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Background A number of non-coding circular RNAs (circRNAs) have recently been implicated in the modulation of gene expression in cancer models. We therefore sought to explore if circZNF236 has a role in oral squamous cell carcinoma (OSCC). Methods We first examined circZNF236 expression in 32 pairs of OSCC and noncancerous tissues. We then investigated a functional role for circZNF236 using knockdown and overexpression approaches in OSCC cancer cell lines. Cell counting kit-8, wound healing, Transwell, and flow cytometry were employed to assess circZNF236 function in vitro. The association between circZNF236 and miR-145-5p, or that between miR-145-5p and malignant brain tumor domain containing 1 (MBTD1) was predicted by bioinformatics and demonstrated by dual-luciferase reporter assays, RNA pull-down assays as well as RNA immunoprecipitation (RIP) assays. A mouse OSCC xenograft model was employed to demonstrate the impacts of circZNF236 inhibition on tumor development in vivo. Results OSCC tissues and cells had higher levels of circZNF236 expression compared with normal controls. Furthermore, high circZNF236 levels in patients with OSCC correlated with a poor prognosis. CircZNF236 silencing decreased the malignant properties of OSCC cells and suppressed OSCC tumor formation in the mouse model. We then noticed that miR-145-5p can be regulated by circZNF236, and that circZNF2361 promoted OSCC development by absorbing miR-145-5p and consequently upregulating MBTD1 expression. Conclusion CircZNF236 modulates OSCC via the miR-145-5p/MBTD1 axis. These results support the potential of circZNF236 as a treatment target for OSCC (AU)
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Humanos , Animales , Ratones , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , MicroARNs/genética , MicroARNs/metabolismo , Línea Celular Tumoral , Proliferación Celular/genética , Proteínas Cromosómicas no Histona , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: The efficacy of 18F-fluorodeoxyglucose (18F-FDG) Positron Emission Tomography/Computed Tomography(PET/CT) in evaluating the neck status in clinically node-negative (cN0) oral squamous cell carcinoma(OSCC) patients was still unsatisfying. We tried to develop a prediction model for nodal metastasis in cN0 OSCC patients by using metabolic and pathological variables. METHODS: Consecutive cN0 OSCC patients with preoperative 18F-FDG PET/CT, subsequent surgical resection of primary tumor and neck dissection were included. Ninety-five patients who underwent PET/CT scanning in Shanghai ninth people's hospital were identified as training cohort, and another 46 patients who imaged in Shanghai Universal Medical Imaging Diagnostic Center were selected as validation cohort. Nodal-status-related variables in the training cohort were selected by multivariable regression after using the least absolute shrinkage and selection operator (LASSO). A nomogram was constructed with significant variables for the risk prediction of nodal metastasis. Finally, nomogram performance was determined by its discrimination, calibration, and clinical usefulness. RESULTS: Nodal maximum standardized uptake value(nodal SUVmax) and pathological T stage were selected as significant variables. A prediction model incorporating the two variables was used to plot a nomogram. The area under the curve was 0.871(Standard Error [SE], 0.035; 95% Confidence Interval [CI], 0.787-0.931) in the training cohort, and 0.809(SE, 0.069; 95% CI, 0.666-0.910) in the validation cohort, with good calibration demonstrated. CONCLUSIONS: A prediction model incorporates metabolic and pathological variables has good performance for predicting nodal metastasis in cN0 OSCC patients. However, further studies with large populations are needed to verify our findings.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello , Tomografía Computarizada por Tomografía de Emisión de Positrones , Fluorodesoxiglucosa F18 , Neoplasias de la Boca/diagnóstico por imagen , Neoplasias de la Boca/cirugía , Metástasis Linfática , China , Estudios Retrospectivos , RadiofármacosRESUMEN
BACKGROUND: Non-smokers, non-drinkers, and non-betel quid chewers (NSNDNBs) with oral squamous cell carcinoma (OSCC) have poor survival outcomes. Tumor microenvironment based on PD-L1/CD8+ T cell infiltrated lymphocyte (TIL) proportion is proposed as a prognostic indicator. METHODS: Immunohistochemistry staining was performed on OSCC samples from 64 patients. The PD-L1/CD8+ TILs were scored and stratified into four groups. Disease-free survival (DFS) was analyzed using a Cox regression model. RESULTS: OSCC in NSNDNB patients was associated with female sex, T1-2 classification, and PD-L1 positivity. Low CD8+ TILs correlated with perineural invasion. High CD8+ TILs correlated with improved DFS. PD-L1 positivity was not correlated with DFS. Type IV tumor microenvironment yielded the highest DFS (85%). CONCLUSION: NSNDNB status relates to PD-L1 expression regardless of CD8+ TILs infiltration. Type IV tumor microenvironment was associated with the best DFS. High CD8+ TILs resulted in better survival, while PD-L1 positivity alone was not correlated to DFS.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Humanos , Femenino , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Pronóstico , Neoplasias de la Boca/terapia , Neoplasias de la Boca/patología , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/metabolismo , Microambiente Tumoral , Factores de Riesgo , Neoplasias de Cabeza y Cuello/patologíaRESUMEN
BACKGROUND: A number of non-coding circular RNAs (circRNAs) have recently been implicated in the modulation of gene expression in cancer models. We therefore sought to explore if circZNF236 has a role in oral squamous cell carcinoma (OSCC). METHODS: We first examined circZNF236 expression in 32 pairs of OSCC and noncancerous tissues. We then investigated a functional role for circZNF236 using knockdown and overexpression approaches in OSCC cancer cell lines. Cell counting kit-8, wound healing, Transwell, and flow cytometry were employed to assess circZNF236 function in vitro. The association between circZNF236 and miR-145-5p, or that between miR-145-5p and malignant brain tumor domain containing 1 (MBTD1) was predicted by bioinformatics and demonstrated by dual-luciferase reporter assays, RNA pull-down assays as well as RNA immunoprecipitation (RIP) assays. A mouse OSCC xenograft model was employed to demonstrate the impacts of circZNF236 inhibition on tumor development in vivo. RESULTS: OSCC tissues and cells had higher levels of circZNF236 expression compared with normal controls. Furthermore, high circZNF236 levels in patients with OSCC correlated with a poor prognosis. CircZNF236 silencing decreased the malignant properties of OSCC cells and suppressed OSCC tumor formation in the mouse model. We then noticed that miR-145-5p can be regulated by circZNF236, and that circZNF2361 promoted OSCC development by absorbing miR-145-5p and consequently upregulating MBTD1 expression. CONCLUSION: CircZNF236 modulates OSCC via the miR-145-5p/MBTD1 axis. These results support the potential of circZNF236 as a treatment target for OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , MicroARNs , Neoplasias de la Boca , Humanos , Animales , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Línea Celular Tumoral , Neoplasias de la Boca/patología , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Proteínas Cromosómicas no HistonaRESUMEN
Oral squamous cell cancer (OSCC) is the most common type of oral cancer (about 80-90% of cases) and various research is being done to cure the disease. This paper aims to verify whether treatment with no-ozone cold plasma (NCP), which is designed for safe usage of the plasma on oral cavities, in combination with gold nanoparticles conjugated with p-FAK antibody (p-FAK/GNP) can trigger the selective and instant killing of SCC-25 cells both in vitro and in vivo. When SCC25 and HaCaT cells are exposed to p-FAK/GNP+NCP, the instant cell death was observed only in SCC25 cells. Such p-FAK/GNP+NCP-mediated cell death was observed only when NCP was directly treated on SCC25 harboring p-FAK/GNP. During NCP treatment, the removal of charged particles from NCP using grounded electric mesh radically decreased the p-FAK/GNP+NCP-mediated cell death. This p-FAK/GNP+NCP-mediated selective cell death of OSCC was also observed in mice xenograft models using SCC25 cells. The mere treatment of p-FAK/GNP and NCP on the xenograft tumor slowly decreased the size of the tumor, and only about 50% of the tumor remained at the end of the experiment. On the other hand, 1 week of p-FAK/GNP+NCP treatment was enough to reduce half of the tumor size, and most of tumor tissue had vanished at the end. An analysis of isolated tissues showed that in the case of individual treatment with p-FAK/GNP or NCP, the cancer cell population was reduced due to apoptotic cell death. However, in the case of p-FAK/GNP+NCP, apoptotic cell death was unobserved, and most tissues were composed of collagen. Thus, this paper suggests the possibility of p-FAK/GNP+NCP as a new method for treating OSCC.
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The malignant potential of oral lichen planus (OLP) has been discussed and disputed for decades. The lesions are often characterized by strong expression of the TP53 protein in the basal layer of the mucosa. In 2002, we reported the presence of TP53 mutations in nine out of 27 OLP lesions tested. At follow-up in 2009, one case of oral squamous cell cancer (OSCC) had occurred in a different site six years later. In contrast, in another case, TP53 mutation persisted for years without malignant transformation. In a longitudinal study of eight selected patients with OSCC or different pre-malignant lesions, it was concluded that TP53 mutations could occur early or late in the development of OSCC. A follow-up in the present, almost 20 years later, revealed that one further case of OSCC had occurred in a TP53-mutated case of OLP, 21 years after the first sample was taken, again in a different site. With this second case, this small study now points towards a risk of developing OSCC in TP53-mutated OLP lesions. A review of recent literature indicates a growing consensus that OLP should be regarded as a potentially pre-malignant lesion. Several protein markers have been studied, but none proved useful for prediction of malignant progression. The great majority of published studies are retrospective, and it has been suggested that multi-centre prospective studies will be needed to reach a definitive answer on the malignant potential of OLP, and particularly, to identify contributing factors. Screening for TP53 mutations could help to identify the subgroup of OLP patients that is truly at risk of developing oral cancer.
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BACKGROUND: In the malignant progression of oral leukoplakia (OLK) to oral squamous cell carcinoma (OSCC), the density of microvessels and expression of angiogenesis-related molecules increases. Emerging evidence indicates that mesenchymal stem cells (MSCs) play an indispensable role in the tumor microenvironment. However, the role and mechanism of action of oral MSCs in inducing angiogenesis remain unclear. Therefore, it is necessary to explore the molecules and mechanisms that play a role in the tissue microenvironment. METHODS: Exosomes were collected from normal oral mucosa (N-Exo), OLK (OLK-Exo), and OSCC (Ca-Exo) MSCs, and their pro-angiogenic capacity was evaluated in human umbilical vein endothelial cells (HUVECs) and a subcutaneously implanted tumor model in nude mice. Quantitative proteomics analysis was used to compare the exosome-derived proteins between N-Exo, OLK-Exo, and Ca-Exo. RESULTS: Compared with that of the N-Exo and control, OLK-Exo and Ca-Exo treatment significantly promoted HUVEC migration, invasion, and tube-formation capability. In the nude mice model, immunofluorescence of CD31 showed that OLK-Exo and Ca-Exo substantially improved neovascularization around the grafts. Quantitative proteomics analysis revealed that matrix metalloproteinase 1 (MMP1) levels were significantly higher in the OLK-Exo and Ca-Exo groups than in the N-Exo groups. Silencing MMP1 expression reversed the functional promoting effect of OLK-Exo and Ca-Exo on HUVECs. CONCLUSION: Exosomes from OLK-MSCs and Ca-MSCs have a stronger pro-angiogenic ability through high MMP1 content. This new finding provides insight into the intervention with the secretion of MSC-derived exosomes, which may be an innovative strategy for carcinogenesis.
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Carcinoma de Células Escamosas , Exosomas , Neoplasias de Cabeza y Cuello , Células Madre Mesenquimatosas , Neoplasias de la Boca , Animales , Carcinogénesis/metabolismo , Carcinoma de Células Escamosas/metabolismo , Exosomas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Leucoplasia Bucal/patología , Metaloproteinasa 1 de la Matriz , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Desnudos , Neoplasias de la Boca/patología , Neovascularización Patológica/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Germline CDKN2A mutations are a well-known cause of familial atypical multiple mole melanoma (OMIM #155601) and melanoma-pancreatic cancer syndrome (OMIM #606719). Increased risk of head and neck squamous cell carcinoma (HNSCC), particularly oral squamous cell carcinoma (OSCC) in those with germline CDKN2A mutations, has been described. However, screening for HNSCC is not a routine practice in patients with CDKN2A germline mutations and these mutations are not a conventional test for HNSCC patients without obvious risk factors. CASE PRESENTATION: We describe a female with no smoking history who developed oral squamous cell carcinoma at age 39 and had a complex clinical course of recurrent multifocal squamous cell carcinoma (SCC) and carcinoma in situ of the oral cavity and oropharynx. Detailed family history demonstrated that her mother was diagnosed with OSCC and melanoma in her 40 s, and her maternal grandfather was diagnosed with metastatic melanoma in his 40 s. Genetic testing of the patient and her mother revealed CDKN2A c.301G>T mutation. She was referred to genetic counseling as well as to dermatology, gastroenterology, and neurology for cancer surveillance. She was treated with resections and has no evidence of disease 3 years after diagnosis. CONCLUSIONS: We report a family with a CDKN2A c.301 G>T mutation who also have significant history of OSCC, adding to the growing body of literature suggesting increased risk of HNSCC, particularly OSCC, in CDKN2A germline mutation carriers. It is important to consider CDKN2A mutation testing in familial HNSCC and young patients without obvious risk factors. Moreover, surveillance for HNSCC should be routine practice in those with a CDKN2A germline mutation.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Neoplasias Cutáneas , Adulto , Carcinoma de Células Escamosas/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Femenino , Mutación de Línea Germinal , Humanos , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/genética , Mutación , Recurrencia Local de Neoplasia , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
OBJECTIVE: This study aimed to develop a nomogram to predict the neck occult metastasis in early (T1-T2 cN0) oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The nomogram was developed in a training cohort of 336 early OSCC patients and was validated in a validation cohort including 88 patients. Independent predictors were calculated by univariate and multivariate logistic regression analyses. RESULTS: In univariate logistical regression analysis, gender, perineural invasion (PNI), blood vessel invasion, mean corpuscular hemoglobin, aspartate aminotransferase, prealbumin, globulin (GLO), lactate dehydrogenase (LDH), serum sodium (NA), and serum chloride were significant associated with neck occult metastasis. Multivariate logistical regression analysis identified PNI (p < .001), LDH (p = .003), GLO (p = .019), and NA (p = .020) as independent predictors of neck occult metastasis. Cut-off values for LDH, GLO, and NA obtained from AUC were 142.5, 26.35, and 139.5, respectively. The nomogram based on PNI and categorical GLO, LDH, and NA exhibited a strong discrimination, with a C-indexes of 0.748 (95%CI = 0.688 to 0.810) in the training cohort and 0.751 (95%CI = 0.639 to 0.863) in the validation cohort. CONCLUSIONS: A nomogram based on PNI, LDH, GLO, and NA for predicting the risk of neck lymph nodes occult metastasis in OSCC could help surgeons with therapy decision-making.
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Carcinoma de Células Escamosas , Globulinas , Neoplasias de la Boca , Metástasis de la Neoplasia , Carcinoma de Células Escamosas/patología , Humanos , L-Lactato Deshidrogenasa/sangre , Neoplasias de la Boca/patología , Invasividad Neoplásica , Estadificación de Neoplasias , Estudios Retrospectivos , Sodio/sangreRESUMEN
The development of new lymphatic tracers and the advancement of hybrid tracers, such as indocyanine green (ICG)-Nanocoll (GE Healthcare), represent an exciting step in the future of sentinel lymph node biopsy (SLNB). These tracers aim to improve our ability to detect sentinel lymph nodes by enhancing their localisation. The aim of this study was to assess the performance of a novel dual tracer, double injection technique of ICG-'cold'-Nanocoll and radiolabelled Nanocoll, in SLNB for early-stage oral cancer. A double injection technique was performed first using 99mTc-Nancoll prior to sentinel node imaging followed by ICG-'cold'-Nanocoll injection in theatre. Analysis involved examination of the number, labelling, and location of the nodes harvested, sentinel node status, survival analysis, false negative rate, and complications associated with use of the technique. ICG 'cold' Nanocoll results showed concordance of fluorescence and radioactivity detection in 74 nodes in 24 patients. Most importantly, all nodes found positive for metastasis (6 nodes) were discovered to be both 'hot' and fluorescent; 74 nodes removed were both 'hot' and fluorescent, eight fluorescent only and six 'hot' only. Our results indicate that two sets of tracer injections given at two different time points will flow to the same sentinel nodes. This double labelling increased our confidence that the retrieved node was a sentinel node.
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Neoplasias de la Boca , Ganglio Linfático Centinela , Colorantes , Humanos , Verde de Indocianina , Ganglios Linfáticos , Biopsia del Ganglio Linfático CentinelaRESUMEN
BACKGROUND: The metastasis of oral cancer is one of the main causes of death. However, the mechanisms underlying oral cancer metastasis have not been completely elucidated. Fermitin family member 1 (FERMT1) plays an -oncogene role in many cancers; however, the role of FERMT1 in oral squamous cell cancer (OSCC) remains unclear. METHODS: In this study, OSCC cells were treated with 5 ng/ml recombinant human Transforming growth factor-ß1 (TGF-ß1) protein. FERMT1 expression was measured in OSCC cell lines by RT-qPCR and western blotting. The effect of FERMT1 knockdown on the migration and invasion of OSCC cells was evaluated by Transwell assay. The epithelial-mesenchymal transition (EMT) and PI3K/AKT signaling pathway-related mRNA expression and protein levels were assessed by RT-qPCR and western blotting. RESULTS: We found that FERMT1 expression was elevated in TGF-ß1-induced OSCC cell lines, and knockdown of FERMT1 inhibited the migration and invasion in TGF-ß1-induced OSCC cells. FERMT1 silencing inhibited vimentin, N-cadherin, matrix metalloproteinase 9 (MMP-9) expression and promoted E-cadherin expression, suggesting that FERMT1 silencing inhibited EMT in TGF-ß1-induced OSCC cells. Furthermore, FERMT1 silencing inactivated the PI3K/AKT signaling pathway in TGF-ß1-induced OSCC cells. Activation of the PI3K/AKT signaling pathway reversed the effect of FERMT1 silencing on OSCC cell migration, invasion, and EMT. CONCLUSIONS: FERMT1 silencing inhibits the migration, invasion, and EMT of OSCC cells via inactivation of the PI3K/AKT signaling pathway, suggesting that FERMT1 is a novel and potential therapeutic target for anti-metastatic strategies for OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular , Células Epiteliales/metabolismo , Transición Epitelial-Mesenquimal , Humanos , Proteínas de la Membrana , Neoplasias de la Boca/genética , Proteínas de Neoplasias , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
BACKGROUND: Tongue squamous cell carcinoma (TSCC) is a common type of oral cancer, with a relatively poor prognosis and low post-treatment survival rate. Various strategies and novel drugs to treat TSCC are emerging and under investigation. Trichosanthin (TCS), extracted from the root tubers of Tian-Hua-Fen, has been found to have multiple biological and pharmacological functions, including inhibiting the growth of cancer cells. Granzyme B (GrzB) is a common toxic protein secreted by natural killer cells and cytotoxic T cells. Our group has reported that TCS combined with GrzB might be a superior approach to inhibit liver tumor progression, but data relating to the use of this combination to treat TSCC remain limited. The aim of this study was to examine the effectiveness of TCS on TSCC processes and underlying mechanisms. METHODS: First, we screened the potential antitumor activity of TCS using two types of SCC cell lines. Subsequently, a subcutaneous squamous cell carcinoma xenograft model in nude mice was established. These model mice were randomly divided into four groups and treated as follows: control group, TCS treatment group, GrzB treatment group, and TCS/GrzB combination treatment group. Various tumorigenesis parameters, such as Ki67, PCNA, caspase-3, Bcl-2 and VEGFA, et al., were performed to determine the effects of these treatments on tumor development. RESULTS: Screening confirmed that the SCC25 line exhibited greater sensitivity than the SCC15 line to TCS in vitro studies. TCS or GrzB treatment significantly inhibited tumor growth compared with the inhibition seen in the control group. The TCS/GrzB combination inhibited tumor growth more than either drug alone. TCS treatment inhibited tumor proliferation by downregulating Ki67 and Bcl2 protein expression while accelerating tumor apoptosis. In the TCS/GrzB-treated group, expression of Ki67 was further downregulated, while the level of activated caspase-3 was increased, compared with their expression in either of the single drug treatment groups. CONCLUSION: These results suggest that the TCS/GrzB combination could represent an effective immunotherapy for TSCC.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Granzimas/uso terapéutico , Neoplasias de la Lengua/tratamiento farmacológico , Tricosantina/uso terapéutico , Animales , Línea Celular Tumoral , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Bone destruction of maxillary and mandibular bone by invasive oral squamous cell cancer (OSCC) raises various problems in the management of patients, resulting in poor outcomes and survival. However, the mechanism behind bone destruction by OSCC remains unclear. High-mobility group box 1 (HMGB1), a highly conserved ubiquitous nuclear non-histone DNA-binding protein, has been demonstrated to be secreted by aggressive cancers and regulate osteoclastogenesis, a central player during bone destruction. We therefore reasoned that HMGB1 secreted by OSCCs contributes to bone destruction. Our results showed that HMGB1 is produced by human cell lines of OSCC and promotes osteoclastogenesis via up-regulation of the expression of receptor activator of nuclear factor kappa-Β ligand in osteoblasts and osteocytes, and consequently osteoclastic bone destruction in mice. Further, we found that these actions of HMGB1 are mediated via the receptor for advanced glycation end products and toll-like receptors. These findings suggest that HMGB1 of OSCC and its down-stream signal pathways are potential targets for the treatment of bone destruction associated with advanced OSCC.
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Huesos/patología , Proteína HMGB1/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Receptor Toll-Like 4/metabolismo , Animales , Benzamidas/farmacología , Resorción Ósea/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/patología , Humanos , Antígeno Ki-67/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Osteoblastos/efectos de los fármacos , Osteoblastos/metabolismo , Osteocitos/efectos de los fármacos , Osteocitos/metabolismo , Osteogénesis/efectos de los fármacos , Ligando RANK/metabolismo , Células RAW 264.7 , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Sulfonamidas/farmacología , Receptor Toll-Like 4/antagonistas & inhibidoresRESUMEN
Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-ß (TGF-ß) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-ß comprises three isoforms, TGF-ß1, -ß2, and -ß3, and transduces intracellular signals via TGF-ß type I receptor (TßRI) and TGF-ß type II receptor (TßRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TßRII (TßRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-ß ligands, but several lines of evidence indicate that TßRII-Fc more effectively traps TGF-ß1 and TGF-ß3 than TGF-ß2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-ß receptor containing both TßRI and TßRII (TßRI-TßRII-Fc) and found that TßRI-TßRII-Fc trapped all TGF-ß isoforms, leading to inhibition of both the TGF-ß signal and TGF-ß-induced EMT of oral cancer cells, whereas TßRII-Fc failed to trap TGF-ß2. Furthermore, we found that TßRI-TßRII-Fc suppresses tumor growth and angiogenesis more effectively than TßRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-ß expression. These results suggest that TßRI-TßRII-Fc may be a promising tool for targeting all TGF-ß isoforms in the TME.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Receptores Fc/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Animales , Carcinoma de Células Escamosas/metabolismo , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias de la Boca/metabolismo , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Receptores Fc/metabolismo , Receptores de Factores de Crecimiento Transformadores beta/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapéutico , Factor de Crecimiento Transformador beta/metabolismo , Microambiente TumoralRESUMEN
BACKGROUND: Local recurrence is the main cause of death among patients with oral squamous cell carcinoma (OSCC). This study assessed near-infrared fluorescence (NIF) imaging and spectroscopy to monitor surgical margins intraoperatively for OSCC. METHODS: Cytological and animal experiments were first performed to confirm the feasibility of monitoring surgical margins with NIF imaging and spectroscopy. Then, 20 patients with OSCC were included in the clinical trials. At 6-8 h after 0.75 mg/kg indocyanine green (ICG) injection, all patients underwent surgery with NIF imaging. During the surgery, both NIF images and quantified fluorescence intensity were acquired to monitor the surgical margins. RESULTS: In cytological and animal experiments, the results showed it was feasible to monitor surgical margins with NIF imaging and spectroscopy. Fluorescence was detected in primary tumors in all patients. The fluorescence intensities of the tumor, peritumoral, and normal tissues were 398.863 ± 151.47, 278.52 ± 84.89, and 274.5 ± 100.93 arbitrary units (AUs), respectively (P < 0.05). The SBR of tumor to peritumoral tissue and normal tissues was computed to be 1.45 ± 0.36 and 1.56 ± 0.41, respectively. After primary tumor excision, the wounds showed abnormal fluorescence in four patients (4/20), and residual cancer cells were confirmed by pathological examination in two patients (2/20). CONCLUSION: These findings confirmed the complementary value of NIF imaging during radical tumor resection of OSCC. Before tumor resection, we could utilize the fluorescence margin produced by ICG NIF imaging to determine the surgical margin. Moreover, after tumor blocks were removed, the status of surgical margin could also be evaluated rapidly by ICG NIF imaging of tumor bed and in vitro specimens.
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Neoplasias de la Boca/cirugía , Recurrencia Local de Neoplasia/prevención & control , Imagen Óptica/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Cirugía Asistida por Computador/métodos , Anciano , Animales , Línea Celular Tumoral , Colorantes/administración & dosificación , Femenino , Humanos , Verde de Indocianina/administración & dosificación , Masculino , Márgenes de Escisión , Ratones , Persona de Mediana Edad , Mucosa Bucal/diagnóstico por imagen , Mucosa Bucal/patología , Mucosa Bucal/cirugía , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/patología , Neoplasia Residual , Espectroscopía Infrarroja Corta/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/diagnóstico , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Oral squamous cell cancer (OSCC) is one of the causes of death worldwide. The purpose of this project was to define the restoring of microRNA-143 in HN-5 cells and discover molecular apparatuses responsible for the anticancer processes. Firstly, expression levels of miR-143, K-Ras, MMP9 and C-Myc were evaluated in OSCC tissues. Then, microRNA-143 was transfected into HN-5 cells. The cytotoxic effects of microRNA-143 on HN-5 cells were evaluated. To estimate the effects of microRNA-143 on cell migration, wound healing assay was done. The expression levels of microRNA-143, K-Ras, MMP9, C-Myc, ADAMTS and CXCR4 were evaluated via the qRT-PCR method. microRNA-143 mimic inhibited cell migration in HN-5 cell line. microRNA-143 mimic decreased K-Ras, MMP9, C-My, ADAMTS and CXCR4 gene expression. microRNA-143 can inhibit HN-5 cells migration in vitro by down-regulating the expression of invasion-linked genes. Hence, microRNA-143 can be a new diagnostic biomarker and new therapeutic target for OSCC.
Asunto(s)
MicroARNs/metabolismo , Neoplasias de la Boca/genética , Neoplasias de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Neoplasias de la Boca/metabolismo , Neoplasias de la Boca/patología , Metástasis de la Neoplasia , Neoplasias de Células Escamosas/metabolismo , Neoplasias de Células Escamosas/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , TransfecciónRESUMEN
Oral squamous cell carcinoma (OSCC) incidence is induced primarily by cigarette smoke (CS). The 5-year survival rate for advanced OSCC stands at only 20%. Studies exploring underlying mechanisms of OSCC development have suggested free radicals such as reactive oxygen species generated by CS as contributing to OSCC, with effects enhanced by transition metal ions iron and copper contained in the saliva. Located on the outer mitochondrial membrane of various cell types, the 18-kDa translocator protein (TSPO) is up-regulated under pathological conditions such as cancer and inflammation. We focused on studying the interaction between TSPO, CS, salivary effects, and OSCC. Increased TSPO expression in OSCC tumors correlates significantly with reduced patient survival rate, indicating the possible role of TSPO in OSCC pathogenesis. We speculate that TSPO in OSCC is dysfunctional or mutated, rendering it ineffective in promoting apoptosis and blocking malignant transformation. Basal, precancer lower function of TSPO may diminish the TSPO capacity for pro-apoptotic and anti-cancer activity, resulting in development of OSCC. In order to overcome this, TSPO over-expression is induced, unfortunately with no benefit, as it is a malfunctioning TSPO, similar to cases where over-expression of a mutated form of the p53 gene in tumors is associated with carcinogenesis.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias de la Boca/metabolismo , Receptores de GABA/metabolismo , Saliva/metabolismo , Fumar/efectos adversos , Carcinoma de Células Escamosas/patología , Humanos , Mitocondrias/efectos de los fármacos , Neoplasias de la Boca/patologíaRESUMEN
BACKGROUND: The eighth international symposium for sentinel node biopsy (SNB) in head and neck cancer was held in 2018. This consensus conference aimed to deliver current multidisciplinary guidelines. This document focuses on the surgical aspects of SNB for oral cancer. METHOD: Invited expert faculty selected topics requiring guidelines. Topics were reviewed and evidence evaluated where available. Data were presented at the consensus meeting, with live debate from panels comprising expert, nonexpert, and patient representatives followed by voting to assess the level of support for proposed recommendations. Evidence review, debate, and voting results were all considered in constructing these guidelines. RESULTS/CONCLUSION: A range of topics were considered, from patient selection to surgical technique and follow-up schedule. Consensus was not achieved in all areas, highlighting potential issues that would benefit from prospective studies. Nevertheless these guidelines represent an up-to-date pragmatic recommendation based on current evidence and expert opinion.
Asunto(s)
Ganglios Linfáticos/patología , Neoplasias de la Boca/cirugía , Estadificación de Neoplasias/métodos , Biopsia del Ganglio Linfático Centinela/normas , Humanos , Ganglios Linfáticos/fisiopatología , Neoplasias de la Boca/patología , Neoplasias de la Boca/radioterapia , Estadificación de Neoplasias/normas , Radioterapia AdyuvanteRESUMEN
OBJECTIVE: Greater time that patients take to present symptoms to health care providers (HCPs) increases the likelihood of later stage cancer, which increases mortality and morbidity in symptomatic cancers. The common-sense model (CSM) is used to understand time to first consultation with a healthcare provider, but inconsistencies exisy between its current use and important empirical findings. METHOD: To resolve inconsistencies, we conducted a qualitative examination to determine how the CSM could be revised to better account for these findings. We conducted in-depth interviews of a consecutive sample of 38 recently diagnosed patients who described events from first noticing symptoms to first consultation. Framework analysis was used to develop a theoretical model of processes leading to presentation or non-presentation. RESULTS: Patients reported median presentation times of 3-4â¯weeks. Early presentation was facilitated by pre-symptomatic perceptions of vulnerability to serious illnesses and beliefs that early intervention could mitigate illness. These patients rarely tried to identify symptoms. They responded inductively, seeking help because symptoms were unusual. Where patients did not describe pre-symptom perceptions of vulnerability, many deductively tried to identify symptoms but misattributed them to minor conditions. Pre-symptomatic perceptions of vulnerability could also prolong presentation. When vulnerability was characterized by intense fears of cancer and cancer treatment, patients tended to avoid thinking about symptoms which extended presentation time. CONCLUSION: Risk perception theories explain how participants' pre-symptomatic perceptions of vulnerability and potential treatment outcomes influence presentation time. Incorporating risk perception perspectives into the CSM can improve its ability explain responses to ambiguous symptoms.