismus   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• MutL homolog 1 metabolismus   MeSH
• nádory hlavy a krku metabolismus   patologie   MeSH
• nádory mazových žláz metabolismus   patologie   MeSH
• obličej MeSH
• oprava chybného párování bází DNA MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• skalp MeSH
• trup MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). METHODS: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). RESULTS: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). CONCLUSION: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.

• MeSH
• adherence a compliance při léčbě MeSH
• afatinib terapeutické užití   MeSH
• chinazoliny aplikace a dávkování   MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   metabolismus   MeSH
• erbB receptory metabolismus   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   MeSH
• methotrexát aplikace a dávkování   MeSH
• nádory hlavy a krku farmakoterapie   metabolismus   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

BACKGROUND/AIM: Having previously initiated genome-wide expression profiling in head and neck squamous cell carcinoma (HNSCC) for regions of the tumor, the margin of surgical resecate (MSR) and normal mucosa (NM), we here proceed with respective analysis of cases after stratification according to the expression status of tenascin (Ten). MATERIALS AND METHODS: Tissue specimens of each anatomical site were analyzed by immunofluorescent detection of Ten, fibronectin (Fn) and galectin-1 (Gal-1) as well as by microarrays. RESULTS: Histopathological examination demonstrated that Ten+Fn+Gal-1+co-expression occurs more frequently in samples of HNSCC (55%) than in NM (9%; p<0.01). Contrary, the Ten-Fn+Gal-1-(45%) and Ten-Fn-Gal-1-(39%) status occurred with significantly (p<0.01) higher frequency than in HNSCC (3% and 4%, respectively). In MSRs, different immunophenotypes were distributed rather equally (Ten+Fn+Gal-1+=24%; Ten-Fn+Gal-1-=36%; Ten-Fn-Gal-1-=33%), differing to the results in tumors (p<0.05). Absence/presence of Ten was used for stratification of patients into cohorts without a difference in prognosis, to comparatively examine gene-activity signatures. Microarray analysis revealed i) expression of several tumor progression-associated genes in Ten+HNSCC tumors and ii) a strong up-regulation of gene expression assigned to lipid metabolism in MSRs of Ten-tumors, while NM profiles remained similar. CONCLUSION: The presented data reveal marked and specific changes in tumors and MSR specimens of HNSCC without a separation based on prognosis.

• MeSH
• fibronektiny genetika   metabolismus   MeSH
• galektin 1 genetika   metabolismus   MeSH
• genová ontologie MeSH
• lidé MeSH
• nádorové biomarkery genetika   MeSH
• nádory hlavy a krku genetika   metabolismus   chirurgie   MeSH
• přežití bez známek nemoci MeSH
• regulace genové exprese u nádorů * MeSH
• resekční okraje MeSH
• sliznice metabolismus   MeSH
• spinocelulární karcinom genetika   metabolismus   chirurgie   MeSH
• stanovení celkové genové exprese metody   MeSH
• tenascin genetika   metabolismus   MeSH
• transkriptom * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Head and neck squamous cell carcinoma is one of the most aggressive tumours and is typically diagnosed too late. Late diagnosis requires an urgent decision on an effective therapy. An individualized test of chemosensitivity should quickly indicate the suitability of chemotherapy and radiotherapy. No ex vivo chemosensitivity assessment developed thus far has become a part of general clinical practice. Therefore, we attempted to explore the new technique of coherence-controlled holographic microscopy to investigate the motility and growth of live cells from a head and neck squamous cell carcinoma biopsy. We expected to reveal behavioural patterns characteristic for malignant cells that can be used to imrove future predictive evaluation of chemotherapy. We managed to cultivate primary SACR2 carcinoma cells from head and neck squamous cell carcinoma biopsy verified through histopathology. The cells grew as a cohesive sheet of suspected carcinoma origin, and western blots showed positivity for the tumour marker p63 confirming cancerous origin. Unlike the roundish colonies of the established FaDu carcinoma cell line, the SACR2 cells formed irregularly shaped colonies, eliciting the impression of the collective invasion of carcinoma cells. Time-lapse recordings of the cohesive sheet activity revealed the rapid migration and high plasticity of these epithelial-like cells. Individual cells frequently abandoned the swiftly migrating crowd by moving aside and crawling faster. The increasing mass of fast migrating epithelial-like cells before and after mitosis confirmed the continuation of the cell cycle. In immunofluorescence, analogously shaped cells expressed the p63 tumour marker, considered proof of their origin from a carcinoma. These behavioural traits indicate the feasible identification of carcinoma cells in culture according to the proposed concept of the carcinoma cell dynamic phenotype. If further developed, this approach could later serve in a new functional online analysis of reactions of carcinoma cells to therapy. Such efforts conform to current trends in precision medicine.

• MeSH
• biopsie MeSH
• buněčný cyklus fyziologie   MeSH
• holografie metody   MeSH
• imunohistochemie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikroskopie metody   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buňky kultivované MeSH
• nádorové supresorové proteiny metabolismus   MeSH
• nádory hlavy a krku metabolismus   patologie   MeSH
• pohyb buněk fyziologie   MeSH
• senioři MeSH
• spinocelulární karcinom metabolismus   patologie   MeSH
• transkripční faktory metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH