RESUMEN
BACKGROUND: Various antigen-presenting cells and tumor cells-expressing PD-L1 inhibits antitumor immune responses in the tumor microenvironment. Recently, numerous studies have shown that tumor cell intrinsic PD-L1 also plays important roles in tumor growth and progression. On the other hand, oral squamous cell carcinoma (OSCC) cells overexpress epidermal growth factor receptor (EGFR) and EGFR signal pathway exacerbates tumor progression. Therefore, this study assessed whether tumor-intrinsic PD-L1 facilitates malignant potential of OSCC cells through regulation of EGFR signaling. METHODS: Two OSCC cell lines, SAS and HSC-3, were transfected with PD-L1 and EGFR-specific small interfering RNA (siRNA). Influences of PD-L1 knockdown on malignant potentials of OSCC cells were examined by Cell Counting kit-8 assay, transwell assay, sphere formation assay, flow cytometry, and Western blot. Effects of PD-L1 and EGFR knockdown on each expression were examined by quantitative real-time PCR (qRT-PCR), Western blot, and flow cytometry. RESULTS: Transfection of an PD-L1-siRNA into OSCC cells decreased the abilities of proliferation, stemness, and mobility of these cells significantly. PD-L1 knockdown also decreased EGFR expression through the promotion of proteasome- and lysosome-mediated degradation and following activation of the EGFR/protekin kinase B (AKT) signal pathway. Meanwhile, EGFR knockdown did not influence PD-L1 expression in SAS and HSC-3 cells, but treatment with a recombinant human EGF induced its expression. Treatment with erlotinib and cetuximab suppressed rhEGF-induced PD-L1 expression and localization in the cellular membrane of both OSCC cells. CONCLUSION: OSCC cells-expressing PD-L1 induced by EGF stimulation may promote malignancy intrinsically via the activation of the EGFR/AKT signaling cascade.
Asunto(s)
Antígeno B7-H1 , Carcinoma de Células Escamosas , Receptores ErbB , Neoplasias de la Boca , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Humanos , Receptores ErbB/metabolismo , Antígeno B7-H1/metabolismo , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proliferación CelularRESUMEN
Oral microbiome studies have mainly focussed on bacteria, with the relationship between viruses and oral cancers remaining poorly understood. Oral cancers can develop even in the absence of any history of daily smoking or drinking. Oral cancer patients frequently have multiple primary cancers in the oral cavity and other organs, such as the upper gastrointestinal tract. Merkel cell polyomavirus (MCPyV) is a novel oncovirus identified from a subtype of skin cancer in 2008. In this study, we investigated the potential involvement of MCPyV in the pathogenesis of oral squamous cell carcinoma (OSCC). Participants comprised 115 Japanese patients with OSCC (single primary: 109 tumours in 109 patients; multiple primaries: 16 tumours in 6 patients) treated in our department between 2014 and 2017. DNA was extracted from formalin-fixed paraffin-embedded specimens of primary lesions. MCPyV DNA copy counts were analysed by quantitative real-time polymerase chain reaction. Twenty-four of the 115 patients (20.9%) were positive for MCPyV DNA. No association was found between presence or absence of MCPyV DNA and clinical characteristics other than number of primary lesions. The MCPyV DNA-positive rate was significantly higher for multiple primary OSCCs (62.5%, 10/16 tumours) than for single primary OSCCs (16.5%, 18/109 tumours; P < 0.001). Furthermore, MCPyV DNA load was significantly higher for patients with multiple primaries (P < 0.05). MCPyV was observed more frequently and DNA load was significantly higher with multiple primary OSCCs than with single primary OSCC. MCPyV may play some role as an oncovirus for multiple primary OSCCs.
Asunto(s)
Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Poliomavirus de Células de Merkel , Neoplasias de la Boca , Neoplasias Primarias Múltiples , Infecciones por Polyomavirus , Humanos , Poliomavirus de Células de Merkel/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones , Infecciones por Polyomavirus/complicaciones , Infecciones por Polyomavirus/diagnóstico , ADN Viral/análisis , ADN Viral/genética , Neoplasias Primarias Múltiples/complicacionesRESUMEN
Various cell types secrete exosomes into their surrounding extracellular space, which consequently affect the function and activity of recipient cells. Numerous studies have showed that tumor cell-derived exosomes play important roles in tumor growth and progression. Although a variety of endocytic pathways are reportedly involved in the cellular uptake of exosomes, detailed mechanisms remain unknown. The present study demonstrated that treatment with recombinant epidermal growth factor (EGF) time- and dose-dependently promoted cellular uptake of oral squamous cell carcinoma (OSCC) cell-derived exosomes into OSCC cells themselves. Conversely, EGF receptor (EGFR) knockdown and treatment with EGFR inhibitors, including erlotinib and cetuximab, abrogated OSCC cell uptake of exosomes. The macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA) blocked the effects of active EGF/EGFR signaling on uptake of OSCC cell-derived exosomes. These EGFR inhibitors also suppressed OSCC cell-derived exosome-induced proliferation, migration, invasion, stemness, and chemoresistance of OSCC cells. Taken together, the data presented herein suggest that EGFR inhibitors might inhibit the malignant potential of OSCC cells through direct inhibition of not only EGFR downstream signaling pathway but also cellular uptake of OSCC cell-derived exosomes through macropinocytosis.
Asunto(s)
Factor de Crecimiento Epidérmico/metabolismo , Exosomas/metabolismo , Neoplasias de la Boca/metabolismo , Pinocitosis , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias de la Boca/patología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Pinocitosis/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND: Constitutive activation of STAT3 promotes oncogenesis and growth of oral squamous cell carcinoma (OSCC). We investigated the mechanism of action of suppressor of cytokine signaling 1 (SOCS1), an endogenous inhibitor of JAK, as gene therapy for OSCC. METHODS: Antitumor effect of SOCS1 was compared to JAK inhibitor I by cell proliferation assay, cell cycle analysis, and apoptosis analysis in vitro. In addition, antitumor effect was evaluated using xenograft mouse models in vivo. RESULTS: JAK inhibitor I inhibited the proliferation of KOSC2 cl3-43 or T3M-1 clone2 OSCC cell lines in vitro. While JAK inhibitor I arrested both cell lines at the G2/M phase, induction of apoptosis was observed in T3M-1 clone2 cells, but not KOSC2-cl3-43 cells. An adenoviral vector expressing SOCS1 (AdSOCS1) significantly decreased the proliferation of both OSCC cell lines and induced G2/M phase cell cycle arrest and apoptosis, suggesting that induction of apoptosis of KOSC2 cl3-43 cells by AdSOCS1 is regulated by the JAK/STAT independent pathway. Overexpression of SOCS1 inhibited activation of the JAK/STAT and p44/42 MAPK pathways, while JAK inhibitor I inhibited activation of the JAK/STAT pathway only. Consistently, expression of Mcl-1 was decreased by overexpression of SOCS1, but not JAK inhibitor I. Additionally, KOSC2 cl3-43 or T3M-1 clone2 OSCC cells were subcutaneously implanted in the flanks of two xenograft mouse models. As compared to a control adenovirus vector (AdLacZ), intratumor injection of AdSOCS1 significantly decreased the tumor volume and induced apoptosis in vivo. CONCLUSION: SOCS1 gene therapy may be a beneficial approach for the treatment of OSCC.
Asunto(s)
Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Carcinoma de Células Escamosas de Cabeza y Cuello , Animales , Apoptosis/genética , Línea Celular Tumoral , Proliferación Celular/genética , Terapia Genética , Humanos , Ratones , Neoplasias de la Boca/genética , Neoplasias de la Boca/terapia , Factor de Transcripción STAT3/genética , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Proteína 1 Supresora de la Señalización de Citocinas/genéticaRESUMEN
Granulocyte colony-stimulating factor (G-CSF)-producing tumors are rare and are associated with a poor prognosis when they occur in the lungs and the head and neck region. Positron emission tomography/computed tomography has been reported to show systemic specific accumulation of fluorodeoxyglucose in these cases, but the systemic complications associated with the cytokines produced are not well known. We herein present the case of a G-CSF-producing maxillary sinus squamous cell carcinoma in a 73-year-old Japanese woman with a vertebral fracture and splenomegaly. These findings are known severe adverse events of high-dose recombinant human G-CSF treatment. The aim of the present study was to further discuss the hypothesis that cytokines produced by solid tumors may induce spinal vertebral fracture and splenomegaly.
RESUMEN
Although chemotherapy is initially effective in debulking tumor mass in a number of different types of malignancy, tumor cells gradually acquire chemoresistance and frequently progress to advanced clinical stage. Accumulating evidence has indicated that the tumor sensitivity to several chemotherapeutic drugs is regulated by tumor stromal cells including macrophages. However, the role of macrophages in the efficacy of chemotherapeutics on oral squamous cell carcinoma (OSCC) cells is poorly understood. In the present study, the effects of macrophagesecreted exosomes on the sensitivity of OSCC cells towards chemotherapeutic agents were examined. Specifically, the effects of exosomes derived from THP1 cells and primary human macrophages (PHM) were assessed on the chemosensitivity of OSC4 cells treated with 5fluorouracil (5FU) and cisdiamminedichloroplatinum (CDDP). The THP1 and PHMderived exosomes promoted dosedependent proliferation, decreased the proliferative inhibitory effects of 5FU and CDDP and decreased apoptosis in OSC4 cells through activation of the AKT/glycogen synthase kinase3ß signaling pathway. LY294002, a PI3K inhibitor, and MK2206, an AKT inhibitor, were both able to suppress the observed decrease in sensitivity to chemotherapeutic agents induced by exosomes. Overall, the data from the present study suggested that the macrophagederived exosomes may decrease the sensitivity to chemotherapeutic agents in OSCC cells. Thus, targeting the interaction between OSCC cells and macrophagederived exosomes may be considered as a therapeutic approach to improve the chemosensitivity of the tumor microenvironment in oral cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Exosomas/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Cisplatino/administración & dosificación , Resistencia a Antineoplásicos , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Voluntarios Sanos , Humanos , Leucocitos Mononucleares , Macrófagos/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Células Tumorales CultivadasRESUMEN
Two Staphylococcus aureus bacteriophages, KSAP7 and KSAP11, were isolated from sewage and characterized. Based on morphology and DNA sequences, they were assigned to the genus Silviavirus, subfamily Twortvirinae, family Herelleviridae, whose members are hypothesized to be suitable for bacteriophage therapy. The KSAP7 and KSAP11 genomes were 137,950 and 138,307 bp in size, respectively. Although their DNA sequences were almost identical, evidence of site-specific DNA rearrangements was found in two regions. Changes in the number of PIEPEK amino acid sequence repeats encoded by orf10 and the insertion/deletion of a 541-bp sequence that includes a possible tail-related gene were identified.
Asunto(s)
Caudovirales/genética , ADN Viral/genética , Genoma Viral , Filogenia , Fagos de Staphylococcus/genética , Staphylococcus aureus/virología , Secuencia de Aminoácidos , Caudovirales/clasificación , Caudovirales/aislamiento & purificación , Reordenamiento Génico , Tamaño del Genoma , Mutación INDEL , Japón , Sistemas de Lectura Abierta , Terapia de Fagos , Alineación de Secuencia , Fagos de Staphylococcus/clasificación , Fagos de Staphylococcus/aislamiento & purificaciónRESUMEN
The NLRP3 inflammasome has been implicated in the pathogenesis of various inflammatory diseases and is activated by particulate stimulants. Oral epithelial keratinocytes are frequently exposed to metal nanoparticles. In this study, we examined the effects of gold, silver, and palladium nanoparticles, which are frequently used for dental metal alloys on cell proliferation, cytotoxicity, autophagy, lysosomal functions, and NLRP3 inflammasome activation using the immortalized human oral keratinocyte cell line RT-7. The metal nanoparticles were agglomerated in the membrane vesicles in RT-7 cells and suppressed cell proliferation and increased lactate dehydrogenase activity as well as the proportion of apoptotic cells. Silver and palladium nanoparticles induced autophagy and lysosomal dysfunctions and all metal nanoparticles tested triggered the secretion of IL-1ß through caspase-1 activation. Furthermore, the epithelium obtained from patients with oral lichenoid lesions (OLLs) had robust NLRP3, ASC, caspase-1, and IL-1ß-positive keratinocytes and cDNA microarray showed significant elevation in the mRNA levels of NLRP3. These results suggest that internalized metal nanoparticles in oral mucosal epithelial cells activate the NLRP3 inflammasome through the induction of lysosomal damage and autophagy dysfunction. This process may be involved in the pathogenesis of OLL and suggest its potential as an alternative target for OLL therapy.
Asunto(s)
Oro/toxicidad , Inflamasomas/metabolismo , Queratinocitos/efectos de los fármacos , Nanopartículas del Metal/toxicidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Plata/toxicidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Niño , Femenino , Humanos , Queratinocitos/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Erupciones Liquenoides , Masculino , Persona de Mediana Edad , Boca/citología , Adulto JovenRESUMEN
In recent years, advances in drug therapy for head and neck squamous cell carcinoma (HNSCC) have progressed rapidly. In addition to cytotoxic anti-cancer agents such as platinum-based drug (cisplatin and carboplatin) and taxane-based drugs (docetaxel and paclitaxel), epidermal growth factor receptor-tyrosine kinase inhibitors (cetuximab) and immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) antibodies (nivolumab and pembrolizumab) have come to be used. The importance of anti-cancer drug therapy is increasing year by year. Therefore, we summarize clinical trials of molecular targeted therapy and biomarkers in HNSCC from previous studies. Here we show the current trends and future prospects of molecular targeted therapy in HNSCC.
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Terapia Molecular Dirigida , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Algoritmos , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Toma de Decisiones Clínicas , Terapia Combinada , Manejo de la Enfermedad , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoterapia/métodos , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Fototerapia/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/etiología , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidadRESUMEN
Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2-specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Efrina-B2/metabolismo , Neoplasias de la Boca/metabolismo , Transducción de Señal , Animales , Apoptosis , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Proliferación Celular , Progresión de la Enfermedad , Efrina-B2/genética , Femenino , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Metástasis Linfática , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Neoplasias de la Boca/enzimología , Neoplasias de la Boca/patología , Proteínas Quinasas/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Microambiente TumoralRESUMEN
Exosomes are 30-100 nm-sized membranous vesicles, secreted from a variety of cell types into their surrounding extracellular space. Various exosome components including lipids, proteins, and nucleic acids are transferred to recipient cells and affect their function and activity. Numerous studies have showed that tumor cell-derived exosomes play important roles in tumor growth and progression. However, the effect of exosomes released from oral squamous cell carcinoma (OSCC) into the tumor microenvironment remains unclear. In the present study, we isolated exosomes from OSCC cells and investigated the influence of OSCC cell-derived exosomes on the tumor cell behavior associated with tumor development. We demonstrated that OSCC cell-derived exosomes were taken up by OSCC cells themselves and significantly promoted proliferation, migration, and invasion through the activation of the PI3K/Akt, MAPK/ERK, and JNK-1/2 pathways in vitro. These effects of OSCC cell-derived exosomes were obviously attenuated by treatment with PI3K, ERK-1/2, and JNK-1/2 pharmacological inhibitors. Furthermore, the growth rate of tumor xenografts implanted into nude mice was promoted by treatment with OSCC cell-derived exosomes. The uptake of exosomes by OSCC cells and subsequent tumor progression was abrogated in the presence of heparin. Taken together, these data suggest that OSCC cell-derived exosomes might be a novel therapeutic target and the use of heparin to inhibit the uptake of OSCC-derived exosomes by OSCC cells may be useful for treatment.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Exosomas/patología , Heparina/farmacología , Neoplasias de la Boca/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral/efectos de los fármacos , Movimiento Celular , Proliferación Celular , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Ratones Endogámicos BALB C , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Proteína Quinasa 9 Activada por Mitógenos/metabolismo , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Merkel cell carcinoma is a rare and aggressive neuroendocrine-derived skin cancer arising most commonly on the sun-exposed head and neck skin of elderly and immunocompromised patients. Although a combination of wide excision and adjuvant radiotherapy is the optimal therapeutic approach for Merkel cell carcinoma, radiation monotherapy has recently been recommended for unresectable tumors. We report here a case of Merkel cell carcinoma treated with radiation monotherapy and reviewed Merkel cell carcinoma cases treated with radiotherapy alone in Japan. A 75-year-old man was referred for treatment of a tumor on the upper lip with a swollen submental lymph node. The histopathological diagnosis from biopsied material was Merkel cell carcinoma (T3N1bM0, stage IIIB). The submental lymph node was extirpated and radiation monotherapy was applied according to the 2014 National Comprehensive Cancer Network Guidelines because the Eastern Cooperative Oncology Group Performance Status of the patient was grade 3 and the patient and his family did not desire surgery. The primary site and bilateral upper neck regions were irradiated with 45 Gy followed by 20 Gy irradiation for the primary site alone. Three months after radiotherapy, the tumor seemed to have completely remitted. Approximately 1 year after radiotherapy, no evidence of local recurrence or late metastasis has been noted. Radiation monotherapy should be considered as a curative treatment for Merkel cell carcinoma, particularly in situations where extensive surgery is not favored.
Asunto(s)
Carcinoma de Células de Merkel/radioterapia , Neoplasias de los Labios/radioterapia , Neoplasias Cutáneas/radioterapia , Anciano , Humanos , Japón , Masculino , Pronóstico , Radioterapia Adyuvante , Inducción de RemisiónRESUMEN
The matricellular protein, secreted protein acidic and rich in cysteine (SPARC) is thought to be involved in cell competition. The objective of this study is to investigate the role of SPARC in cancerization of oral squamous epithelium. Clinical specimens from 57 pre- and early cancerous lesion, 66 invasive squamous cell carcinoma (SCC) and controls were immunostained with SPARC. Clinical features and SPARC expression were evaluated. Furthermore, effects of SPARC knockdown and overexpression were examined in oral cancer and keratinocyte cell lines. Leukoplakia, carcinoma in situ, and early invasive SCC had more SPARC-positive cells than normal mucous epithelium. However, there were no significant differences between leukoplakia, carcinoma in situ, and early SCC, and there were no correlations between SPARC immunoreactivity and prognosis of invasive oral SCCs. Cell proliferation was down-regulated by SPARC siRNA, and enhanced by SPARC transformed keratinocytes. But SPARC overexpression did not enhance cell migration activity. SPARC is induced by dysplastic cells in the early stage of cancerization, and may improve survival capability, but is not involved in malignancy. SPARC may act to escape from elimination by cell competition.
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Carcinoma de Células Escamosas/metabolismo , Neoplasias de la Boca/metabolismo , Osteonectina/genética , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatología , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/genética , Neoplasias de la Boca/fisiopatología , Regulación hacia ArribaRESUMEN
Dioxins (e.g. 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) cause cleft palate at a high rate. A post-fusional split may contribute to the pathogenesis, and tissue fragility may be a concern. The objective of this study was to investigate the effects of TCDD on the palatal epithelium, bone and muscle, which contribute to tissue integrity. ICR mice (10-12 weeks old) were used. TCDD was administered on E12.5 at 40 mg/kg. Immunohistochemical staining for AhR, ER-α, laminin, collagen IV, osteopontin, Runx2, MyoD, and desmin were performed. Furthermore, western blot analysis for osteopontin, Runx2, MyoD, and desmin were performed to evaluate protein expression in the palatal tissue. Immunohistologically, there was little difference in the collagen IV and laminin localization in the palatal epithelium between control versus TCDD-treated mice. Runx2 and osteopontin immunoreactivity decreased in the TCDD-treated palatal bone, and MyoD and desmin decreased in the TCDD-treated palatal muscle. AhR and ER-α immunoreactivity were localized to the normal palatal bone, but ER-α was diminished in the TCDD-treated palate. On western blot analysis, Runx2, MyoD, and desmin were all downregulated in the TCDD-treated palate. TCDD may suppress palatal osteogenesis and myogenesis via AhR, and cause cleft palates via a post-fusional split mechanism, in addition to a failure of palatal fusion.
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Fisura del Paladar/inducido químicamente , Hueso Paladar/efectos de los fármacos , Dibenzodioxinas Policloradas/efectos adversos , Teratógenos , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/efectos de los fármacos , Western Blotting , Fisura del Paladar/embriología , Colágeno Tipo IV/efectos de los fármacos , Subunidad alfa 1 del Factor de Unión al Sitio Principal/efectos de los fármacos , Desmina/efectos de los fármacos , Regulación hacia Abajo , Epitelio/efectos de los fármacos , Epitelio/embriología , Receptor alfa de Estrógeno/efectos de los fármacos , Femenino , Edad Gestacional , Inmunohistoquímica , Laminina/efectos de los fármacos , Ratones , Ratones Endogámicos ICR , Desarrollo de Músculos/efectos de los fármacos , Proteína MioD/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Osteopontina/efectos de los fármacos , Músculos Palatinos/efectos de los fármacos , Músculos Palatinos/embriología , Hueso Paladar/embriología , Paladar Duro/efectos de los fármacos , Paladar Duro/embriología , Embarazo , Receptores de Hidrocarburo de Aril/efectos de los fármacosRESUMEN
Mucinous cystadenoma of the salivary gland is a very rare disease, and only a few cases have been reported. We report here 2 cases of mucinous cystadenoma in the upper lip. The first case was a 57-year-old man and the second was a 42-year-old woman. The tumors were painless nodules with a smooth-surfaced mucosa, and surgical excisions were performed. Histologically, the tumors were surrounded by a fibrous capsule and were composed of multiple cysts lined with columnar epithelial cells. The tumor cells contain mucous substances that reacted with periodic acid-Schiff base and Alcian blue. Immunohistochemical staining revealed that the tumor cells expressed cytokeratin (AE1/3 and CK7), but their immunoreactivity with MIB-1 (Ki-67) was less than 3%. They had negative immunoreactivity for neuroectoderm markers, S-100 protein, and myoepithelial markers, p63, α-smooth muscle actin, and calponin, except for the accompanying myoepithelial-like cells. No recurrences were noted after surgery at 7 years and 1 year, respectively.
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Cistoadenoma Mucinoso/patología , Neoplasias de los Labios/patología , Neoplasias de las Glándulas Salivales/patología , Glándulas Salivales Menores/patología , Adulto , Biomarcadores de Tumor/análisis , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana EdadRESUMEN
Low-grade myofibroblastic sarcoma (LGMS) is a rare, malignant tumor with myofibroblastic differentiation. Despite it being classified as a distinct entity by the World Health Organization, a few cases were reported in the oral and maxillofacial region. Here, a LGMS developed on the palate of a 73-year-old man who presented with a 1-cm tumor on the posterior border of the palate. Based on the histological and immunohistochemical features, a diagnosis of LGMS was established. The tumor was resected, and no recurrence was observed over 2 years. Although the tongue is the most preferred site for LGMS, it may occur in any region of the oral cavity.
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Miofibroblastos/patología , Osteosarcoma/patología , Neoplasias Palatinas/patología , Paladar Duro/patología , Anciano , Humanos , Masculino , Osteosarcoma/cirugía , Neoplasias Palatinas/cirugíaRESUMEN
OBJECTIVE: The objective of this study was to analyze the relationship between the uptake of (18)F-2-fluoro-2-deoxy-d-glucose (FDG) by positron emission tomography-computerized tomography (PET-CT) and glucose metabolism/hypoxia markers in oral squamous cell carcinoma (OSCC). STUDY DESIGN: Thirty-six patients with OSCC (tongue [n = 23], buccal mucosa [n = 7], and floor of the mouth [n = 6]) were assessed and underwent incisional biopsy and subsequently received FDG-PET-CT. Expressions of hypoxia-inducible factor 1α (HIF-1α), glucose transporter protein 1 (GLUT-1), hexokinase-II (HK-II), and glucose-6-phosphatase (G6Pase) were immunohistochemically quantified, and FDG uptake was evaluated by the maximum standardized uptake values (SUV(max)) at the primary tumor site. RESULTS: FDG uptake was found to be significantly correlated with the T classification of OSCC but not with other clinicopathologic characteristics, such as the N classification, clinical type, and histologic grade of malignancy. In the early-stage (T1 and T2) tumor, FDG uptake was significantly associated with the expression levels of GLUT-1, HK II, and HIF-1α, and the expression levels of GLUT-1 and HK-II significantly correlated with HIF-1α expression levels. However, there were no correlations between the expression levels of these molecules and SUV(max) in the late-stage (T3 and T4) tumor. CONCLUSIONS: FDG uptake was significantly associated with the expression levels of glucose metabolism-related molecules, such as GLUT-1, HK II, and HIF-1α, especially in early-stage tumors.
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Carcinoma de Células Escamosas/metabolismo , Glucosa/metabolismo , Hipoxia/metabolismo , Neoplasias de la Boca/metabolismo , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Femenino , Fluorodesoxiglucosa F18 , Transportador de Glucosa de Tipo 1/biosíntesis , Transportador de Glucosa de Tipo 1/genética , Glucosa-6-Fosfatasa/biosíntesis , Glucosa-6-Fosfatasa/genética , Hexoquinasa/biosíntesis , Hexoquinasa/genética , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/biosíntesis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Masculino , Persona de Mediana Edad , Suelo de la Boca/metabolismo , Mucosa Bucal/metabolismo , Neoplasias de la Boca/patología , Clasificación del Tumor , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Estadísticas no Paramétricas , Lengua/metabolismoRESUMEN
Some members of the Toll-like receptor (TLR) family, which plays key roles in both innate and adaptive immune responses, are involved in the pathogenesis of autoimmune, chronic inflammatory and infectious diseases. However, the role of TLR in the pathogenesis of oral lichen planus (OLP) has not been investigated. The aim of this study was to understand the roles of TLR in OLP. The expression of TLR genes in OLP tissues was analyzed by cDNA microarray and reverse transcription polymerase chain reaction, and TLR protein expression in OLP tissues and peripheral blood monocytes was examined by immunohistochemical analysis and flow cytometry, respectively. Furthermore, TLR ligand-induced cytokine production from peripheral blood monocytes was measured by enzyme-linked immunosorbent assay. Among 10 TLR genes, the average expression ratio of the genes for TLR1, 2, 3, 5, 6 and 10 in OLP tissues compared to that in the normal buccal mucosae was more than 1.0. In contrast, the average ratio of the genes for TLR7, 8 and 9 was less than 1.0. TLR2 but not TLR4 was highly expressed in the cells of the spinous layer and infiltrating monocytes in OLP tissues, and the mean fluorescence intensity of TLR2 on peripheral blood monocytes was significantly higher in OLP patients than in healthy controls. Furthermore, the peripheral blood monocytes from OLP patients produced considerably higher amounts of interleukin (IL)-12 and lower amounts of IL-10 than those from healthy controls. In OLP, the T-helper cell (Th)1/Th2 balance appears to shift toward Th1 dominance, probably depending on the upregulation of TLR2 expression and these alterations in TLR2-mediated immunity may be involved in the pathogenesis and maintenance of OLP.
Asunto(s)
Liquen Plano Oral/genética , Liquen Plano Oral/inmunología , Receptor Toll-Like 2/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Estudios de Casos y Controles , Citocinas/sangre , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Liquen Plano Oral/sangre , Masculino , Persona de Mediana Edad , Monocitos/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoAsunto(s)
Carcinoma Adenoide Quístico/terapia , Inmunoterapia/métodos , Neoplasias Pulmonares/terapia , Neoplasias de las Glándulas Salivales/patología , Proteínas WT1/uso terapéutico , Anciano , Carcinoma Adenoide Quístico/secundario , Femenino , Genes del Tumor de Wilms , Humanos , Neoplasias Pulmonares/secundarioRESUMEN
We compared the nutritional condition, immunological function, and frequency of adverse effects during concurrent chemoradiotherapy for oral cancer between patients simultaneously receiving enteral hyperalimentation (Racol) (n=20; EHA group) and patients receiving peripheral vein nutrition (n=20; PVN group). Although there was no significant difference in the change of body weight between the two groups, the decrease of plasma albumin values in the EHA group appeared later than in the PVN group. In the PVN group, the number of lymphocytes and lymphocyte blastogenesis significantly decreased on and after day 14. On the other hand, in the EHA group, the number of lymphocytes decreased only on day 14 and no decrease in lymphocyte blastogenesis was observed. While stomatitis developed in all patients, the severity was lower in the EHA group than the PVN one. These results suggest that the simultaneous administration of Racol during concurrent chemoradiotherapy for oral cancer inhibits the deterioration of nutritional and immunological conditions as well as the severity of stomatitis. This nutrient therapy is therefore considered to be a supportive therapy for oral cancer patients.