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Silveira FM, Schuch LF, Pereira-Prado V, Molina-Frechero N, Lopez-Verdin S, Gómez Palacio-Gastélum M, Arocena M, Niklander S, Sicco E, Bologna-Molina R. Hypoxia-inducible factor-1α at the invasive tumor front in oral squamous cell carcinoma. World J Exp Med 2025; 15:102175. [DOI: 10.5493/wjem.v15.i2.102175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 02/02/2025] [Accepted: 02/28/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Hypoxia in oral cancer promotes tumoral invasion by inducing epithelial-mesenchymal transition, leading to aggressive tumor progression.
AIM To characterize the expression of hypoxia-inducible factor 1-alpha (HIF-1α) at the invasive tumor front (ITF) in comparison to tumor islands (TI) in oral squamous cell carcinoma (OSCC) and to explore its relationship with E-cadherin and Vimentin expression.
METHODS Thirty-eight cases of OSCC and five cases of normal oral mucosa (NOM) were included in this study. The ITF was identified based on the region and immune expression of AE1/AE3. Immunohistochemistry was performed to assess the expression of HIF-1α, Vimentin, and E-cadherin. The immunostaining was analyzed using an immunoreactive score, and the results were illustrated using immunofluorescence.
RESULTS HIF-1α expression was significantly higher in the TI region compared to the ITF region (P = 0.0134). Additionally, a significant difference was observed between TI and NOM (P = 0.0115). In the ITF regions, HIF-1α expression showed a significant correlation with Vimentin expression, with higher levels of HIF-1α associated with increased Vimentin expression (P = 0.017).
CONCLUSION Based on the results of this study, HIF-1α appears to play a distinct role in OSCC tumor progression, underscoring the importance of exploring hypoxia-driven changes in cellular phenotype at the ITF of OSCC. Further research is needed to better understand their impact on OSCC prognosis.
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Affiliation(s)
- Felipe Martins Silveira
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Lauren Frenzel Schuch
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Vanesa Pereira-Prado
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Nelly Molina-Frechero
- Division of Biological and Health Sciences, Autonomous Metropolitan University, Coyoacan 04960, Mexico
| | - Sandra Lopez-Verdin
- Health Science Center, Research Institute of Dentistry, Universidad de Guadalajara, Guadalajara 44100, Jalisco, Mexico
| | | | - Miguel Arocena
- Departamento de Biología Odontológica, Facultad de Odontología, Universidad de la República, Montevideo 11600, Uruguay
| | - Sven Niklander
- Unit of Oral Pathology and Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar 2520000, Chile
| | - Estefania Sicco
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
| | - Ronell Bologna-Molina
- Molecular Pathology Area, Department of Diagnosis in Pathology and Oral Medicine, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
- Department of Research, Universidad Juarez del Estado de Durango, Durango 34000, Mexico
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Tkachev S, Brosalov V, Kit O, Maksimov A, Goncharova A, Sadyrin E, Dalina A, Popova E, Osipenko A, Voloshin M, Karnaukhov N, Timashev P. Unveiling Another Dimension: Advanced Visualization of Cancer Invasion and Metastasis via Micro-CT Imaging. Cancers (Basel) 2025; 17:1139. [PMID: 40227647 PMCID: PMC11988112 DOI: 10.3390/cancers17071139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/15/2025] Open
Abstract
Invasion and metastasis are well-known hallmarks of cancer, with metastatic disease accounting for 60% to 90% of cancer-related deaths [...].
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Affiliation(s)
- Sergey Tkachev
- Institute for Regenerative Medicine, Sechenov University, 119992 Moscow, Russia
| | | | - Oleg Kit
- National Medical Research Centre for Oncology, 344037 Rostov-on-Don, Russia
| | - Alexey Maksimov
- National Medical Research Centre for Oncology, 344037 Rostov-on-Don, Russia
| | - Anna Goncharova
- National Medical Research Centre for Oncology, 344037 Rostov-on-Don, Russia
| | - Evgeniy Sadyrin
- Laboratory of Mechanics of Biocompatible Materials, Don State Technical University, 344003 Rostov-on-Don, Russia
| | - Alexandra Dalina
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119334 Moscow, Russia
| | - Elena Popova
- Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies, 115682 Moscow, Russia
| | - Anton Osipenko
- Department of Pharmacology, Siberian State Medical University, 634050 Tomsk, Russia
| | - Mark Voloshin
- A.S. Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
| | - Nikolay Karnaukhov
- A.S. Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia
- Institute of Clinical Morphology and Digital Pathology, Sechenov University, 119991 Moscow, Russia
| | - Peter Timashev
- Institute for Regenerative Medicine, Sechenov University, 119992 Moscow, Russia
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O'Grady I, O'Sullivan J. Alcohol consumption modulates Candida albicans-induced oral carcinogenesis and progression. J Oral Biosci 2023; 65:293-304. [PMID: 37806338 DOI: 10.1016/j.job.2023.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 09/29/2023] [Accepted: 10/02/2023] [Indexed: 10/10/2023]
Abstract
OBJECTIVES This study aimed to determine the impact of low levels of alcohol consumption on the interaction of the oral cavity with Candida albicans, a species that is commonly found at higher levels in the oral cavities of regular alcohol consumers, patients with pre-malignant diseases, and patients with existing oral cancer (OC). METHODS The gingival squamous cell carcinoma cell line, Ca9-22, was subjected to low-level ethanol exposure before co-culture with heat-inactivated C. albicans (HICA). We performed cell viability assays, measured reactive oxygen species, and used Western blot analysis for cell death markers to examine the effect of ethanol and HICA on cells. Scratch assays and anchorage-independent growth assays were used to determine cell behavioral changes. RESULTS The results showed that ethanol in combination with HICA exacerbated cell death and cell cycle disruption, delayed NF-κB signaling, increased TIMP-2 secretion, and subsequently decreased MMP-2 secretion when compared to exposure to HICA alone. Conversely, both ethanol and HICA independently increased proliferation of Ca9-22 cells in scratch assays, and in combination, increased their capacity for anchorage-independent growth. CONCLUSION Low levels of ethanol may provide protective effects against Candida-induced inflammatory oral carcinogenesis or OC progression.
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Affiliation(s)
- Isabel O'Grady
- School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland.
| | - Jeff O'Sullivan
- School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland
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Hakim SG, Taubitz C, Hoppe S, Steller D, Rades D, Ribbat-Idel J, Alsharif U, Falougy M. Prognostic impact of the loss of E-cadherin and de novo expression of N-cadherin at the invasive front of primary and recurrent oral squamous cell carcinoma. Front Oncol 2023; 13:1151879. [PMID: 37265789 PMCID: PMC10231494 DOI: 10.3389/fonc.2023.1151879] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Accepted: 05/02/2023] [Indexed: 06/03/2023] Open
Abstract
The epithelial-mesenchymal transition (EMT) is a biological mechanism in multiple pathophysiological diseases. Related alterations in cadherin expression play a crucial role in carcinogenesis, progression, angiogenesis, and immune response. EMT cells exhibit a transition from an epithelial to a mesenchymal phenotype (cadherin-switch). This process is characterized by the de novo development of N-cadherin (N-CAD), which replaces E-cadherin (E-CAD) and signifies an increased migratory capacity and malignant transformation. The cadherin switch is a hallmark of EMT and has been studied in various cancer entities. We predicted that the cadherin switch in the primary and recurrent oral squamous cell carcinoma (re-OSCC) tissues is an inherent characteristic of the tumor, affects the biologic behavior, and further reflects the post-recurrence survival outcome of these patients. Survival outcome was analyzed by calculating the post-recurrence survival of the high-risk group and correlating the standardized h-score-based IHC expression of both cadherin types with the clinical follow-up. 94 patients with re-OSCC were observed within the cohort. Tissue samples from both primary and recurring tumors were collected. There was a significant association between loss of E-CAD expression and both oral cancer-specific and overall survival, (HR=2.72, CI:1.50-4.95, p=0.001) and (HR=3.84, CI:1.93-7.63, p=0.001), respectively, for expression loss higher than 60%. There was no statistically significant correlation between N-CAD de novo expression and Overall, oral cancer-specific and disease-free post-recurrence survival. The current study clearly shows that cadherin-switch, identified as E-CAD loss and N-CAD de novo expression in the invasion front of a re-OSCC, appears to be an inherent histological hallmark that does not change from primary manifestation to recurrence within the same tumor, regardless of the form of adjuvant therapy used for the primary tumor. The loss of E-CAD expression in re-OSCC is an independent risk factor for poor survival, and may be used to stratify therapy and de/escalate the multimodal treatment.
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Affiliation(s)
- Samer George Hakim
- Department of Oral and Maxillofacial Surgery, Head and Neck Cancer Center, University Hospital Schleswig-Holstein, Lübeck, Germany
- Department of Oral and Maxillofacial Surgery, Helios Medical Center, Schwerin, Germany
| | - Clara Taubitz
- Department of Oral and Maxillofacial Surgery, Head and Neck Cancer Center, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Steffen Hoppe
- Department of Oral and Maxillofacial Surgery, Head and Neck Cancer Center, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Daniel Steller
- Department of Oral and Maxillofacial Surgery, Head and Neck Cancer Center, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Dirk Rades
- Department of Radiation Oncology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Julika Ribbat-Idel
- Institute of Pathology, University Hospital Schleswig-Holstein, Lübeck, Germany
| | - Ubai Alsharif
- Department of Oral and Maxillofacial Surgery, Dortmund General Hospital, Dortmund, and Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Mohamed Falougy
- Department of Oral and Maxillofacial Surgery, Head and Neck Cancer Center, University Hospital Schleswig-Holstein, Lübeck, Germany
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Overexpression of E-Cadherin Is a Favorable Prognostic Biomarker in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. BIOLOGY 2023; 12:biology12020239. [PMID: 36829516 PMCID: PMC9953277 DOI: 10.3390/biology12020239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
Oral squamous cell carcinoma (OSCC) is characterized by poor survival, mostly due to local invasion, loco-regional recurrence, and metastasis. Given that the weakening of cell-to-cell adhesion is a feature associated with the migration and invasion of cancer cells, different studies have explored the prognostic utility of cell adhesion molecules such as E-cadherin (E-cad). This study aims to summarize current evidence in a meta-analysis, focusing on the prognostic role of E-cad in OSCC. To find studies meeting inclusion criteria, Scopus, Web of Science, EMBASE, Medline, and OpenGrey databases were systematically assessed and screened. The selection process led to 25 studies, which were considered eligible for inclusion in the meta-analysis, representing a sample of 2553 patients. E-cad overexpression was strongly associated with longer overall survival (OS) with Hazard Ratio (HR) = 0.41 95% confidence interval (95% CI) (0.32-0.54); p < 0.001 and disease-free survival with HR 0.47 95% CI (0.37-0.61); p < 0.001. In terms of OS, patients with tongue cancer experienced better survivability when expressing E-cad with HR 0.28 95% CI (0.19-0.43); p < 0.001. Globally, our findings indicate the prognostic role of the immunohistochemical assessment of E-cad in OSCC and its expression might acquire a different role based on the oral cavity subsites.
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An Overview of Epithelial-to-Mesenchymal Transition and Mesenchymal-to-Epithelial Transition in Canine Tumors: How Far Have We Come? Vet Sci 2022; 10:vetsci10010019. [PMID: 36669020 PMCID: PMC9865109 DOI: 10.3390/vetsci10010019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/31/2022] Open
Abstract
Historically, pre-clinical and clinical studies in human medicine have provided new insights, pushing forward the contemporary knowledge. The new results represented a motivation for investigators in specific fields of veterinary medicine, who addressed the same research topics from different perspectives in studies based on experimental and spontaneous animal disease models. The study of different pheno-genotypic contexts contributes to the confirmation of translational models of pathologic mechanisms. This review provides an overview of EMT and MET processes in both human and canine species. While human medicine rapidly advances, having a large amount of information available, veterinary medicine is not at the same level. This situation should provide motivation for the veterinary medicine research field, to apply the knowledge on humans to research in pets. By merging the knowledge of these two disciplines, better and faster results can be achieved, thus improving human and canine health.
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The Emerging Impact of Tumor Budding in Oral Squamous Cell Carcinoma: Main Issues and Clinical Relevance of a New Prognostic Marker. Cancers (Basel) 2022; 14:cancers14153571. [PMID: 35892830 PMCID: PMC9332070 DOI: 10.3390/cancers14153571] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/16/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
Tumor Budding (TB) represents a single cancer cell or a small cluster of less than five cancer cells on the infiltrative tumor front. Accumulating evidence suggests TB is an independent prognostic factor in oral squamous cell carcinoma (OSCC). However, its exact role is not yet elucidated, and a standardized scoring system is still necessary. The study aims to extensively review the literature data regarding the prognostic role of TB in OSCC. The results of TB are an independent prognostic factor of poor survival outcomes in OSCC. To date, the manual detection of hematoxylin and eosin-staining or pancytokeratin-immunostaining sections are the most commonly used methods. Between the several cut-offs, the two-tier system with five buds/field cut-offs provides better risk stratification. The prognostic role of the BD model in predicting survival outcomes was extensively validated; however, the inclusion of DOI, which is already a staging parameter, encouraged other authors to propose other models, integrating TB count with other adverse risk factors, such as the tumor–stroma ratio and tumor-infiltrated lymphocytes. The prognostic relevance of TB in OSCC highlights its evaluation in daily pathological practice. Therefore, the TB detection method and the TB scoring system should be validated based on tumor stage and site.
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Mascitti M, Togni L, Caponio C, Zhurakivska K, Lo Muzio L, Rubini C, Santarelli A, Troiano G. Prognostic significance of tumor budding thresholds in oral tongue squamous cell carcinoma. Oral Dis 2022. [PMID: 35316866 DOI: 10.1111/odi.14193] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 02/28/2022] [Accepted: 03/15/2022] [Indexed: 11/26/2022]
Abstract
Oral tongue squamous cell carcinoma (OTSCC) represents the most common malignancy of the oral cavity. Tumor budding (TB) is a reliable prognostic factor in OTSCC; however, a standardized scoring system is not still validated. The study aims to evaluate the prognostic role of TB in 211 OTSCC patients treated between 1997-2018. TB was evaluated on haematoxylin and eosin-stained sections in the hotspot area of the infiltrative front (×200-magnification). It was scored using a two-tier, a three-tier system, and according to BD-model and revised-Grading system. Univariate and multivariate Cox regression analyses of disease-specific survival (DSS) and disease-free survival (DFS) were performed. A p-values<0.05 was considered as statistically significant. The two-tier and three-tier system resulted an independent prognostic factor of DSS. High-risk patients had a 2.21 and 3.08 times-increased probability of poor DSS compared to low-risk group. It is significantly increased even for intermediate-risk group. No significant differences emerged classifying patients according to BD-model and revised-Grading. These data confirm the prognostic value of TB in predicting DSS in OTSCC. Classifying patients in two groups using the 5-buds cut-off significantly discriminates their outcomes. Since the established role of DOI and the poor prognostic value of grading, TB could be considered an independent prognostic marker.
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Affiliation(s)
- Marco Mascitti
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Lucrezia Togni
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Carlo Caponio
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | | | - Lorenzo Lo Muzio
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
| | - Corrado Rubini
- Department of Biomedical Sciences and Public Health, Marche Polytechnic University, Ancona, Italy
| | - Andrea Santarelli
- Department of Clinical Specialistic and Dental Sciences, Marche Polytechnic University, Ancona, Italy.,National Institute of Health and Science of Ageing, IRCCS INRCA, Ancona, Italy
| | - Giuseppe Troiano
- Department of Clinical and Experimental Medicine, Foggia University, Foggia, Italy
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Hu X, Chen S, Xie C, Li Z, Wu Z, You Z. DPP4 gene silencing inhibits proliferation and epithelial-mesenchymal transition of papillary thyroid carcinoma cells through suppression of the MAPK pathway. J Endocrinol Invest 2021; 44:1609-1623. [PMID: 33387351 DOI: 10.1007/s40618-020-01455-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 10/18/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Papillary thyroid carcinoma (PTC) is characterized by epithelial malignancy and is the most prevalent thyroid neoplasm with the best overall prognosis. Notably, recently published studies have indicated remarkably high expression of dipeptidyl peptidase 4 (DPP4) in PTC. However, the underlying molecular mechanism and regulatory factors of PTC progression remain unknown. Therefore, the current study aimed to elucidate the effects of DPP4 gene silencing on PTC and further investigated whether the mechanism of PTC progression is related to the mitogen-activated protein kinase (MAPK) pathway. METHODS Herein, microarray-based gene expression profiling of PTC was conducted to identify the differentially expressed genes between tumor thyroid tissue and normal thyroid tissue as well as the underlying signaling pathway involved in PTC pathogenesis. Moreover, protein quantification was performed to assess the protein expression of DPP4 in PTC tissues collected from 65 patients. In addition, DPP4 was silenced in PTC cell lines (GLAG-66 and TPC-1) through siRNA-mediated DPP4 knockdown or sitagliptin (inhibitor of DPP4)-mediated inhibition to assess the effects of DPP4 on the MAPK pathway and cellular processes, including proliferation, apoptosis, and epithelial-to-mesenchymal transition (EMT). RESULTS Intriguingly, our data revealed markedly high expression of DPP4 in PTC tissues. However, in GLAG-66 and TPC-1 cells, the silencing of DPP4 resulted in significantly reduced expression of ERK1/2, JNK1, P38 MAPK, VEGF, FGFR-1, TGF-β1, Snail, HIF-1α, N-cadherin, and Bcl-2 along with reduced phosphorylation of ERK1/2, JNK1, and P38 MAPK, whereas the expression of E-cadherin and Bax was increased. Furthermore, DPP4 silencing was found to hinder cell proliferation and potentiate cell apoptosis. CONCLUSION Collectively, the present study demonstrated that DPP4 gene silencing inhibits PTC cell proliferation and EMT and promotes cell apoptosis via suppression of the MAPK pathway, thus highlighting a possible regulatory pathway in PTC progression.
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Affiliation(s)
- X Hu
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China
| | - S Chen
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China
| | - C Xie
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China
| | - Z Li
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China
| | - Z Wu
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China
| | - Z You
- The First Department of General Surgery, Affiliated Dongguan People's Hospital, Southern Medical University (Dongguan People's Hospital), No. 3, Wandao Road South, Dongguan, 523059, Guangdong Province, People's Republic of China.
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de Lima MAP, Cavalcante RB, da Silva CGL, Nogueira RLM, Macedo GEC, de Galiza LE, Pinheiro JV, Maia Filho PHB, Santos SF, Rabenhorst SHB. Evaluation of HPV and EBV in OSCC and the expression of p53, p16, E-cadherin, COX-2, MYC, and MLH1. Oral Dis 2021; 28:1104-1122. [PMID: 33660890 DOI: 10.1111/odi.13814] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 02/09/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study aimed to evaluate the presence of human papillomavirus (HPV) and Epstein-Barr virus (EBV) and the expression of p53, p16, E-cadherin, COX-2, MLH1, and MYC in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS One hundred OSCC specimens were submitted to in situ hybridization for HPV and EBV, and immunohistochemistry for detection of the human proteins. RESULTS Thirty-one cases showed HPV in tumor tissue. EBV was not detected in any case investigated. The HPV(+) group demonstrated an increase of staining scores for nuclear p16 (p = .047), cytoplasmic MYC (p = .002), while a decrease for nuclear MLH1 (p = .048), suggesting that HPV may upregulate the expression of the first two proteins and down-regulate the latter. CONCLUSION Our findings reinforce the hypothesis of the HPV-related oral carcinogenesis involving the expression of p16 and MYC, and MLH1 suppression. Exclusively cytoplasmic stainings for p16, MLH1, and MYC were also associated with more advanced tumors. Finally, in view of the lack of studies correlating the HPV or EBV infection to the expression of oncoproteins, more researches assessing a broader panel of markers and employing different approaches are still necessary in order to understand the role of these viruses as well as the molecular mechanisms involved in the development and progression of oral carcinomas.
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López-Verdín S, Martínez-Fierro ML, Garza-Veloz I, Zamora-Perez A, Grajeda-Cruz J, González-González R, Molina-Frechero N, Arocena-Sutz M, Bologna-Molina R. E-Cadherin gene expression in oral cancer: Clinical and prospective data. Med Oral Patol Oral Cir Bucal 2019; 24:e444-e451. [PMID: 31256188 PMCID: PMC6667017 DOI: 10.4317/medoral.23029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 04/05/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Low protein expression of E-cadherin in oral squamous cell carcinoma (OSCC) has been associated with clinical and histopathological traits such as metastases, recurrence, low survival and poor tumor differentiation, and it is considered a high-risk marker of malignancy. However, it is still unknown whether low expression of E-cadherin is also present at the mRNA level in OSCC cases. OBJECTIVE The aim of this study was to compare E-cadherin mRNA expression in OSCC patients and controls and to correlate the expression with clinical and prospective characteristics. MATERIAL AND METHODS Forty patients and 40 controls were enrolled. E-cadherin mRNA expression was evaluated by quantitative real-time polymerase chain reaction using TaqMan probes. RESULTS E-cadherin mRNA expression was significantly decreased in OSCC patients compared to that of controls (p<0.001). Whereas no significant association between clinical parameters and E-cadherin expression levels was observed, we noted lower E-cadherin expression levels in patients with positive lymph node metastasis. CONCLUSIONS E-cadherin mRNA expression was markedly diminished in OSCC, in agreement with previous results that examined E-cadherin expression at the protein level. E-cadherin is downregulated in the early clinical stages of OSCC, and its mRNA levels do not change significantly in the advanced stages, suggesting that there is limited usefulness of this parameter for predicting disease progression.
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Affiliation(s)
- S López-Verdín
- Molecular Pathology, School of Dentistry Universidad de la República (UDELAR) Las Heras 1925, Montevideo, Uruguay
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Yazdani J, Ghavimi MA, Jabbari Hagh E, Ahmadpour F. The Role of E-Cadherin as a Prognostic Biomarker in Head and Neck Squamous Carcinoma: A Systematic Review and Meta-Analysis. Mol Diagn Ther 2019; 22:523-535. [PMID: 30006812 DOI: 10.1007/s40291-018-0351-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE In this study, we systematically investigated and analyzed articles focusing on the prognostic value of E-cadherin (E-cad) in human head and neck squamous cell carcinoma (HNSCC). METHODS Searching through the different databases, the studies examining the associations between E-cad and HNSCC prognosis were identified. Outcomes such as disease-specific survival and overall survival were considered acceptable. Hazard ratio (HR) with 95% confidence interval (CI) was used to demonstrate prognostic value. RESULTS A total of 40 studies were systematically analyzed, and finally, 1939 subjects were included in our meta-analysis. Our findings showed that significant aberrant expression of E-cad was associated with poor survival. However, some studies showed increased expression of E-cad in metastatic lesions was associated with poor prognosis. Alteration in location of E-cad expression also showed significant association with cancer survival, i.e., increased cytoplasmic E-cad. We conducted a meta-analysis on the eligible articles using a random effect model because of moderate heterogeneity. Strong association between aberrant expression of E-cad and poor survival was demonstrated (pooled HR = 2.28; 95% CI 1.78-2.91). CONCLUSIONS Aberrant expression of E-cad may be a promising prognostic signature for HNSCC, especially when it is used with other prognostic markers.
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Affiliation(s)
- Javad Yazdani
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran
| | - Mohhamad Ali Ghavimi
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran
| | - Elahe Jabbari Hagh
- Department of Internal Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzin Ahmadpour
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Tabriz University of Medical Sciences, Golgasht St., Tabriz, Iran.
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13
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Wei LY, Lee JJ, Yeh CY, Yang CJ, Kok SH, Ko JY, Tsai FC, Chia JS. Reciprocal activation of cancer-associated fibroblasts and oral squamous carcinoma cells through CXCL1. Oral Oncol 2019; 88:115-123. [DOI: 10.1016/j.oraloncology.2018.11.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/30/2018] [Accepted: 11/03/2018] [Indexed: 01/29/2023]
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14
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Ioannou M, Kouvaras E, Papamichali R, Samara M, Chiotoglou I, Koukoulis G. Smad4 and epithelial-mesenchymal transition proteins in colorectal carcinoma: an immunohistochemical study. J Mol Histol 2018; 49:235-244. [PMID: 29468299 DOI: 10.1007/s10735-018-9763-6] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 02/19/2018] [Indexed: 12/24/2022]
Abstract
Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. During EMT, tumor cells acquire the capacity to migrate and invade the stroma. Activation of the transforming growth factor-b (TGF-b) signaling pathway is of major importance for the initiation of EMT. Smad4, an essential protein of this pathway, is known to complex with multiple transcription factors (e.g. Snail-1, Slug, Twist-1), in various types of cancer, promoting the repression or activation of target genes. The role of Smad4 in colorectal cancer (CRC) is not straightforward so far. In the present study forty eight resected CRC tumor specimens were immunohistochemically examined in order to assess the expression of Smad4 and its association with E-cadherin, Snail-1, Slug, Twist-1 protein expression and with various pathological parameters. Smad4 was found to be positively correlated with Snail-1, Slug and Twist-1 expression (p < 0.001). On the other hand it was negatively correlated with the expression of E-cadherin (p < 0.001). Furthermore, lymphatic invasion could be clearly associated with Smad4 expression, a finding complying with the metastatic ability of EMT cells. In conclusion, Smad4 could be considered as a central component of EMT transition in human colorectal cancer that combines with transcriptional factors to reduce E-cadherin and alter the expression of the epithelial phenotype.
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Affiliation(s)
- M Ioannou
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece.
- Department of Pathology, School of Medicine, University of Thessaly, Biopolis, Larissa, 41110, Greece.
| | - E Kouvaras
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - R Papamichali
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - M Samara
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - I Chiotoglou
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
| | - G Koukoulis
- Department of Pathology, University of Thessaly, Biopolis, Larisa, 41110, Greece
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15
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Prgomet Z, Andersson T, Lindberg P. Higher expression of WNT5A protein in oral squamous cell carcinoma compared with dysplasia and oral mucosa with a normal appearance. Eur J Oral Sci 2017; 125:237-246. [PMID: 28603941 PMCID: PMC5519933 DOI: 10.1111/eos.12352] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
WNT5A is a secreted signaling protein that promotes migration and invasion of oral squamous cell carcinoma (OSCC) cells through activation of non‐canonical WNT signaling. Here, we examined expression of WNT5A, β‐catenin, and E‐cadherin by immunohistochemistry in 21 human diagnostic incision biopsies that each had regions of oral mucosa with a normal appearance adjacent to the affected tissue, dysplasia, and OSCC. We also investigated the effect of recombinant WNT5A (rWNT5A) on expression of the cell‐adhesion proteins E‐cadherin and β‐catenin by western blot analysis. No expression of WNT5A protein was present in oral mucosa with a normal appearance or in mild grade dysplasia. However, expression of WNT5A increased along with increasing grade of dysplasia, and the highest expression was detected in OSCCs. Expression of membranous β‐catenin and of E‐cadherin was lower, whereas expression of cytoplasmic β‐catenin was higher, in OSCCs than in non‐cancerous regions. However, there was no correlation between expression of WNT5A and expression of either β‐catenin or E‐cadherin. Furthermore, treatment of OSCC cells with rWNT5A had no effect on the expression of β‐catenin or E‐cadherin. Taken together with previous results, we conclude that WNT5A influences the progression of OSCC without affecting the canonical WNT/β‐catenin pathway and without down‐regulating E‐cadherin. WNT5A may have potential as a biological marker for malignant transformation of dysplasia to OSCC.
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Affiliation(s)
- Zdenka Prgomet
- Oral Pathology, Faculty of Odontology, Malmö University, Malmö, Sweden.,Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Tommy Andersson
- Cell and Experimental Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Pia Lindberg
- Oral Pathology, Faculty of Odontology, Malmö University, Malmö, Sweden
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16
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Nagamine E, Hirayama K, Matsuda K, Okamoto M, Ohmachi T, Uchida K, Kadosawa T, Taniyama H. Invasive Front Grading and Epithelial-Mesenchymal Transition in Canine Oral and Cutaneous Squamous Cell Carcinomas. Vet Pathol 2017; 54:783-791. [PMID: 28494700 DOI: 10.1177/0300985817707005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Oral and cutaneous tissues are the most frequent origin in canine squamous cell carcinoma (SSC). In SCC, changes in adhesion molecule expression and transition from epithelial to mesenchymal phenotype are thought to be important in development of invasive behavior of neoplastic cells at the leading front of the tumor. We therefore investigated histological invasive front grading and epithelial-mesenchymal transition (EMT) in both oral SCCs and cutaneous SCCs. EMT was assessed by evaluating immunohistochemical expression of E-cadherin, β-catenin, desmoglein, vimentin, and N-cadherin. Regardless of the anatomic location, invasive front grading resulted in higher histological grades than grading of the surface. Most oral SCCs were of significantly higher histologic grade than cutaneous SCCs ( P < .01). Expression of E-cadherin, β-catenin, and desmoglein was significantly lower in oral SCC compared with cutaneous SCC ( P < .01). A significant association was found between invasive front grading and loss of E-cadherin, β-catenin, and desmoglein ( P < .01). Also, vimentin-positive neoplastic cells had low immunoreactivity of these adhesion molecules, and a few of these neoplastic cells were positive for N-cadherin. These results suggest not only E-cadherin and β-catenin but also desmoglein as markers for predicting biological behavior of canine SCC. Depending on their primary sites, EMT correlates with biological behavior and therefore histological grade of canine SCC. We suggest that combining invasive front grading with assessment of immunohistochemical expression of E-cadherin, β-catenin, and desmoglein may allow more accurate prediction of biological behavior of canine SCCs.
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Affiliation(s)
- E Nagamine
- 1 Sanritsu Zelkova Veterinary Laboratory, Takatsu-ku, Kawasaki, Kanagawa, Japan
| | - K Hirayama
- 2 Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | - K Matsuda
- 2 Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | - M Okamoto
- 2 Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | | | - K Uchida
- 4 Department of Veterinary Pathology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - T Kadosawa
- 5 Department of Small Animal Clinical Sciences, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
| | - H Taniyama
- 2 Department of Veterinary Pathology, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu, Hokkaido, Japan
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17
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Wagner VP, Webber LP, Curra M, Klein IP, Meurer L, Carrad VC, Martins MD. Bryne's grading system predicts poor disease-specific survival of oral squamous cell carcinoma: a comparative study among different histologic grading systems. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 123:688-696. [PMID: 28411003 DOI: 10.1016/j.oooo.2017.02.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 02/10/2017] [Accepted: 02/20/2017] [Indexed: 11/30/2022]
Abstract
OBJECTIVES The aim of this study was to access the prognostic value of 4 histopathologic grading systems of oral squamous cell carcinoma (OSCC): The World Health Organization (WHO), Anneroth, Bryne (1989), and Bryne (1992). STUDY DESIGN Eighty-five cases of OSCC diagnosed between 1996 and 2010 at the Clinics Hospital of Porto Alegre (Porto Alegre, Brazil) were included. Slides stained with hematoxylin and eosin were obtained, and a histologic grade was assigned on the basis of the consensus of 3 expert oral pathologists, who were blinded to the clinicopathologic factors. Each system was correlated with proliferative labeling index, accessed through Ki67 immunostaining, clinicopathologic factors, patient outcome (alive or deceased), and survival time. RESULTS The increase in Bryne (1992) histologic grades was accompanied by an increase in proliferative labeling index. Moreover, this system was the only one associated with patient outcome (P = .01) and survival. Bryne (1992) grading system grade III tumors were associated with poor disease-specific survival according to univariate and multivariate cox regression analyses and the log-rank test (P < .05). The other systems evaluated presented no association with patients' outcome or survival. CONCLUSIONS The Bryne (1992) grading system is more effective in predicting survival in OSCC compared with the systems proposed by the WHO, Anneroth, or Bryne (1989).
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Affiliation(s)
- Vivian Petersen Wagner
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Liana Preto Webber
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Marina Curra
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Isadora Peres Klein
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Luise Meurer
- Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil; Department of Pathology, School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Vinicius Coelho Carrad
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil
| | - Manoela Domingues Martins
- Experimental Pathology Unit, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil; Department of Oral Pathology, School of Dentistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil.
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18
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Mahmood MQ, Ward C, Muller HK, Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med Oncol 2017; 34:45. [PMID: 28197929 DOI: 10.1007/s12032-017-0900-y] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 02/03/2017] [Indexed: 12/19/2022]
Abstract
NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of airway changes in clinical settings.
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Affiliation(s)
- Malik Quasir Mahmood
- NHMRC Centre for Research Excellence in Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, MS1, 17 Liverpool Street, Private Bag 23, Hobart, TAS, 7000, Australia
| | - Chris Ward
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Hans Konrad Muller
- NHMRC Centre for Research Excellence in Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, MS1, 17 Liverpool Street, Private Bag 23, Hobart, TAS, 7000, Australia
| | - Sukhwinder Singh Sohal
- NHMRC Centre for Research Excellence in Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, MS1, 17 Liverpool Street, Private Bag 23, Hobart, TAS, 7000, Australia.,Faculty of Health, School of Health Sciences, University of Tasmania, Launceston, TAS, 7248, Australia
| | - Eugene Haydn Walters
- NHMRC Centre for Research Excellence in Chronic Respiratory Disease and Lung Ageing, School of Medicine, University of Tasmania, MS1, 17 Liverpool Street, Private Bag 23, Hobart, TAS, 7000, Australia.
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19
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Chung YC, Wei WC, Hung CN, Kuo JF, Hsu CP, Chang KJ, Chao WT. Rab11 collaborates E-cadherin to promote collective cell migration and indicates a poor prognosis in colorectal carcinoma. Eur J Clin Invest 2016; 46:1002-1011. [PMID: 27696383 DOI: 10.1111/eci.12683] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 09/28/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Collective cell migration, whereby the cell-cell contacts such as E-cadherin are maintained during migration, has only recently emerged, and its detailed mechanisms are still unclear. In this study, the role of Rab11, which functions in recycling endosomes, and its relationship to E-cadherin in colorectal carcinoma were identified, and the role of Rab11 in the collective cell migration of colon cancer cells was clarified. MATERIALS AND METHODS A total of 107 patients with surgically resected colorectal carcinoma were enrolled in this immunohistochemical study. Relationships between the overexpression of Rab11 and E-cadherin and survival were evaluated. The cell biology of Rab11 overexpression or knock-down in HT-29 colon cells was studied. RESULTS The expression of Rab11 and E-cadherin was not correlated with the stage of cancer or lymph node metastasis. However, the overall survival was poor in the group of 67 patients with duo-positive Rab11 and E-cadherin expression compared to the group (40 patients) without dual-positive expression (P = 0·038). Rab11 was demonstrated to have a physical interaction with E-cadherin, and overexpression of Rab11 was found to promote collective cell migration through the increased distribution of E-cadherin, which enhanced cell-cell connections. In addition, Rac1 activation and matrix metalloproteinase-2 expressions were upregulated upon Rab11 expression. CONCLUSIONS This study demonstrated that Rab11 and E-cadherin expressions are indicators of poor survival time in colorectal carcinoma, but that Rab11 overexpression may contribute to increased collective cell invasion in colorectal carcinoma.
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Affiliation(s)
- Yuan-Chiang Chung
- Department of Surgery, Cheng-Ching General Hospital, Chung-Kang Branch, Taichung, Taiwan.,Department of Medicinal Botanicals and Health Applications, Da-Yeh University, Dacun, Changhua, Taiwan
| | - Wan-Chen Wei
- Department of Surgery, Cheng-Ching General Hospital, Chung-Kang Branch, Taichung, Taiwan.,Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Chia-Nung Hung
- Department of Life Science, Tunghai University, Taichung, Taiwan
| | - Jen-Fang Kuo
- Department of Pathology, Cheng-Ching General Hospital, Chung-Kang Branch, Taichung, Taiwan
| | - Chih-Ping Hsu
- Department of Medical Laboratory Science and Biotechnology, Yuanpei University, HsinChu, Taiwan
| | - King-Jen Chang
- Department of Surgery, Cheng-Ching General Hospital, Chung-Kang Branch, Taichung, Taiwan.,Department of Surgery, Taiwan Adventist Hospital, Taipei, Taiwan
| | - Wei-Ting Chao
- Department of Life Science, Tunghai University, Taichung, Taiwan
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20
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Parajuli H, Teh MT, Abrahamsen S, Christoffersen I, Neppelberg E, Lybak S, Osman T, Johannessen AC, Gullberg D, Skarstein K, Costea DE. Integrin α11 is overexpressed by tumour stroma of head and neck squamous cell carcinoma and correlates positively with alpha smooth muscle actin expression. J Oral Pathol Med 2016; 46:267-275. [PMID: 27699902 PMCID: PMC5396328 DOI: 10.1111/jop.12493] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/07/2016] [Indexed: 01/17/2023]
Abstract
Background Cancer‐associated fibroblasts (CAFs) were shown to be important for tumour progression in head and neck squamous cell carcinomas (HNSCCs). Their heterogeneity and lack of specific markers is increasingly recognized. Integrin α11 was recently shown to be expressed by CAFs and might serve as a specific CAF marker. Aim To investigate integrin α11 expression and its correlation with the expression of a well‐known marker of CAF, alpha smooth muscle actin (α‐SMA), in HNSCC. Methods Fresh frozen (FF) and formalin‐fixed paraffin‐embedded (FFPE) samples from healthy volunteers (n = 24), oral lichen planus (OLP) (n = 32) and HNSCC (n = 106) were collected together with clinical data after ethical approval. Immunohistochemistry to detect integrin α11 and α‐SMA was performed on FF and FFPE samples. qPCR for integrin α11 (ITGA11) and α‐SMA(ACTA2) was performed on FF samples. Data were analysed using chi‐square test and Kaplan–Meier survival analysis. Results Significantly higher levels of integrin α11 and α‐SMA at both protein and mRNA levels were found in HNSCC vs. normal controls and OLP. A strong correlation was found between integrin α11 and α‐SMA expression, and double staining showed their colocalization. Both integrin α11 and α‐SMA were detected surrounding metastatic islands. Expression of α‐SMA at tumour front but not tumour centre correlated with patient survival. Conclusion Integrin α11 was overexpressed in HNSCC stroma and colocalized with α‐SMA. Expression of α‐SMA at tumour front but not tumour centre had prognostic value for survival, pinpointing the importance of assessing tumour front when evaluating stromal molecules as prognostic biomarkers.
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Affiliation(s)
- Himalaya Parajuli
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway
| | - Muy-Teck Teh
- Centre for Clinical & Diagnostic Oral Sciences, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, London, UK
| | - Siren Abrahamsen
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway
| | - Ingrid Christoffersen
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway
| | - Evelyn Neppelberg
- Department of Oral Surgery, Institute of Clinical Dentistry, University of Bergen, Bergen, Norway.,Department of Maxillofacial Surgery, Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway
| | - Stein Lybak
- Department of Maxillofacial Surgery, Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway.,Department of Ear-Nose-and-Throat Surgery, Head and Neck Clinic, Haukeland University Hospital, Bergen, Norway
| | - Tarig Osman
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway
| | - Anne Chr Johannessen
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Donald Gullberg
- Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Biomatrix Research Group, Department of Biomedicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway
| | - Kathrine Skarstein
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Daniela Elena Costea
- Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Centre for Cancer Biomarkers (CCBIO), Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.,Department of Global Public Health and Primary Care, Centre for International Health, University of Bergen, Bergen, Norway.,Department of Pathology, Haukeland University Hospital, Bergen, Norway
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21
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Thangaraj SV, Shyamsundar V, Krishnamurthy A, Ramani P, Ganesan K, Muthuswami M, Ramshankar V. Molecular Portrait of Oral Tongue Squamous Cell Carcinoma Shown by Integrative Meta-Analysis of Expression Profiles with Validations. PLoS One 2016; 11:e0156582. [PMID: 27280700 PMCID: PMC4900586 DOI: 10.1371/journal.pone.0156582] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Accepted: 05/17/2016] [Indexed: 12/24/2022] Open
Abstract
Oral Tongue Squamous cell carcinoma (OTSCC), the most frequently affected oral cancer sub-site, is associated with a poor therapeutic outcome and survival despite aggressive multi- modality management. Till date, there are no established biomarkers to indicate prognosis and outcome in patients presenting with tongue cancer. There is an urgent need for reliable molecular prognostic factors to enable identification of patients with high risk of recurrence and treatment failure in OTSCC management. In the current study, we present the meta-analysis of OTSCC microarray based gene expression profiles, deriving a comprehensive molecular portrait of tongue cancer biology, showing the relevant genes and pathways which can be pursued further to derive novel, tailored therapeutics as well as for prognostication. We have studied 5 gene expression profiling data sets available on exclusively oral tongue subsite comprising of sample size; n = 190, consisting of 111 tumors and 79 normals. The meta- analysis results showed 2405 genes differentially regulated comparing OTSCC tumor and normal. The top up regulated genes were found to be involved in Extracellular matrix degradation (ECM) and Epithelial to mesenchymal transition (EMT) pathways. The top down regulated genes were found to be involved in detoxication pathways. We validated the results in clinical samples (n = 206), comprising of histologically normals (n = 10), prospective (n = 29) and retrospective (n = 167) OTSCC by evaluating MMP9 and E-cadherin gene expression by qPCR and immunohistochemistry. Consistent with meta-analysis results, MMP9 mRNA expression was significantly up regulated in OTSCC primary tumors compared to normals. MMP9 protein over expression was found to be a significant predictor of poor prognosis, disease recurrence and poor Disease Free Survival (DFS) in OTSCC patients. Analysis by univariate and multivariate Cox proportional hazard model showed patients with loss of E-cadherin expression in OTSCC tumors having a poorer DFS (HR = 1.566; P value = 0.045) and poorer Overall Survival (OS) (HR = 1.224; P value = 0.003) respectively. Combined over-expression of MMP9 and loss of E-cadherin membrane positivity in the invasive tumor front (ITF) of OTSCC had a significant association with poorer DFS (Log Rank = 16.040; P value = 0.001). These results suggest that along with known clinical indicators of prognosis like occult node positivity, assessment of MMP9 and E-cadherin expression at ITF can be useful to identify patients at high risk and requiring a more intensive treatment strategy for OTSCC. Meta-analysis study of gene expression profiles indicates that OTSCC is a disease of ECM degradation leading to activated EMT processes implying the aggressive nature of the disease. The triggers for these processes should be studied further. Newer clinical application with agents that can inhibit the mediators of ECM degradation may be a key to achieving clinical control of invasion and metastasis of OTSCC.
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Affiliation(s)
| | - Vidyarani Shyamsundar
- Centre for Oral Cancer Prevention Awareness and Research, Sree Balaji Dental College and Hospital, Chennai, India
| | | | - Pratibha Ramani
- Department of Oral and Maxillofacial Pathology, Saveetha Dental College, Saveetha University, Kumanchavadi, Chennai, India
| | - Kumaresan Ganesan
- Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Muthulakshmi Muthuswami
- Department of Genetics, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Vijayalakshmi Ramshankar
- Department of Preventive Oncology (Research), Cancer Institute (W.I.A.), Chennai, India
- * E-mail:
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22
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Siar CH, Rahman ZABA, Tsujigiwa H, Mohamed Om Alblazi K, Nagatsuka H, Ng KH. Invadopodia proteins, cortactin, N-WASP and WIP differentially promote local invasiveness in ameloblastoma. J Oral Pathol Med 2016; 45:591-8. [PMID: 26752341 DOI: 10.1111/jop.12417] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2015] [Indexed: 01/17/2023]
Abstract
BACKGROUND Cell migration and invasion through interstitial tissues are dependent upon several specialized characteristics of the migratory cell notably generation of proteolytic membranous protrusions or invadopodia. Ameloblastoma is a benign odontogenic epithelial neoplasm with a locally infiltrative behaviour. Cortactin and MMT1-MMP are two invadopodia proteins implicated in its local invasiveness. Other invadopodia regulators, namely N-WASP, WIP and Src kinase remain unclarified. This study addresses their roles in ameloblastoma. MATERIALS AND METHOD Eighty-seven paraffin-embedded ameloblastoma cases (20 unicystic, 47 solid/multicystic, 3 desmoplastic and 17 recurrent) were subjected to immunohistochemistry for expression of cortactin, N-WASP, WIP, Src kinase and F-actin, and findings correlated with clinicopathological parameters. RESULTS Invadopodia proteins (except Src kinase) and F-actin were widely detected in ameloblastoma (cortactin: n = 73/87, 83.9%; N-WASP: n = 59/87; 67.8%; WIP: n = 77/87; 88.5%; and F-actin: n = 87/87, 100%). Protein localization was mainly cytoplasmic and/or membranous, and occasionally nuclear for F-actin. Cortactin, which functions as an actin-scaffolding protein, demonstrated significantly higher expression levels within ameloblastoma tumoral epithelium than in stroma (P < 0.05). N-WASP, which coordinates actin polymerization and invadopodia-mediated extracellular matrix degradation, was overexpressed in the solid/multicystic subtype (P < 0.05). WIP, an upstream regulator of N-WASP, and F-actin were significantly upregulated along the tumour invasive front compared to tumour centres (P < 0.05). Except for males with cortactin overexpression, other clinical parameters (age, ethnicity and anatomical site) showed no significant correlations. CONCLUSIONS Present results suggest that local invasiveness of ameloblastoma is dependent upon the migratory potential of its tumour cells as defined by their distribution of cortactin, N-WASP and WIP in correlation with F-actin cytoskeletal dynamics.
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Affiliation(s)
- Chong Huat Siar
- Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Zainal Ariff Bin Abdul Rahman
- Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Hidetsugu Tsujigiwa
- Laboratory of Histopathology, Department of Life Science, Faculty of Science, Okayama University of Science, Okayama, Japan
| | - Kamila Mohamed Om Alblazi
- Department of Oro-Maxillofacial Surgical and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
| | - Hitoshi Nagatsuka
- Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kok Han Ng
- Unit of Stomatology, Cancer Research Centre, Institute for Medical Research, Kuala Lumpur, Malaysia
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Pereira CH, Morais MO, Martins AFL, Soares MQS, Alencar RDCG, Batista AC, Leles CR, Mendonça EF. Expression of adhesion proteins (E-cadherin and β-catenin) and cell proliferation (Ki-67) at the invasive tumor front in conventional oral squamous cell and basaloid squamous cell carcinomas. Arch Oral Biol 2016; 61:8-15. [DOI: 10.1016/j.archoralbio.2015.10.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 06/30/2015] [Accepted: 10/04/2015] [Indexed: 02/05/2023]
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24
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Costa LCMC, Leite CF, Cardoso SV, Loyola AM, Faria PRD, Souza PEA, Horta MCR. Expression of epithelial-mesenchymal transition markers at the invasive front of oral squamous cell carcinoma. J Appl Oral Sci 2015; 23:169-78. [PMID: 26018309 PMCID: PMC4428462 DOI: 10.1590/1678-775720140187] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 01/28/2015] [Indexed: 12/14/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignances. In epithelial-mesenchymal transition (EMT), epithelial cells switch to mesenchymal-like cells exhibiting high mobility. This migratory phenotype is significant during tumor invasion and metastasis.
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Affiliation(s)
| | - Camila Ferreira Leite
- Department of Dentistry, Pontifícia Universidade Católica de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Sérgio Vitorino Cardoso
- Laboratory of Oral and Maxillofacial Pathology, School of Dentistry, Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Adriano Mota Loyola
- Laboratory of Oral and Maxillofacial Pathology, School of Dentistry, Federal University of Uberlândia, Uberlândia, MG, Brazil
| | - Paulo Rogério de Faria
- Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, MG, Brazil
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25
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Udagawa H, Ishii G, Morise M, Umemura S, Matsumoto S, Yoh K, Niho S, Ohmatsu H, Tsuboi M, Goto K, Ochiai A, Ohe Y. Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung. J Cancer Res Clin Oncol 2015; 141:1417-25. [PMID: 25573625 DOI: 10.1007/s00432-015-1912-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 01/05/2015] [Indexed: 12/17/2022]
Abstract
PURPOSE Immunohistochemical analysis for the identification of clinically relevant biomarkers is important. However, there have been no detailed reports about the heterogeneous expressions of the various markers in squamous cell carcinoma of the lung. METHODS A total of 113 patients with squamous cell carcinoma of the lung with lymph node metastasis were included. The expression levels of 9 molecules (E-cadherin, S100A4, CD44, ALDH1, SOX2, EGFR, HER2, FGFR1 and VEGFR2) in the peripheral area and central area of primary tumor and metastatic lymph nodes were evaluated by immunohistochemistry. The differences in the staining scores of these molecules among the three areas were assessed. We also analyzed the relationships between the expression levels of these molecules and the recurrence-free survival. RESULTS The E-cadherin expression was higher in the central area than in the peripheral area and metastatic lymph nodes (median staining score: 60 vs. 50, 30); the CD44 expression was higher in the central area than in the metastatic lymph nodes (117 vs. 90); and the EGFR expression was higher in the central area than in the peripheral area and metastatic lymph nodes (163 vs. 130, 110). Low CD44 expression in the central area, low EGFR expression in the peripheral area and high SOX2 expression in the metastatic lymph nodes were associated with a shorter recurrence-free survival (p < 0.01, p = 0.02, p = 0.03, respectively). CONCLUSIONS Our findings confirmed that some molecular markers exhibited different expression levels in anatomically different areas and suggested that area-by-area immunohistochemical analysis for biomarkers may provide useful information for more precise prediction of the recurrence.
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Affiliation(s)
- Hibiki Udagawa
- Pathology Division, Department of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan
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26
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Abstract
Oral squamous cell carcinoma (OSCC) is an aggressive disease accounting for more than 260,000 cancer cases diagnosed and 128,000 deaths worldwide. A large majority of cancer deaths result from cancers that have metastasized beyond the primary tumor. The relationship between genetic changes and clinical outcome can reflect the biological events that promote cancer's aggressive behavior, and these can serve as molecular markers for improved patient management and survival. To this end, epithelial-mesenchymal transition (EMT) is a major process that promotes tumor invasion and metastasis, making EMT-related proteins attractive diagnostic biomarkers and therapeutic targets. In this study, we used immunohistochemistry to study the expression of a panel of transcription factors (TWIST1, SNAI1/2, ZEB1 and ZEB2) and other genes intimately related to EMT (CDH1 and LAMC2) at the invasive tumor front of OSCC tissues. The association between the expression of these proteins and clinico-pathological parameters were examined with Pearson Chi-square and correlation with survival was analyzed using Kaplan Meier analysis. Our results demonstrate that there was a significant differential expression of CDH1, LAMC2, SNAI1/2 and TWIST1 between OSCC and normal oral mucosa (NOM). Specifically, CDH1 loss was significantly associated with Broder's grading, while diffused LAMC2 was similarly associated with non-cohesive pattern of invasion. Notably, co-expression of TWIST1 and ZEB2 in OSCC was significantly associated with poorer overall survival, particularly in patients without detectable lymph node metastasis. This study demonstrates that EMT-related proteins are differentially expressed in OSCC and that the co-expression of TWIST1 and ZEB2 could be of clinical value in identifying patients with poor survival for appropriate patient management.
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27
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Suresh TN, Hemalatha A, Harendra Kumar ML, Azeem Mohiyuddin SM. Evaluation of histomorphological and immunohistochemical parameters as biomarkers of cervical lymph node metastasis in squamous cell carcinoma of oral cavity: A retrospective study. J Oral Maxillofac Pathol 2015; 19:18-24. [PMID: 26097301 PMCID: PMC4451659 DOI: 10.4103/0973-029x.157195] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 04/01/2015] [Indexed: 12/17/2022] Open
Abstract
Introduction: Oral squamous cell carcinoma (OSCC) is seen worldwide but is more common in India. Lymph node (LN) metastasis has been shown to be the strongest prognostic factor in OSCC. Many histopathological and immunohistochemical markers have been studied to predict the LN metastasis. Aims: To identify clinicopathological factors and immunohistochemical (IHC) biomarkers which predict cervical metastasis in OSCC patients. Study and Design: A total of 105 cases of OSCC were taken up for our study. Histopathological parameters such as tumor thickness, depth, degree of differentiation, pattern of invasion (POI), lymphovascular and neural invasion were assessed. IHC was done on all cases using antibodies against Ki-67, cyclin D, E-cadherin, p53, CD31 and each antibody was assessed according to the standard protocol. Statistical Analysis: To calculate the relation between clinical, histopathological parameter, IHC marker and the occurrence of LN metastasis, chi-square test was used. Variables were tested using multivariate logistic regression method to assess the predictive significance. Results: Out of 105 cases studied, 29 cases showed LN metastasis. Maximum numbers of cases affected were females with involvement of buccal mucosa. We found significant association of cervical LN metastasis with high grade of differentiation, lack of E-cadherin expression, high Ki-67 and cyclin D1 expression. In our study; tumor depth, thickness, extent of peritumoral lympho-plasmacytic infiltration, presence of eosinophils, tumor nest type, p53 and microvessel density (MVD) showed no significant correlation. Conclusion: Significant association of cervical LN metastasis with high grade of differentiation, lack of E-cadherin expression, high Ki-67 and cyclin D1 expression was seen.
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Affiliation(s)
- T N Suresh
- Department of Pathology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research Center, Kolar, Karnataka, India
| | - A Hemalatha
- Department of Pathology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research Center, Kolar, Karnataka, India
| | - M L Harendra Kumar
- Department of Pathology, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research Center, Kolar, Karnataka, India
| | - S M Azeem Mohiyuddin
- Department of Pathology, Ear, Nose and Throat, Head and Neck Surgery, Sri Devaraj Urs Medical College, Sri Devaraj Urs Academy of Higher Education and Research Center, Kolar, Karnataka, India
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Jensen DH, Reibel J, Mackenzie IC, Dabelsteen E. Single cell migration in oral squamous cell carcinoma - possible evidence of epithelial-mesenchymal transition in vivo. J Oral Pathol Med 2015; 44:674-9. [PMID: 25880532 DOI: 10.1111/jop.12321] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND The invasion of cancer cells into the surrounding normal tissue is one of the defining features of cancer. While the phenomena of tumour budding, epithelial-mesenchymal transition and the presence of myofibroblasts have independently been shown to be related to a poor prognosis of oral carcinomas, their relationship has not been examined in detail. METHODS Paraffin-embedded tissues from 28 patients with oral squamous cell carcinomas were stained with antibodies to cytokeratin, α-SMA, vimentin, E-cadherin, N-cadherin and Twist and evaluated for their expression in relation to invasive cancer cells and the surrounding tumour stroma. RESULTS AND CONCLUSIONS A direct, histological relationship between invading, budding tumour cells and myofibroblasts was occasionally seen but was not a general feature. Most of the budding tumour cells at the invasive front had a decreased expression of E-cadherin, but we did not find that this was associated with a consistent or clear increase in either N-cadherin or vimentin. We therefore suggest that the budding of tumour cells is not dependent upon either myofibroblasts or a complete epithelial-mesenchymal transition and that these phenomena most likely represent separate processes in tumour progression.
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Affiliation(s)
- David H Jensen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | - Jesper Reibel
- Oral Pathology and Oral Medicine, Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ian C Mackenzie
- Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Erik Dabelsteen
- Department of Odontology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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29
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Böhrnsen F, Fricke M, Sander C, Leha A, Schliephake H, Kramer FJ. Interactions of human MSC with head and neck squamous cell carcinoma cell line PCI-13 reduce markers of epithelia-mesenchymal transition. Clin Oral Investig 2014; 19:1121-8. [DOI: 10.1007/s00784-014-1338-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 10/14/2014] [Indexed: 11/28/2022]
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30
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Mehendiratta M, Solomon MC, Boaz K, Guddattu V, Mohindra A. Clinico-pathological correlation of E-cadherin expression at the invasive tumor front of Indian oral squamous cell carcinomas: An immunohistochemical study. J Oral Maxillofac Pathol 2014; 18:217-22. [PMID: 25328302 PMCID: PMC4196290 DOI: 10.4103/0973-029x.140753] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 07/07/2014] [Indexed: 02/03/2023] Open
Abstract
Background: Recent studies have indicated that although malignant cells at the invasive tumor front, bare morphological resemblance to the cells at central portion of the tumor, their molecular character differs significantly. E-cadherin is a cell-cell adhesion molecule that connects epithelial cells. This study attempts to correlate the E-cadherin expression at the invasive tumor front with tumor differentiation along with its clinico-pathological parameters. Materials and Methods: Immunohistochemical staining with E-cadherin was carried out on archival cases of primary oral squamous cell carcinomas (n = 30). The E-cadherin expression at the invasive tumor front was analyzed and was linked to clinico-pathological parameters including patient prognosis. Results: The downregulation of E-cadherin expression at the invasive tumor edge when compared with patient's prognosis yielded a significant correlation (P = 0.041) but its correlation with the degree of differentiation determined was not significant (P = 0.27). Also, its association with tumor size and lymph node status was negative. Conclusions: Loss of E-cadherin expression at the invasive tumor front is an important event in the progression of oral squamous cell carcinomas. Tumors with a loss of expression of E-cadherin are those which had a poor prognosis
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Affiliation(s)
- Monica Mehendiratta
- Department of Oral Pathology, Sudha Rustagi Dental College, Faridabad, Haryana, India
| | | | - Karen Boaz
- Department of Oral Pathology, Manipal College of Dental Sciences, Mangalore, India
| | - Vasudeva Guddattu
- Department of Biostatistics, Manipal University, Manipal, Karnataka, India
| | - Aashima Mohindra
- Department of Oral Pathology, Manipal College of Dental Sciences, Mangalore, India
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31
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Almangush A, Salo T, Hagström J, Leivo I. Tumour budding in head and neck squamous cell carcinoma - a systematic review. Histopathology 2014; 65:587-94. [PMID: 24897954 DOI: 10.1111/his.12471] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2014] [Accepted: 06/02/2014] [Indexed: 12/11/2022]
Abstract
Tumour budding is a specific type of invasive growth in carcinomas characterized by invading single tumour cells or small clusters of tumour cells (<5 cells) at the invasive front (IF). It has been documented in numerous publications during the past few decades, but its value as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) has been analysed only recently. In this review we aimed to address the question of whether or not tumour budding has an impact upon the progression and prognosis of HNSCC. We systematically reviewed the databases of PubMed, Scopus and Web of Science for articles that studied tumour budding in squamous cell carcinoma of the head and neck region. The search was limited to articles published in the English literature before March 2014. A total of 122 hits were retrieved; however, only five reports met the inclusion criteria. The findings of these reports suggested a strong association between tumour budding and tumour progression, in addition to strong correlation with patient prognosis. Standardization of the scoring method and the risk stratification cut-off point is necessary before the inclusion of tumour budding in pathological reports during daily practice.
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Affiliation(s)
- Alhadi Almangush
- Department of Pathology, Haartman Institute, University of Helsinki, Helsinki, Finland; Institute of Dentistry, University of Misurata, Misurata, Libya
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32
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Siar CH, Ishak I, Ng KH. Podoplanin, E-cadherin, β-catenin, and CD44v6 in recurrent ameloblastoma: their distribution patterns and relevance. J Oral Pathol Med 2014; 44:51-8. [DOI: 10.1111/jop.12203] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/08/2014] [Indexed: 01/08/2023]
Affiliation(s)
- Chong Huat Siar
- Department of Oro-Maxillofacial Surgical and Medical Sciences; Faculty of Dentistry; University of Malaya; Kuala Lumpur Malaysia
| | - Ismadi Ishak
- Department of Oro-Maxillofacial Surgical and Medical Sciences; Faculty of Dentistry; University of Malaya; Kuala Lumpur Malaysia
| | - Kok Han Ng
- Formerly; Unit of Stomatology; Cancer Research Centre; Institute for Medical Research; Kuala Lumpur Malaysia
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Balasundaram P, Singh MK, Dinda AK, Thakar A, Yadav R. Study of β-catenin, E-cadherin and vimentin in oral squamous cell carcinoma with and without lymph node metastases. Diagn Pathol 2014; 9:145. [PMID: 25047112 PMCID: PMC4223686 DOI: 10.1186/1746-1596-9-145] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Accepted: 02/09/2014] [Indexed: 11/24/2022] Open
Abstract
Abstract Virtual slides The virtual slide(s) for this article can be found here:
http://www.diagnosticpathology.diagnomx.eu/vs/6506095201182002.
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Affiliation(s)
| | - Manoj Kumar Singh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
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34
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Niwa Y, Yamada S, Koike M, Kanda M, Fujii T, Nakayama G, Sugimoto H, Nomoto S, Fujiwara M, Kodera Y. Epithelial to mesenchymal transition correlates with tumor budding and predicts prognosis in esophageal squamous cell carcinoma. J Surg Oncol 2014; 110:764-9. [PMID: 24975035 DOI: 10.1002/jso.23694] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 05/14/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES Epithelial to mesenchymal transition (EMT) is considered to play an important role in cancer invasion. Tumor budding is a prognostic factor in esophageal squamous cell carcinoma (ESCC). The aim of this study was to explore the correlation between EMT and tumor budding. METHODS Surgical specimens from 78 cases of ESCC resected without preoperative treatment between 2001 and 2013 were enrolled in the study. The mRNA expressions of E-cadherin and vimentin were measured in cancerous tissues using real-time PCR, and each tumor was classified into either epithelial or mesenchymal group. Tumor budding was evaluated in H&E-stained slides and divided into two groups; low-grade budding (<3) and high-grade budding (≥3). RESULTS The 5-year survival rate in the epithelial group was significantly higher than that in the mesenchymal group (62.0% vs. 31.5%, P = 0.021). Survival rate of patients in the low-grade budding group was significantly higher than that of patients in the high-grade budding group (75.1% vs. 25.9%, P < 0.001). High-grade tumor budding was significantly associated with the mesenchymal group (P = 0.009). CONCLUSION EMT was found to occur in ESCC and was significantly associated with tumor budding. Tumor budding was identified as a significant independent prognostic factor among the current population of ESCC.
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Affiliation(s)
- Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Sharma M, Sah P, Sharma SS, Radhakrishnan R. Molecular changes in invasive front of oral cancer. J Oral Maxillofac Pathol 2014; 17:240-7. [PMID: 24250086 PMCID: PMC3830234 DOI: 10.4103/0973-029x.119740] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Treatment planning for oral squamous cell carcinoma (OSCC) is based on the clinical TNM (Tumor, Node and Metastasis) classification. This system operates on the assumption that small tumours without clinical spread have a better prognosis than larger tumours with metastases. However, it is a well-known fact that some tumours with the same clinical staging show different growth patterns and clinical behaviour. This makes the prognosis for patients with OSCC difficult to predict on the basis of clinical staging alone. Although many histopathological characteristics of OSCC have been identified as prognostic factors, none is believed to be completely infallible. Therefore, a great need exists for more reliable prognostic markers, which will assist in treatment decisions. It is now well documented that several molecular events of significance for tumour spread, such as gain and loss of adhesion molecules, secretion of proteolytic enzymes, increased cell proliferation and initiation of angiogenesis occur at the tumour–host interface or invasive front, where the deepest and presumably most aggressive cells reside. This review describes the various molecular events and interactions, which take place in the invasive front of the OSCC, and elucidates their role as prognostic markers.
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Affiliation(s)
- Mohit Sharma
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Bareilly, Uttar Pradesh, India
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36
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Rivera C, Venegas B. Histological and molecular aspects of oral squamous cell carcinoma (Review). Oncol Lett 2014; 8:7-11. [PMID: 24959211 PMCID: PMC4063640 DOI: 10.3892/ol.2014.2103] [Citation(s) in RCA: 137] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 02/13/2014] [Indexed: 12/12/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) represents 95% of all forms of head and neck cancer, and over the last decade its incidence has increased by 50%. Oral carcinogenesis is a multistage process, which simultaneously involves precancerous lesions, invasion and metastasis. Degradation of the cell cycle and the proliferation of malignant cells results in the loss of control mechanisms that ensure the normal function of tissues. The aim of the current review is to present the histopathological features of OSCC, including potentially malignant changes, the international classification of tumors, the tumor invasion front and tumor biomarkers (Ki-67, p53, homeobox genes and collagen type IV), as well as the tumor microenvironment and function of cancer-associated fibroblasts in the most common type of oral cancer that is encountered by dental surgeons. In OSCC, associations have been identified between the proliferation, basal lamina degradation and connective tissue modulation. Therefore, the comparison of these factors with the survival time of OSCC patients from the histopathological diagnosis is of interest.
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Affiliation(s)
- César Rivera
- Unit of Histology and Embryology, Department of Basic Biomedical Sciences, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile ; Biomedical Sciences Master Program, Oral Pathology Mention, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile
| | - Bernardo Venegas
- Unit of Oral Pathology, Department of Dentistry, Faculty of Health Sciences, University of Talca, Talca 3460000, Chile
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Song Y, Zhang C, Cao Z, Xu J, Wang L, Lin X. [Significance of epithelial-mesenchaymal transition phenotype in invasive tumor front cells of lung squamous cell carcinoma]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014; 17:315-20. [PMID: 24758906 PMCID: PMC6000016 DOI: 10.3779/j.issn.1009-3419.2014.04.05] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
背景与目的 肿瘤浸润前沿（invasive tumor front, ITF）细胞是指肿瘤与宿主组织交界处的细胞或浸润的细胞团，对判断患者预后具有较高的价值。本研究旨在探讨肺鳞状细胞癌（squamous cell carcinoma, SCC）ITF细胞的上皮-间叶转化（epithelial-mesenchaymal transition, EMT）表型特点，并分析与临床病理特征和预后的关系。 方法 采用免疫组织化学SP法检测104例肺SCC ITF细胞中上皮性标志物E-cadherin/β-catenin和间叶性标志物vimentin的表达。 结果 E-cadherin在53.8%（56/104）的肺SCC ITF细胞中表达下调，较非ITF细胞表达降低（P=0.04），而vimentin在42.3%（44 /104）ITF细胞中表达，较非ITF肿瘤细胞表达升高；两者均与肿瘤浸润方式、肺门淋巴结转移和患者预后有相关性（P < 0.01）。β-catenin在肺SCC ITF细胞的表达阳性率为67.3%（70/104），低于非ITF细胞（P < 0.01），在ITF细胞呈胞质和胞核阳性表达，并与肺门淋巴结转移密切相关。 结论 肺SCC ITF细胞中E-cadherin/β-catenin表达缺失和vimentin高表达可能与患者的不良预后有关。
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Affiliation(s)
- Yinghua Song
- Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Ji'nan 250014, China
| | - Caiqing Zhang
- Department of Respiratory Medicine, Shandong Provincial Qianfoshan Hospital, Shandong University, Ji'nan 250014, China
| | - Zhixin Cao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan 250021, China
| | - Jiawen Xu
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan 250021, China
| | - Lingcheng Wang
- Department of Respiratory Medicine, the Forth People's Hospital of Jinan, Ji'nan 250031, China
| | - Xiaoyan Lin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan 250021, China
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Chan SW, Kallarakkal TG, Abraham MT. Changed Expression of E-cadherin and Galectin-9 in Oral Squamous Cell Carcinomas but Lack of Potential as Prognostic Markers. Asian Pac J Cancer Prev 2014; 15:2145-52. [DOI: 10.7314/apjcp.2014.15.5.2145] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Gomes Henriques ÁC, Ginani F, Oliveira RM, Keesen TSL, Galvão Barboza CA, Oliveira Rocha HA, de Castro JFL, Della Coletta R, de Almeida Freitas R. Low-level laser therapy promotes proliferation and invasion of oral squamous cell carcinoma cells. Lasers Med Sci 2014; 29:1385-95. [PMID: 24526326 DOI: 10.1007/s10103-014-1535-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 01/28/2014] [Indexed: 01/27/2023]
Abstract
Low-level laser therapy (LLLT) has been shown to be effective in promoting cell proliferation. There is speculation that the biostimulatory effect of LLLT causes undesirable enhancement of tumor growth in neoplastic diseases since malignant cells are more susceptible to proliferative stimuli. This study evaluated the effects of LLLT on proliferation, invasion, and expression of cyclin D1, E-cadherin, β-catenin, and MMP-9 in a tongue squamous carcinoma cell line (SCC25). Cells were irradiated with a diode laser (660 nm) using two energy densities (0.5 and 1.0 J/cm(2)). The proliferative potential was assessed by cell growth curves and cell cycle analysis, whereas the invasion of cells was evaluated using a Matrigel cell invasion assay. Expression of cyclin D1, E-cadherin, β-catenin, and MMP-9 was analyzed by immunofluorescence and flow cytometry and associated with the biological activities studied. LLLT induced significantly the proliferation of SCC25 cells at 1.0 J/cm(2), which was accomplished by an increase in the expression of cyclin D1 and nuclear β-catenin. At 1.0 J/cm(2), LLLT significantly reduced E-cadherin and induced MMP-9 expression, promoting SCC25 invasion. The results of this study demonstrated that LLLT exerts a stimulatory effect on proliferation and invasion of SCC25 cells, which was associated with alterations on expression of proteins studied.
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Melchers LJ, Bruine de Bruin L, Schnell U, Slagter-Menkema L, Mastik MF, de Bock GH, van Dijk BAC, Giepmans BNG, van der Laan BFAM, van der Wal JE, Roodenburg JLN, Schuuring E. Lack of claudin-7 is a strong predictor of regional recurrence in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 2013; 49:998-1005. [PMID: 23953778 DOI: 10.1016/j.oraloncology.2013.07.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2013] [Revised: 06/24/2013] [Accepted: 07/18/2013] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Adequate treatment of oral and oropharyngeal squamous cell carcinoma (OSCC) is dependent on correctly predicting the presence of lymph node metastases. Current methods to diagnose nodal metastases partly result in overtreatment with associated morbidity and undertreatment with decreased disease-free survival. E-cadherin has been studied extensively as potential marker for lymph node metastases. EpCAM and claudin-7 have a functional relationship with E-cadherin, forming a complex that promotes tumourigenicity in vitro. We hypothesize that the co-expression patterns of these related molecules is a better prognostic marker for nodal status and regional recurrences. MATERIALS AND METHODS We constructed separate tissue microarrays of tumour centre and tumour invasive front of 227 OSCC with complete clinicopathological and follow-up data, including HPV status, and performed immunohistochemistry for these molecules. RESULTS Lack of E-cadherin and presence of cytoplasmic EpCAM expression in the tumour front were predictive for nodal metastasis, but no co-expression pattern was found clinically relevant. Lack of claudin-7 in the tumour centre was highly and independently predictive for shorter regional disease-free survival (HR=0.19; 95%CI: 0.06-0.62) and disease-specific survival (HR=0.43; 95%CI: 0.21-0.87). High-risk HPV was not associated with any marker. CONCLUSIONS The expression of E-cadherin and EpCAM, depending on the specific tumour sublocalization, is predictive for nodal status. However, co-expression did not improve the prediction of nodal status, indicating that the proposed in vitro complex is not functional in clinical samples. Additionally, lack of claudin-7 expression in the tumour centre may be used to identify patients with increased risk for regional recurrence.
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Affiliation(s)
- L J Melchers
- Dept. of Oral & Maxillofacial Surgery, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700RB Groningen, The Netherlands; Dept. of Pathology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, P.O. Box 30.001, 9700RB Groningen, The Netherlands.
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Mashhadiabbas F, Mahjour F, Mahjour SB, Fereidooni F, Hosseini FS. The immunohistochemical characterization of MMP-2, MMP-10, TIMP-1, TIMP-2, and podoplanin in oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2013; 114:240-50. [PMID: 22769410 DOI: 10.1016/j.oooo.2012.04.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2011] [Revised: 04/17/2012] [Accepted: 04/20/2012] [Indexed: 10/28/2022]
Abstract
OBJECTIVES The aim of this study was to immunohistochemically evaluate the expression of matrix metalloproteinase (MMP)-1, MMP- 2, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, and podoplanin in oral squamous cell carcinoma (OSCC). Immunohistochemical staining of podoplanin-positive lymphatic vessel density (LVD) was also assessed. STUDY DESIGN Forty cases of OSCC were analyzed by immunohistochemistry. RESULTS MMP-2, MMP-10, TIMP-1, TIMP-2, and podoplanin were detected in each of the 40 OSCC cases. The expression of MMP-2 was significantly correlated with histologic grade. The expression of podoplanin was positively correlated with gender and negatively correlated with tumor size. A significant positive correlation was also detected between LVD and the presence of lymph node metastases, gender, age, and diameter of the lymph node (if involved), as well as histologic grade. CONCLUSIONS The results are suggestive of important roles that MMP-2, MMP-10, TIMP-2, and podoplanin play in pathologic processes of OSCC, including invasion. Our findings also suggest that LVD may play a role in lymphatic metastasis and tumor progression.
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Affiliation(s)
- Fatemeh Mashhadiabbas
- Department of Oral and Maxillofacial Pathology, Dental School, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran
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Snail promotes Cyr61 secretion to prime collective cell migration and form invasive tumor nests in squamous cell carcinoma. Cancer Lett 2013. [DOI: 10.1016/j.canlet.2012.11.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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González-Moles MA, Bravo M, Ruiz-Avila I, Gil-Montoya JA, Acebal F, Esteban F. E-cadherin in non-tumor epithelium adjacent to oral cancer as risk marker for the development of multiple tumors. Br J Oral Maxillofac Surg 2012; 51:157-63. [PMID: 22658605 DOI: 10.1016/j.bjoms.2012.05.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 05/04/2012] [Indexed: 01/04/2023]
Abstract
Our aim was to find out whether the loss of E-cadherin is a risk factor for the development of multiple tumours in the oral cavity and whether it could serve as a diagnostic marker for oral premalignant fields. We studied 77 oral squamous cell carcinomas (SCC) with associated non-tumour epithelia from 61 patients. Immunohistochemical studies (antibody NHC-38) were used to investigate E-cadherin expression, which was completely lost in basal (48% of cases) and parabasal (43%) layers of non-tumour epithelia close to the tumour and in basal (47%) and parabasal (38%) layers of non-tumour epithelia distant from the tumour. In multiple tumours E-cadherin expression was significantly lower than in single tumours in the basal, parabasal layers, and the middle third of close (p=0.002, <0.001, <0.001) and distant (p=0.041, p<0.001, p=0.005) non-tumour epithelia, respectively. Downregulation of E-cadherin may be valuable as a risk marker for the development of multiple tumours in the oral cavity and for the diagnosis of premalignant fields.
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Affiliation(s)
- M A González-Moles
- Oral Medicine Department, School of Dentistry, University of Granada, Paseo de Cartuja s/n, 18071 Granada, Spain.
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Wang C, Liu X, Huang H, Ma H, Cai W, Hou J, Huang L, Dai Y, Yu T, Zhou X. Deregulation of Snai2 is associated with metastasis and poor prognosis in tongue squamous cell carcinoma. Int J Cancer 2012; 130:2249-58. [PMID: 21647877 PMCID: PMC3242857 DOI: 10.1002/ijc.26226] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2010] [Revised: 04/28/2011] [Accepted: 05/12/2011] [Indexed: 11/06/2022]
Abstract
The members of the Snail superfamily of zinc-finger transcription factors, including Snai1 and Snai2, are involved in essential biological processes, such as epithelial-mesenchymal transition (EMT). Although Snai1 has been investigated in a number of cancers, our knowledge on Snai2 and its role(s) in squamous cell carcinoma of oral tongue (SCCOT) is limited. In this study, we confirmed the previous observation that over-expression of Snai2 is a frequent event in SCCOT. We further demonstrated that Snai2 over-expression is associated with lymph node metastasis in two independent SCCOT patient cohorts (total n = 129). Statistical analysis revealed that Snai2 over-expression was correlated with reduced overall survival. Furthermore, over-expression of Snai2 was correlated with reduced E-cadherin expression and enhanced Vimentin expression, suggesting a functional role of Snai2 in EMT. These observations were confirmed in vitro, in which knockdown of Snai2 induced a switch from a mesenchymal-like morphology to an epithelial-like morphology in SCCOT cell lines, and suppressed the cell invasion and migration. In contrast, ectopic transfection of Snai2 led to enhanced cell invasion and migration. Furthermore, Snai2 knockdown attenuated TGFβ1-induced EMT in SCCOT cell lines. Taken together, these data suggest that Snai2 plays major roles in EMT and the progression of SCCOT and may serve as a therapeutic target for patients at risk of metastasis.
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Affiliation(s)
- Cheng Wang
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Xiqiang Liu
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Hongzhang Huang
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
| | - Huibin Ma
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
| | - Weixin Cai
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
| | - Jingsong Hou
- Department of Oral and Maxillofacial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong 510055, China
| | - Lei Huang
- Bioinformatics Program, Department of Bioengineering College of Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Yang Dai
- Bioinformatics Program, Department of Bioengineering College of Engineering, University of Illinois at Chicago, Chicago, IL 60612, USA
- Graduate College, UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Tianwei Yu
- Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA
| | - Xiaofeng Zhou
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Graduate College, UIC Cancer Center, University of Illinois at Chicago, Chicago, IL 60612, USA
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Zhao Z, Ge J, Sun Y, Tian L, Lu J, Liu M, Zhao Y. Is E-cadherin immunoexpression a prognostic factor for head and neck squamous cell carcinoma (HNSCC)? A systematic review and meta-analysis. Oral Oncol 2012; 48:761-7. [PMID: 22455948 DOI: 10.1016/j.oraloncology.2012.02.024] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2011] [Revised: 02/28/2012] [Accepted: 02/29/2012] [Indexed: 11/16/2022]
Abstract
We summarized existing evidence about whether the aberrant E-cadherin expression is a prognostic factor for patients with HNSCC. Identifying relevant articles, filtrating studies and extracting data were independently conducted by two reviewers. The quality of eligible studies was assessed according to systematic score criteria. Associations between aberrant E-cadherin expression and overall survival (OS) or disease-free survival (DFS) were summarized by hazard ratio (HR) estimates. Random or fixed effects models were used to investigate the effect of E-cadherin across the studies. According to the multivariate and univariate analyses, the meta-analysis of the included studies gave a statistically significant pooled HR for OS in HNSCC [the pooled HR=2.533; 95% confidence interval (CI)=1.971-3.254]. In addition, the subgroup analyses showed that the pooled HR of each subgroup also exhibited statistical significance according to the subpopulations (Asian and other subpopulations), treatments (surgery and other treatments), locations of primary tumors (oral cavity and other subsites), and data sources of HR (reported and estimated HR). Similar to the results of OS, the analysis of four included trials showed that the aberrant E-cadherin expression could predict low DFS. Meanwhile, a cumulative meta-analysis showed that the pooled HR became statistically significant. However, a meta-regression analysis showed that the OS was not statistically significant with the cutoff values of the included studies. Our study gives an important piece of evidence that aberrant E-cadherin expression was associated with a poor prognosis in patients with HNSCC.
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Affiliation(s)
- ZhiGang Zhao
- Department of Otorhinolaryngology-Head and Neck Surgery, The Second Affiliated Hospital, Harbin Medical University, Harbin 150081, Heilongjiang Province, People's Republic of China
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Analysis of inflammatory infiltrate, perineural invasion, and risk score can indicate concurrent metastasis in squamous cell carcinoma of the tongue. J Oral Maxillofac Surg 2011; 70:1703-10. [PMID: 22154400 DOI: 10.1016/j.joms.2011.08.023] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2011] [Revised: 08/12/2011] [Accepted: 08/13/2011] [Indexed: 11/21/2022]
Abstract
PURPOSE In this retrospective study, the aim was to compare individual histopathologic parameters of malignancy between nonmetastatic and metastatic squamous cell carcinoma of the tongue. MATERIALS AND METHODS Sixty-two cases of squamous cell carcinoma of the tongue were selected and examined according to the system established by Brandwein-Gensler et al (Am J Surg Pathol 29:167, 2005) and included the pattern of invasion (most to least favorable), lymphocytic infiltration, perineural invasion, risk score, keratinization, eosinophilia, perivascular invasion, and tumor thickness. RESULTS The least favorable pattern had no association with nodal metastasis (P > .05). The scarcity or density of the lymphocytic infiltration, perineural invasion, and a risk score ≥ 3 were associated with nodal metastasis (P < .05). Keratinization, eosinophilia, perivascular invasion, and tumor thickness had no association with nodal metastasis (P > .05). A significant positive correlation was found between the pattern of invasion and perineural invasion and between the pattern of invasion and tumor thickness (P < .05). CONCLUSIONS The scarcity or density of the lymphocytic infiltration, perineural invasion, and histopathologic risk score may be helpful as parameters of histologic malignancy for the evaluation of metastatic and nonmetastatic squamous cell carcinoma of the tongue.
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Friedl P, Alexander S. Cancer Invasion and the Microenvironment: Plasticity and Reciprocity. Cell 2011; 147:992-1009. [DOI: 10.1016/j.cell.2011.11.016] [Citation(s) in RCA: 1462] [Impact Index Per Article: 104.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2011] [Indexed: 02/07/2023]
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Wang C, Huang H, Huang Z, Wang A, Chen X, Huang L, Zhou X, Liu X. Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med 2011; 40:545-51. [PMID: 21481005 PMCID: PMC3135705 DOI: 10.1111/j.1600-0714.2011.01041.x] [Citation(s) in RCA: 149] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Tumor budding is a readily detectable histopathological feature and has been recognized as an adverse prognostic factor in several human cancers. However, the prognostic value of tumor budding in tongue squamous cell carcinoma (TSCC) has not been reported. The purpose of this study was to assess the correlation of tumor budding with the clinicopathologic features, and the known molecular biomarkers (E-cadherin and Vimentin), as well as to evaluate its prognostic significance for TSCC. METHODS Archival clinical samples of 230 patients with TSCC were examined for tumor budding. Immunohistochemistry analyses were performed to examine the expression of E-cadherin and Vimentin. Statistical analyses were carried out to assess the correlation of tumor budding with clinicopathologic parameters and patient survival. The potential association between tumor budding and alterations of E-cadherin and Vimentin expression was also assessed. RESULTS Of the 230 TSCC cases examined, tumor budding was observed in 165 cases (71.7%), with a mean tumor bud count of 7.5 (range from 1 to 48 buds). High-intensity budding (≥5 tumor buds) was observed in 111 cases (48.3%). Statistical analysis revealed that tumor budding was associated with tumor size (P < 0.05), differentiation (P < 0.05), clinical stage (P < 0.05), lymph node metastasis (P < 0.01), and correlated with reduced overall survival. In addition, significant associations were observed among tumor budding and the deregulation of E-cadherin (P < 0.001) and Vimentin (P < 0.001). CONCLUSIONS Tumor budding, which associates with epithelial-mesenchymal transition, is a frequent event and appears to be an independent prognostic factor in TSCC.
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Affiliation(s)
- Cheng Wang
- Department of Oral and Maxillofcial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Hongzhang Huang
- Department of Oral and Maxillofcial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Zhiquan Huang
- Department of Oral and Maxillofcial Surgery, the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Anxun Wang
- Department of Oral and Maxillofcial Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510075, China
| | - Xiaohua Chen
- Department of Oral Pathology, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
| | - Lei Huang
- Department of Bioengineering College of Engineering, University of Illinois at Chicago, Chicago, IL 60612
| | - Xiaofeng Zhou
- Department of Oral and Maxillofcial Surgery, Guanghua School and Research Institute of Stomatology, Sun Yat-sen University, Guangzhou, 510055, China
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
- Graduate College, UIC Cancer Center, University of Illinois at Chicago, Chicago, IL60612, USA
| | - Xiqiang Liu
- Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA
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Pease JC, Tirnauer JS. Mitotic spindle misorientation in cancer--out of alignment and into the fire. J Cell Sci 2011; 124:1007-16. [PMID: 21402874 DOI: 10.1242/jcs.081406] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mitotic spindle orientation can influence tissue organization and vice versa. Cells orient their spindles by rotating them parallel or perpendicular to the cell--and hence the tissue--axis. Spindle orientation in turn controls the placement of daughter cells within a tissue, influencing tissue morphology. Recent findings implicating tumor suppressor proteins in spindle orientation bring to the forefront a connection between spindle misorientation and cancer. In this Commentary, we focus on the role of three major human tumor suppressors--adenomatous polyposis coli (APC), E-cadherin and von Hippel-Lindau (VHL)--in spindle orientation. We discuss how, in addition to their better-known functions, these proteins affect microtubule stability and cell polarity, and how their loss of function causes spindles to become misoriented. We also consider how other cancer-associated features, such as oncogene mutations, centrosome amplification and the tumor microenvironment, might influence spindle orientation. Finally, we speculate on the role of spindle misorientation in cancer development and progression. We conclude that spindle misorientation alone is unlikely to be tumorigenic, but it has the potential to synergize with cancer-associated changes to facilitate genomic instability, tissue disorganization, metastasis and expansion of cancer stem cell compartments.
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Affiliation(s)
- Jillian C Pease
- Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030-3101, USA
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Mostaan LV, Khorsandi MT, Sharifian SMR, Shandiz FH, Mirashrafi F, Sabzari H, Badiee R, Borghei H, Yazdani N. Correlation between E-cadherin and CD44 adhesion molecules expression and cervical lymph node metastasis in oral tongue SCC: Predictive significance or not. Pathol Res Pract 2011; 207:448-51. [DOI: 10.1016/j.prp.2011.04.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Revised: 03/27/2011] [Accepted: 04/11/2011] [Indexed: 02/03/2023]
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