DigitalUM :: Browsing by Subject "Squamous cell carcinoma"

Browsing by Subject "Squamous cell carcinoma"

Now showing 1 - 20 of 23

Open Access
A study of Ki-67, c-erbB2 and cyclin D-1 expression in CIN-I, CIN-III and squamous cell carcinoma of the cervix
(Murcia : F. Hernández, 2007) Carreras, R.; Alameda, F.; Mancebo, G.; García Moreno, Pedro; Mariñoso, M.L.M.; Costa, C.; Fusté, P.; Baró, Teresa; Serrano, S.
The histological criteria for cervical intraepithelial neoplastic lesions and their follow-ups have been established, but their reproducibility, specificity and sensibility are not certain. Immunohistochemical markers provide more information on each specific case, in order to facilitate its classification and, eventually, its prognosis. Using immunohistochemical techniques, this study analyzes the prognostic value of three markers (Ki-67, c-erbB2 and Cyclin D1) in cases of low grade squamous intraepithelial neoplasia (CIN-I), high grade squamous intraepithelial neoplasia (CIN-III), and infiltrating squamous cell carcinoma (SCC) taken from a group of cervical samples. In situ hybridization was performed in order to detect high-risk HPV. High risk HPV was demonstrated in 82%, 89% and 100% of the LGSIL, HGSIL and SCC cases, respectively. C-erbB2 expression was detected in 9%, 33% and 50% of the LSIL, HGSIL and SCC cases, respectively. The Ki-67 LI was 25%, 68% and 65.5% in the LGSIL, HGSIL and SCC cases, respectively. Nuclear Cyclin D1 expression was seen in 82%, 11% and 30% of the CINI, CIN-III and SCC cases, respectively. We observed that the cytoplasmic cyclin D1 expression increased with the severity of the lesion instead of the nuclear expression decreasing with the progression of the pathology. Nuclear and cytoplasmic Cyclin D1 expression seemed to be related to HPV high risk infection. We concluded that Cyclin D1, cerbB2 and The Ki- 67 LI expression changed in relation to the severity of the lesion and that they could be helpful in making a differential diagnosis.
Open Access
CDC28 protein kinase regulatory subunit 1B (CKS1B) expression and genetic status analysis in oral squamous cell carcinoma
(Murcia: Universidad de Murcia, Facultad de Biología, 2011) Martín-Ezquerra, Gemma; Salgado, Rocio; Toll, Agustí; Baró, Teresa; Mojal, Sergi; Yébenes, Mireia; Garcia-Muret, María Pilar; Solé, Francesc; Alameda Quitllet, Francesc; Espinet, Blanca; Pujol, Ramón M.
CKS1B is a member of the highly conserved cyclin kinase subunit 1 (CKS1) protein family which interacts with cyclin-dependent kinases and plays a critical role in cell cycle progression. In oral squamous cell carcinoma (OSCC), as in other malignancies, CKS1B overexpression has been correlated with reduced survival. To our knowledge, no studies evaluating the genetic status of CKS1B gene in OSCC have been reported. Herein, genetic and protein status of CKS1B were analyzed by immunohistochemical (IHC) and fluorescence in situ hybridization (FISH) techniques in a series of primary OSCC (n=51) and lymph node OSCC metastases samples (n=14). The observed results were compared with those obtained in either inflammatory (oral lichen planus [OLP]) (n=13) and premalignant oral mucosal lesions (oral leukoplakia) (n=16). A significant CKS1B overexpression was observed in OSCC and lymph node metastases samples than in OLP and oral leukoplakia (mean 70% vs 35%, p<0.001). CKS1B overexpression correlated with p27 loss of expression (p=0.0013) and SKP2 overexpression (p<0.00). FISH study disclosed statistical differences in both gene amplifications and gains between samples corresponding to OSCC and metastases from those of OLP and leukoplakia (p<0.001). Amplifications were present in 53% of OSCC samples and 33% of lymph node metastases vs 14% of oral leukoplakia and 0% of OLP biopsy specimens (p=0.002). Polysomies of chromosome 1 were seen in 46% of OSCC, 33% of ganglionar metastases, 14% of oral leukoplakia and 10% of OLP (p=0.036). Correlation of CKS1B overexpression and gains (both polysomies and amplifications) determined by FISH was statistically significant (p<0.001). Our results indicate that a high CKS1B expression is a common finding in primary OSCC which correlates with p27 low expression and SKP2 overexpression. This phenomenon may be due either to numerical (chromosome 1 polysomy) or structural (amplifications) CKS1B genetic abnormalities. This phenotypical and cytogenetic profile is not observed in premalignant or inflammatory oral mucosal lesions.
Open Access
Correlation of epithelial-mesenchymal transition markers with clinicopathologic parameters in adenocarcinomas and squamous cell carcinoma of the lung
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Kim, Seok-Hyung; Kim, Jin Man; Shin, Myeong-hee; Kim, Chul Woung; Huang, Song-Mei; Kang, Dong Wook; Suh, Kwang Sun; Yi, Eunhee S.; Kim, Kyung Hee
Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial cell junction proteins and the gain of mesenchymal markers. The aim of this study was to analyze the associations between the EMT-related markers vimentin, E-cadherin, ß-catenin, slug, snail, and twist1 and clinicopathologic parameters as well as epidermal growth factor receptor (EGFR) gene copy number and protein expression in non-small cell lung carcinoma (NSCLC). Fifty-nine squamous cell carcinomas (SCC) and 43 adenocarcinomas (AD) were immunohistochemically examined for respective EMT markers and for EGFR, using the EGFR PharmDx kit (Dako) for protein expression and automated silver enhanced in situ hybridization (SISH) for copy number. Vimentin expression in tumor epithelia was significantly higher in AD samples than in SCC samples (P=0.015). Among AD samples, vimentin expression was positively correlated with histologic grade (2 vs. 3; P=0.021) and exhibited a tendency toward a positive correlation with pTNM stage (I vs. II-IV; P=0.052). EGFR gene copy number was positively correlated with EGFR protein expression among both AD samples (P=0.008) and SCC samples (P=0.042), with EGFR protein expression being significantly higher in SCC samples compared with AD (P=0.038). Among AD samples, EGFR protein expression was associated with higher cytoplasmic expression of ß-catenin (P=0.031). Among SCC samples, EGFR protein expression was negatively correlated with nuclear expression of ß-catenin (P=0.033) but positively with nuclear slug (P=0.021). The expression pattern of EMT markers in AD suggests that vimentin is a possible immunohistochemical predictor of tumor progression
Open Access
Desmosomes in verrucous carcinoma of the head and neck
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Odar, Katarina; Zidar, Nina; Bonin, Serena; Gale, Nina; Cardesa, Antonio; Stanta, Giorgio
Verrucous carcinoma (VC) is a variant of squamous cell carcinoma (SCC), characterised by its inability to metastasize. In contrast, hybrid carcinomas, composed of VC and foci of conventional SCC, harbour a metastatic potential. Correct pathohistological diagnosis is therefore crucial for the choice of treatment. There is mounting evidence that desmosomes are involved in several aspects of carcinogenesis. Previous studies have shown an altered expression of desmosomal components in conventional SCC, which was associated with tumour behaviour, but no data have been found on desmosomes in VC. We therefore analysed the expression of desmosomal components in biopsy samples of 21 cases of VC and 5 cases of hybrid carcinoma of the head and neck in comparison to 23 cases of conventional SCC and 47 samples of normal squamous epithelium of similar localisation, using immunohistochemistry and real-time reverse-transcription polymerase chain reaction. We found that the expression patterns of desmosomal components in VC were fairly similar to those in normal epithelium but differed significantly from those in conventional SCC. Immunohistochemical reactions against desmosomal components disclosed the foci of SCC in hybrid carcinomas. In conclusion, we believe that expression patterns of desmosomal components in VC are consistent with its less aggressive behaviour. Differential expression of desmosomal components between VC and SCC makes some desmosomal components potentially useful in the diagnostics of VC, especially for the detection of hybrid carcinoma
Open Access
Diabetes enhances the expression of H-ras and suppresses the expression of EGFR leading to increased cell proliferation
(Murcia : F. Hernández, 2009) Vairaktaris, Eleftherios; Goutzanis, Lampros; Yapijakis, Christos; Vassiliou, Stavros; Spyridonidou, Sofia; Vylliotis, Antonis; Nkenke, Emeka; Lazaris, A. Ch.; Strantzias, Pashalis; Patsouris, Efstratios
EGFR kinase activity triggers numerous signaling pathways, such as the Ras/Raf/MAPK cascade, leading to the activation of various mitogen activated protein kinases, which are implicated in cell proliferation through induction of several genes, including c-fos. The possible effect of diabetes on the expression of the oncogenes EGFR, H-ras and c-fos was investigated in an experimental model of chemically induced oral oncogenesis in normal and diabetic (type I) Sprague- Dawley rats. Thirteen diabetic and twelve normal rats developed cancer after 4NQO treatment, while six diabetic and six normal animals were used as controls. The biopsies were classified pathologically (ranging from dysplasia to moderately differentiated oral squamous cell carcinoma) and were studied immunohistochemically. Several representative histological regions from each biopsy were analysed in regard to EGFR, H-ras and c-fos expression, and a comparison between normal and diabetic rats was effected. A trend of decreased EGFR expression in diabetic compared to normal rats was revealed throughout oncogenesis, which was significant in the stage of dysplasia (P<0.05). On the contrary, a trend of increased H-ras expression was observed in diabetic compared to normal rats during oncogenesis, which rose significantly in early invasion and well differentiated OSCC (P<0.001 and P<0.01 respectively). Finally, no statistical differences concerning c-fos expression were detected between diabetic and normal animals. In conclusion, it seems that diabetes reduces the expression of EGFR and initiates the Ras/Raf/MAPK signal transduction pathway by enhancing activation of other signalling molecules, such as the diabetes-associated Insulin Receptor Substrate-1, leading to increased cell proliferation without c-fos involvement.
Open Access
E-cadherin, β-catenin, and α2β1 and α3β1 integrin expression in primary oral squamous cell carcinoma and its regional metastasi
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Quirino Silveira Soares, Mariana; Andrade Mendonça, Juliana; Oliveira Morais, Marília; Rodrigues Leles, Claudio; Carvalho Batista, Aline; Mendonça, Elismauro Francisco
. To investigate E-cadherin, β-catenin, and α2β1 and α3β1 integrins in 40 samples of nonmetastatic and metastatic oral squamous cell carcinoma (OSCC) with positive cervical lymph nodes (LN). Immunohistochemistry was used to evaluate expression in the lesion center (LC) and invasive tumor front (ITF) of non-metastatic (n=18) and metastatic (n=22) OSCC and in the LN on the metastatic neoplastic cells (MNC; n=22). In metastatic OSCC, E-cadherin and β-catenin presented significantly lower cytoplasmic membrane expression in the ITF and MNC when compared to the LC and lower cytoplasmic expression in MNC when compared to the LC and ITF (p<0.05). Integrins α2β1 and α3β1 showed high cytoplasmic expression in the LC, ITF and MNC (p>0.05). A positive correlation was observed between E-cadherin cytoplasmic expression and α2β1 (ρ=0.860) and α3β1 (ρ=0.975) expression. When comparing the primary sites of metastatic and non-metastatic disease, β-catenin presented lower cytoplasmic membrane (p=0.013) expression in metastatic OSCC. E-cadherin presented low expression and the integrins high expression in both groups. Abnormal expression of β-catenin and E-cadherin associated with high expression of α2β1 and α3β1 integrins contribute to LN metastasis in OSCC.
Open Access
Eosinophil depletion protects mice from tongue squamous cell carcinoma induced by 4-nitroquinoline-1-oxide
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Silva, Janine Mayra da; Queiroz-Junior, Celso Martins; Batista, Aline Carvalho; Rachid, Milene Alvarenga; Teixeira, Mauro Martins; Silva, Tarcília Aparecida da
Aims: Tumor-associated tissue eosinophilia (TATE) has been correlated with prognosis in oral squamous cell carcinoma (OSCC). This study aimed to investigate whether eosinophils depletion affects experimental oral carcinogenesis. Methods and Results: BALB/c (wild type - WT) and eosinophil-deficient (Δdb/GATA-1) mice were treated with the carcinogen 4-nitroquinoline-1-oxide (4NQO) in drinking water for 28 weeks. Tongues were collected for histopathological and immunohistochemical analysis, as well as for the evaluation of cytokines/chemokines by ELISA. The tongue SCC induced by 4NQO was associated with a rise in eosinophil numbers. WT-treated group showed a significantly increased incidence of SCC, with higher cytological atypia, in comparison with Δdb/GATA-1 mice. Consistently, the proliferative index was higher in WT compared to the Δdb/GATA-1/GATA1-treated group. No significant changes in the concentration of CCL3, CCL11 and TNF-α were detected for both groups after 4NQO treatment. Conclusions: These results suggest that eosinophils might be responsible for the deleterious outcome of experimental tongue carcinogenesis, given that their ablation protects mice from OSCC.
Open Access
Expression and prognostic value of glucose transporters and hexokinases in tonsil and mobile tongue squamous cell carcinoma
(F. Hernández y J.F. Madrid. Murcia: Universidad de Murcia, Departamento de Biología Celular e Histología., 2011) Deron, Philippe; Vermeersch, Hubert; Mees, Gilles; Vangestel, Christel; Pauwels, Patrick; Van de Wiele, Christophe
The aim of this study was to assess the expression pattern and prognostic value of the high affinity glucose transporters GLUT-1, 3, 4, 8 and 9, SGLT-1 and of hexokinases (HK) I, II and III in squamous cell carcinoma of the tonsil and mobile tongue (TTSCC) by means of immunohistochemistry. Seventy-one consecutive patients suffering from TTSCC were included. The intensity and amount of positive tumour cells in the immunoreaction (histology score (H-score)) for GLUT-1, 3, 4, 8 and 9 as well as for HK-I, II and III were assessed independently by two experienced observers, blinded to the clinical results. H-scores as well as clinical variables were related to patient outcome. Median follow-up time was 49 months (range 1-123 months). Mean H-scores for GLUT expression in decreasing order of magnitude were respectively 10.99 for GLUT-1 (sd 3.9), 5.7 for GLUT-8 (sd 4.0), 5.4 for GLUT-3 (sd 3.7), 1.0 for GLUT-4 (sd 2.0), 1.1 (sd 1.3) for SGLT-1, and 0.4 for GLUT-9 (sd 0.6); GLUT-1 > GLUT-8 = GLUT-3 > GLUT-4 = GLUT-9 = SGLT-1 (with > meaning significantly (p<0.05 on ANOVA + posthoc Bonferroni correction) higher than and =, meaning not significantly different from). Mean H-scores for hexokinase expression were respectively 5.8 for HK-I (sd 3.5), 4.6 for HK-II (sd 3.0) and 2.0 for HK-III (sd 2.0); HK-I > HK-II > HK-III. Finally high H-scores for GLUT-4 were favourably related to disease-free and overall survival on multivariate analysis. To conclude, TTSCC expresses a wide variety of glucose transporter systems and hexokinase enzymes with the “housekeeping” GLUT-1 and HK-I being the most intensely expressed. GLUT-4 over-expression appears to confer a favourable prognosis in squamous cell carcinoma of the tonsil and mobile tongue. Additional studies confirming this finding in larger cohorts of patients are mandatory.
Open Access
Expression of desmosomal proteins in acantholytic squamous cell carcinoma of the skin
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Jurčić, Vesna; Kukovič, Jernej; Zidar, Nina
Acantholytic (adenoid) squamous cell carcinoma (ASCC) is a subtype of squamous cell carcinoma (SCC) in which neoplastic tumour cells form gland-like structures. Little is known about the pathogenetic mechanisms of ASCC. We hypothesised that they may be related to the compositon of desmosomes. We analysed the immunohistochemical expression of desmosomal proteins in 5 cases of ASCC of the skin, in comparison to 5 cases of conventional SCC of the skin. The most consistent findings were loss of desmoglein 1 (DSG 1), desmoglein 3 (DSG3), desmocollin 1 (DSC1), desmocollin 2 (DSC2), desmocollin 3 (DSC 3), and plakophilin 1 (PKP 1), and decreased expression of desmoplakin 1 (DP 1) and plakoglobin (PG). In conventional well to moderately differentiated SCC, the expression of desmosomal proteins was decreased, but membranous staining was mostly preserved with patterns similar to normal epidermis. Our results suggest that loss of desmosomal cadherins and decreased expression of desmosomal plaque proteins might be responsible for the formation of gland-like structures in ASCC. It seems that desmosomal cadherins, which correspond to the transmembrane core of desmosomes, are predominantly affected in ASCC, while DP 1 and PG, which correspond to cytoplasmic plaque of desmosomes, probably play a lesser role in maintenance of tumour cell cohesion. Our results also indicate that, in addition to previously described verrucous and spindle cell carcinoma, ASCC is another subtype of SCC with a characteristic expression pattern of desmosomal proteins.
Open Access
HSP 27 as possible prognostic factor in patients with oral squamous cell carcinoma
(Murcia : F. Hernández, 2004) Lo Muzio, L.; Leonardi, R.; Mariggiò, M.A.; Mignogna, M.D.; Rubini, C.; Vinella, A.; Pannone, G.; Giannetti, L.; Serpico, R.; Testa, N.F.; De Rosa, G.; Staibano, S.
HSP27 belongs to the Heat shock protein (HSP) family, which plays essential functions in cells under physiological conditions and prevents stressinduced cellular damage. The aim of this study was to investigate the biological role of HSP27 in oral tumorigenesis. Materials and methods: Seventy-nine cases of oral squamous cell carcinoma and 10 cases of normal mucosa were analysed for HSP27 expression by immunohistochemistry. Moreover, the western blot analysis was performed on two cases of normal mucosa and five cases of OSCC. Results: Normal oral mucosa showed a suprabasal expression of HSP27. Twenty-four cases of SCC (30.7%) showed a diffuse staining for HSP27, and 48 cases (60.3%) showed instead a decrease in staining, which was diffuse, homogeneous, or with alternation of positive and negative areas in a single tumor (“mosaic” pattern). Only 7 cases of OSCC (7.5%) were completely negative for HSP27. Frequency of lymph node metastases was higher in HSP27-negative tumours (3/7, 42.8%) than in HSP-reduced (16/48, 33.3%) or positive ones (5/26, 19.2%). Regard staging, stages I and II had a higher score than stages III and IV (stage I > stage II > stage III > stage IV). There was also a statistically significant correlation between HSP27 expression and grade: HSP27 expression was reduced in poorly differentiated tumours (P < 0.05). When analysed for prognostic significance, patients with negative/reduced HSP27 expression had poorer survival rates than the group with positive HSP27 expression (P < 0.05). The statistical analysis of these findings showed no significant correlation between HSP27 expression, sex, and tumour size. Conclusion: Cases with reduced expression were more aggressive and poorly differentiated. These data suggest that HSP27 expression may be useful in order to identify cases of oral squamous cell carcinoma with more aggressive and invasive phenotype providing novel diagnostic and prognostic information on individual patient survival with oral cancers.
Open Access
Human papillomavirus (HPV)-induced neoplasia in the urinary bladder: a missing link?
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2016) Alexander, Riley E.; Wang, Lisha; Lopez-Beltran, Antonio; Emerson, Robert E.; Montironi, Rodolfo; Pedrosa, Jose A.; Kaimakliotis, Hristos Z.; Koch, Michael O.; Cheng, Liang
The discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPVinduced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma.
Open Access
Immunohistochemical evaluation of EGFR expression in lip squamous cell carcinoma. Correlation with clinicopathological characteristics
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Carballeira, Alexo; Ginarte, Manuel; Diniz-Freitas, Marcio; Fernández-Campos, Inés; Gude, Francisco; Fraga, Maximo; Antúnez, José Ramón; García-Caballero, Tomás
Background: The majority of lip cancer is the squamous cell carcinoma (SCC) type that exhibits clinical and biological characteristics intermediate between skin and oral SCC. The aim of this study was to assess the impact of epidermal growth factor receptor (EGFR) expression on prognosis of lip squamous cell carcinoma (LSCC) and to relate it with clinicopathological features. The role of EGFR expression as a possible therapeutic target was also discussed. Methods: A series of 55 patients with LSCC was analyzed. EGFR expression was determined by standardized immunohistochemistry (pharmDx assay) and evaluated by both manual and automated image analysis (ACIS III). The Kappa statistic test was used to evaluate the concordance of manual and automated scores. EGFR results were correlated with clinicopathologic characteristics. Statistical differences between proportions were determined by the chi-squared test (with linear-by-linear correction where appropriate). The Mann-Whitney and the Kruskal-Wallis test were employed for comparison of continuous variables. Results: Correlation between manual and automated score was obtained in 50/55 cases (90.9%). EGFR expression was absent or weak in 14 cases (25.5%); borderline (2+) in 20 cases (36.4%) and positive (3+) in 21 cases (38.2%). Significant relationships were found between EGFR expression and tumour ulceration (p=0.022) and tumour thickness (p=0,002) and width (p=0.021). Conclusions: Our results revealed EGFR high expression in LSCC and its relationship with bad prognosis criteria (tumour size and ulceration).
Open Access
Langerhans cells in lichen sclerosus of the vulva and lichen sclerosus evolving in vulvar squamous cell carcinoma
(Murcia : F. Hernández, 2009) Raspollini, María Rosaria; Baroni, Gianna; Taddei, Gian Liugi
Vulvar lichen sclerosus (LS) represents a benign chronic inflammatory skin lesion that carries a risk for development of vulvar squamous cell carcinoma (SCC). We aimed at determining whether premalignant changes in vulvar LS, a multifactorial disease, presenting a welter of evidence implicating the immune system in its pathogenesis, could be identified by analysing the Langerhans’ cells (LCs), the primary cell responsible for antigen recognition and presentation. The relationship existing between inflammation and cancer due to chronic infection, and demonstrated in many solid tumors, led us to study LCs in eight cases of vulvar LS, which showed an evolution to carcinoma of the vulva and in ten cases of unchanged vulvar LS in matched patients by immunohistochemistry for antibodies CD1a and S100. We did not find a statistically significantly different number of LCs counted either in S100 stained specimens, nor in CD1a stained specimens of LS epithelium in unchanged or evolving cases. The data emerging in our study do not support the hypothesis that the variation in the number of LCs may be related to the development of SCC in late stage LS cases.
Open Access
Matrix metalloproteinases in squamous cell carcinoma
(Murcia : F. Hernández, 2000) Johansson, N.; Kahari, V.M.
Controlled degradation of extracellular matrix (ECM) is essential in many physiological situations including developmental tissue remodeling, angiogenesis, tissue repair, and normal turnover of ECM. In addition, degradation of matrix components is an important feature of tumor growth, invasion, metastasis, and tumor-induced angiogenesis. Matrix metallo-proteinases (MMPs) are a family of zincdependent neutral endopeptidases, which are collectively capable of degrading essentially all ECM components. MMPs apparently play an important role in all the above mentioned aspects of tumor development. In addition, there is recent evidence that MMP activity is required for tumor cell survival. At present, several MMP inhibitors are in clinical trials of malignant tumors of different histogenetic origin. In this review we discuss the current view on the role of MMPs and their inhibitors in development and invasion of squamous cell carcinomas, as a basis for prognostication and therapeutic intervention in these tumors.
Open Access
Multiple kallikrein (KLK 5, 7, 8, and 10) expression in squamous cell carcinoma of the oral cavity
(Murcia : F. Hernández, 2009) Pettus, Jason R.; Johnson, Jeffrey J.; Shi, Zonggao; Davis, J.Wade; Koblinski, Jennifer; Ghosh, Supurna; Liu, Yueying; Ravosa, Matthew J.; Frazier, Shellaine; Stack, M. Sharon
Oral squamous cell carcinoma (OSCC) represents 3% of all cancer deaths in the U.S. and is ranked one of the top 10 cancers worldwide. The 5-year survival rate has remained at a low 50% for the past several decades, necessitating discovery of novel biomarkers of aggressive disease and therapeutic targets. As overexpression of urinary type plasminogen activator and receptor (uPA/R) in OSCC is associated with malignant progression and poor outcome, cell lines were generated with either overexpression (SCC25-uPAR+) or silencing (SCC25-uPAR-KD) of uPAR. As SCC25- uPAR+ tumors behaved more aggressively both in vitro and in vivo, comparative cDNA microarray analysis was used to identify additional genes that may be associated with aggressive tumors. Four members of the human tissue kallikrein family (KLK 5, 7, 8, and 10) were identified and real-time RT-PCR (qPCR) was used to verify and quantify gene expression. qPCR analysis revealed 2.8-, 5.3-, 4.0-, and 3.5-fold increases in gene expression for KLK5, 7, 8, and 10, respectively, in SCC25-uPAR+ versus SCC25-uPAR-KD. Immunohistochemical analysis demonstrated strong reactivity for KLKs 5, 7, 8 and 10 in both orthotopic murine tumors and human OSCC tissues. Control experiments show lack of reactivity against KLK3 (prostate specific antigen). These results demonstrate that kallikreins 5, 7, 8, and 10 are abundantly expressed in human OSCC and may be implicated in malignant progression.
Open Access
Myeloid CD11c+ S100+ dendritic cells express indoleamine 2,3-dioxygenase at the inflammatory border to invasive lower lip squamous cell carcinoma
(Editores F. Hernandez y Juan F. Madrid. Murcia, Universidad de Murcia, Departamento de Biologia Celular e Histologia, 2011) Kuales, Melanie Alice; Wenzel, Jörg; Schmid-Wendtner, Monika-Hildegard; Bieber, Thomas; Bubnoff, Dagmar von
The prevalence of squamous cell carcinoma of the lower lip (SCC-LL) is increasing worlwide. The expression of the enzyme indoleamine 2,3-dioxygenase (IDO) by antigen-presenting cells and/or tumor cells leads to tumor escape by inhibiting T cell-mediated rejection responses. The aim of this study was to determine the expression of IDO in SCC-LL. IDOexpression was analyzed in 47 SCC-LL, together with the expression of markers of T-cells (CD3), myeloid DCs (S100, CD11c), macrophages (CD68, CD11c), Langerhans cells (CD1a, Langerin (CD207)), plasmacytoid DCs (CD123), and regulatory T cells (Foxp3) by immunohistochemistry and immunofluorescence analysis. Twelve specimens out of 47 LLSCCs contained cells that expressed IDO. IDO-positivity was strongly associated with the intensity of the cancerassociated infiltrate (P=0.0007). IDO-positive cells are located right along the border between the developing tumor and the inflammatory infiltrate. Immunofluorescence stainings showed that CD11c+S100+CD68- dendritic cells (DCs) express IDO in SCC-LL. IDO expression in LL-SCC may aid immune escape and chronic inflammation to promote cancer progression. Inhibition of IDO might be a therapeutic strategy to increase the anti-tumor immune response in SCC-LL.
Open Access
N-cadherin expression is involved in malignant behavior of head and neck cancer in relation to epithelial-mesenchymal transition
(Murcia: F. Hernández, 2011) Nguyen, Phuong Thao; Kudo, Yasusei; Yoshida, Maki; Kamata, Nobuyuki; Ogawa, Ikuko; Takata, Takashi
The loss of E-cadherin and the gain of Ncadherin expression are known as “cadherin switching”. Cadherin switching is a major hallmark of epithelialmesenchymal transition (EMT). EMT is a crucial process in cancer progression, providing cancer cells with the ability to escape from the primary focus, to invade stromal tissues and to migrate to distant regions. Although down-regulation of E-cadherin is well known in various cancers, there are a few studies on N-cadherin expression in cancer. Here, therefore, we investigated whether N-cadherin expression was associated with the progression of head and neck squamous cell carcinoma (HNSCC). First, we examined the expression of Ncadherin by immunohistochemistry and its correlation with clinico-pathological findings. High expression of N-cadherin was observed in 52 of 80 HNSCC cases and was significantly correlated with malignant behaviors. Next, we examined the correlation between N-cadherin and E-cadherin. Cadherin switching (high expression of N-cadherin and low expression of E-cadherin) was found in 30 of 80 HNSCC cases and was well correlated with histological differentiation, pattern of invasion and lymph node metastasis in HNSCC cases. Moreover, we examined the expression of N-cadherin and E-cadherin by RT-PCR in 16 HNSCC cell lines to confirm the immunohistochemical findings. N-cadherin expression was observed in 7 of 16 HNSCC cells, and cadherin switching was observed in 2 HNSCC cells. Interestingly, HNSCC cells with cadherin switching have EMT features. In conclusion, we suggest that i) N-cadherin may play an important role in malignant behaviors of HNSCC, and ii) cadherin switching might be considered as a discrete critical event in EMT and metastatic potential of HNSCC.
Open Access
Overexpression of γ-tubulin in non-small cell lung cancer
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2012) Maounis, Nicoletta F.; Dráberová, Eduarda; Mahera, Heleni; Chorti, María; Caracciolo, Valentina; Sulimenko, Tetyana; Riga, Dimitra; Trakas, Nikolaos; Emmanouilidou, Aphrodite; Giordano, Antonio; Dráber, Pavel; Katsetos, Christos D.
We and others have previously shown that increased expression and altered compartmentalization of γ-tubulin may contribute to tumorigenesis and tumor progression (J. Cell Physiol. 2009;223:519-529; Cancer Biol. Ther. 2010;9:66-76). Here we have determined by immunohistochemistry the localization and cellular distribution of γ-tubulin in clinical tissue samples from 109 non-small cell lung cancer (NSCLC) cases. The expression and distribution of γ-tubulin protein and transcripts was also determined in the NSCLC tumor cell lines NCI-H460 (HTB-177) and NCI-H69 (HTB-119) by immunocytochemistry, quantitative immunoblotting and reverse transcription quantitative real-time PCR (RT-qPCR). Polyclonal and monoclonal anti-peptide antibodies recognizing epitopes in the C- or N-terminal domains of γ-tubulins and human gene-specific primers for γ-tubulins 1 (TUBG1) and 2 (TUBG2) were used. In non-neoplastic cells of the airway epithelium in situ, γ-tubulin exhibited predominantly apical surface and pericentriolar localizations. In contrast, markedly increased, albeit heterogeneous and variously prominent γ-tubulin immunoreactivity was detected in clinical tumor specimens and in the NCI-H460 and NCI-H69 cell lines, where tumor cells exhibited overlapping multi-punctate and diffuse patterns of localization. Co-expression of γ-tubulin and Ki-67 (MIB-1) was detected in a population of proliferating tumor cells. A statistically significant increase of γ-tubulin expression was found in Stage III compared to lesser stage tumors (p<0.001 v. Stages I/II) regardless of histological subtype or grade. By quantitative immunoblotting NCI-H460 and NCI-H69 cells expressed higher levels of γ-tubulin protein compared to small airway epithelial cells (SAEC). In both tumor cell lines increase in TUBG1 and TUBG2 transcripts was detected by RT-qPCR. Our results reveal for the first time an increased expression of γ-tubulin in lung cancer
Open Access
Prognostic significance of nuclear and cytoplasmic expression of metallothioneins as related to proliferative activity in squamous cell carcinomas of oral cavity
(Murcia : F. Hernández, 2008) Szelachowska, Jolanta; Dziegiel, Piotr; Jelen-Krzeszewska, Joanna; Jelen, Michal; Tarkowski, Radoslaw; Wlodarska, Iwona; Spytkowska, Barbara; Gisterek, Iwona; Matkowski, Rafal; Kornafel, Jan
Metallothioneins (MT) are low molecular weight proteins with high metal and cystein contents. This study was designed to test the hypothesis that cytoplasmic and nuclear MT expression are of prognostic importance in patients with squamous cell carcinomas of the oral cavity, treated by surgery with subsequent radiotherapy. The second aim of the study was to test the potential correlation between the nuclear and cytoplasmic MT expressions as compared to expression of proliferation markers and other clinicopathological variables. Material and Methods: The studies were performed on tumor samples from 50 patients with diagnosis of squamous cell carcinoma of the oral cavity floor or of oral part of the tongue. All the patients were subjected to radical surgery, accompanied by removal of lymph nodes and post-operative radiotherapy. Results: No significant correlation could be detected between percentage and intensity of MT expression on one hand and proportions of cells with Mcm-2 (minichromosome maintenance protein 2), Ki-67 expressions, nor the grade of malignancy (G) on the other. A significantly shorter survival was detected among patients with tumors of MT expression rated 9 or 12 according to the Remmele scale and among patients with a high percentage (> 50%) of nuclear MT staining. In mulivariate analyses, only OTT (Overall Treatment Time), lymph node involvement and high expression of Mcm-2 were found to be independent risk factors for decreased patient’s survival. Conclusion: This is relevant evidence that MT overexpression could be related to worse prognosis in patients with oral cancer. We have found no relationship between MT expression and proliferative activity.
Open Access
Role of podoplanin expression in squamous cell carcinoma of upper aerodigestive tract
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Chuang, Wen-Yu; Chang, Yu-Sun; Yeh, Chi-Ju; Wu, Yi-Chin; Hsueh, Chuen
Podoplanin, a type-1 transmembrane glycoprotein, was originally named due to its expression in renal podocytes of rats. It was subsequently detected in a variety of normal human tissues, including lymphatic endothelium. Although podoplanin has been identified as the endogenous ligand of C-type lectin-like receptor 2 (CLEC-2) on platelets, its physiological functions and pathways remain largely unknown. A role in lymphangiogenesis has been suggested, since podoplanin-deficient mice were found to die at birth with a phenotype of dilated, malfunctioning lymphatic vessels and lymphedema. Podoplanin is invariably expressed in some tumors, such as lymphangioma, seminoma and follicular dendritic cell tumor, but tumor cell expression of podoplanin is highly variable in squamous cell carcinoma (SCC). It has been found that high podoplanin expression is associated with lymph node metastasis and poor prognosis in SCC of the upper aerodigestive tract. Now there is growing evidence that podoplanin is also involved in carcinogenesis, cell motility, tumor invasiveness, platelet aggregation and hematogenous metastasis. Additionally, animal studies confirmed some in vivo effects of podoplaninoverexpressing tumors, including formation of more tumor lymphatic vessels, larger lymph node metastases, more platelet aggregation, and more pulmonary metastases. Several recently developed anti-podoplanin antibodies, such as NZ-1, P2-0 and hP2-0, have been shown to attenuate podoplanin-induced platelet aggregation and prevent experimental hematogenous metastasis in nude mice. These antibodies may be applied in preclinical and clinical studies to evaluate the possibility of podoplanin-targeted therapy.