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It is well documented that the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR), which has been implicated in cancer invasion and metastasis, is regulated by several inhibitors such as maspin. In this study, we investigated the interrelationship between clinicopathologic findings and expression of uPA, uPAR and maspin in...
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We investigated whether the expression levels of urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) correlate with clinicopathological features of oral squamous cell carcinoma (SCC). We immunohistochemically examined the expression levels of uPA, uPAR, and PAI-1 in 160 biopsy specimens of...
We investigated whether the expression levels of urokinase‐type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor‐1 (PAI‐1) correlate with clinicopathological features of oral squamous cell carcinoma (SCC). We immunohistochemically examined the expression levels of uPA, uPAR, and PAI‐1 in 160 biopsy specimens of...
Citations
... In some studies, regarding the expression of Maspin in oral SCC, it has been shown that its expression correlated with a better survival rate but instead no correlation was found with differentiation degree, type of invasion, Tstage, and lymph-node metastasis [55][56][57]. At the same time, it was shown that cytoplasmic expression was associated with a high risk of neck lymph node metastasis in oral SCCs [58]. ...
Squamous cell carcinoma (SCC) is the most frequent cancer in oral cavity and its prognosis has exhibited little improvement in the last decades. Although much less common palate SCCs manifests a higher local aggression invading very quickly the adjacent muscles and jawbones, thus being able frequently to lead to dysfunctions in chewing, swallowing, and speech. To elucidate what underlies such local aggression, we investigated the immunohistochemical expression in palate SCCs of Podoplanin (D2-40), Galectin-3 (Gal-3), mammary serine protease inhibitor (Maspin) and minichromosome maintenance complex component 7 (MCM7), markers that are known to be involved in tumor invasiveness. We found a progressive increase in reactivity for D2-40 and MCM7 from the normal epithelium toward dysplastic epithelium and respectively to SCC, which suggests the intervention of these markers in the early stages of squamous cell carcinogenesis in the palate. The highest D2-40, Gal-3 and MCM7 reactivity was observed in basaloid and in poorly differentiated (G3) palate SCCs, while for Maspin the well-differentiated (G1) palate SCCs were the most reactive. The first three markers mentioned above were most intensely expressed at the invasion front, while the Maspin reactivity was low or absent at this level. Statistically, we found significant stratification on localization, grading, muscle invasion, and survival for all investigated markers, but with very high direct correlations between D2-40, Gal-3, and MCM7 immunoreactive score (IRS) values, while between the Maspin and each of the previous markers there were very high inverse correlations. Overall, all these investigate markers proved to be responsible for the local invasiveness and regional lymph node metastasis, thus allowing a prognostic and therapeutic stratification of patients with palate SCCs.
... uPA/uPAR was proved to distinguish OSCC with higher invasive grades (grades 4C and 4D), whereas claudin-7 with a tight junction component was proved to distinguish OSCC with lower invasive grades (grades 1-3) in an immunohistochemical analysis of pathologic tissue specimens according to the YK classification. 15,35 The sections were then reacted with a secondary antibody (biotin-labeled goat anti-rabbit immunoglobulin polyclonal antibody; Dako Japan, Kyoto, Japan) at room temperature for 60 min. Sections treated with PBS instead of the primary antibody were used as the negative controls. ...
Objective
The Yamamoto–Kohama criteria are clinically useful for determining the mode of tumor invasion, especially in Japan. However, this evaluation method is based on subjective visual findings and has led to significant differences in determinations between evaluators and facilities. In this retrospective study, we aimed to develop an automatic method of determining the mode of invasion based on the processing of digital medical images.
Study Design
Using 101 digitized photographic images of anonymized stained specimen slides, we created a classifier that allowed clinicians to introduce feature values and subjected the cases to machine learning using a random forest approach. We then compared the Yamamoto–Kohama grades (1, 2, 3, 4C, 4D) determined by a human oral and maxillofacial surgeon with those determined using the machine learning approach.
Results
The input of multiple test images into the newly created classifier yielded an overall F-measure value of 87%, (Grade 1: 93%, Grade 2: 67%, Grade 3: 89%, Grade 4C: 83%, Grade 4D: 94%). These results suggest that the output of the classifier was very similar to the judgments of the clinician.
Conclusions
This system may be valuable for diagnostic support to provide an accurate determination of the mode of invasion.
... Despite improvements in treatment options over the past few decades, the 5-year survival rates have remained fairly low (50-55%) among OSCC patients [1,2]. Treatment failure in a case of OSCC is mainly ascribed to the highly invasive nature of the tumor [3,4]. As the tumor becomes more invasive, the invasion front progresses from the epithelium through the stroma to in ltrate the lymphatic and blood vasculature [5]. ...
Background: The Yamamoto-Kohama criteria (YK), which are used to classify the morphology of the infiltrating protrusions of an oral squamous cell carcinoma (OSCC), are clinically useful for determining the mode of tumor invasion, especially in Japan. However, evaluations of the mode of OSCC invasion are based on subjective visual observations, and this approach has created considerable inter-evaluator and inter-facility differences. In this retrospective study, we aimed to develop an automatic method of determining the mode of invasion of OSCC based on the processing of digital medical images of the invasion front.
Methods: Using 101 digitized photographic images of anonymized stained specimen slides from consecutive patients with OSCC at Kanazawa University, we created a classifier that allowed clinicians to introduce feature values and subjected the cases to machine learning using a random forest approach. We then compared the YK grades (1, 2, 3, 4C, 4D) determined by a human oral and maxillofacial surgeon with those determined using the machine learning approach.
Results: The input of multiple test images into the newly created classifier yielded an overall F-measure value of 87%, (Grade 1: 93%, Grade 2: 67%, Grade 3: 89%, Grade 4C: 83%, Grade 4D: 94%). These results suggest that the output of the classifier was very similar to the judgments of the clinician.
Conclusions: We successfully developed an automatic machine-learning method for discriminating the mode of invasion of OSCC. Our results suggest that a medical diagnostic imaging system could feasibly be used to provide an accurate determination of the mode of OSCC invasion.
... uPA/uPAR plays critical roles in promoting extracellular proteolysis, regulation of cell/ECM interactions, and cell migration, all of which are related to the malignant progression of various tumors [43]. Elevated expression of uPA was observed in OSCC tissues, which was correlated with increased invasiveness of OSCC [44]. ...
Background
The aim of this study was to identify biomarkers closely related to the pathogenesis and prognosis of oral squamous cell carcinoma (OSCC) by using weighted gene co-expression network analysis (WGCNA) based on integrative transcriptome datasets.
Material/Methods
Gene expression profiles of OSCC were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained and we then performed with Gene ontology (GO) and pathway enrichment analysis as well as protein–protein interactions (PPI) network analysis. WGCNA was used to construct the co-expression network. Multipart results were intersected to acquire the candidate genes, and survival analysis was used to identify the hub genes.
Results
A total of 568 DEGs, including 272 upregulated genes and 296 downregulated genes, were identified. GO and pathway analyses revealed that these DEGs were mainly enriched in extracellular matrix (ECM), ECM organization, structural constituent of muscle, and ECM-receptor interaction. The PPI network of DEGs was established, comprising 428 nodes and 1944 edges. In the co-expression network, pink module was the key module, in which 34 genes with high connectivity were identified. After the intersection of multipart results, 24 common genes were chosen as the candidate genes, among which 7 hub genes (PLAU, SERPINE1, LAMC2, ITGA5, TGFBI, FSCN1, and HLF) were identified using survival analysis.
Conclusions
Seven potential biomarkers were identified as being closely related with the initiation and prognosis of OSCC and might serve as potential targets for early diagnosis and personalized therapy of OSCC.
... PLAU, the serine protease, has been indicated in promoting pericellular proteolysis and oncogenic signal transduction in cancer cells. Yoshizawa implied that cases with PLAU/PLAU receptor/maspin expression should be considered as the high risk of poor prognosis of OSCC, which may lead to severe invasiveness, as well as the increased risk for cervical lymph node metastasis [40]. ...
Porphyromonas gingivalis is a pivotal periodontal pathogen, and the epithelial cells serve as the first physical barrier to defend the host from bacterial attack. Within this host-bacteria interaction, P. gingivalis can modify the host immune reaction and adjust the gene expression, which is associated with periodontitis pathogenesis and developing strategies. Herein, a meta-analysis was made to get the differential gene expression profiles in epithelial cells with or without P. gingivalis infection. The network-based meta-analysis program for gene expression profiling was used. Both the gene ontology analysis and the pathway enrichment analysis of the differentially expressed genes were conducted. Our results determined that 290 genes were consistently up-regulated in P. gingivalis infected epithelial cells. 229 gene ontology biological process terms of up-regulated genes were discovered, including "negative regulation of apoptotic process" and "positive regulation of cell proliferation/migration/angiogenesis". In addition to the well-known inflammatory signaling pathways, the pathway associated with a transcriptional misregulation in cancer has also been increased. Our findings indicated that P. gingivalis benefited from the survival of epithelial cells, and got its success as a colonizer in oral epithelium. The results also suggested that infection of P. gingivalis might contribute to oral cancer through chronic inflammation. Negative regulation of the apoptotic process and transcriptional misregulation in cancer pathway are important contributors to the cellular physiology changes during infection development, which have particular relevance to the pathogenesis and progressions of periodontitis, even to the occurrence of oral cancer.
... 4,6 Increased expression of uPA/uPAR has been observed in some tumors, including those in stomach, 7 colorectal 8 and oral cavity. 9,10,11 Oral squamous cell carcinoma (OSCC) is a common tumor with a 5-year survival rate that ranges from 15-50%. 12,13 The oral tongue (SCCOT) is the most common site, representing 25-40% of the cases. ...
... Previous studies 21,22 on different tumors found that uPA is overexpressed in advanced tumors with lymph node metastasis and recurrence. Regarding OSCC, Yoshiwaza et al. 9 observed a higher survival rate in cases with a lower uPA expression. Zhang et al. 10 reported that uPA was more common in cases of SCCOT with lymph node metastasis and stages III-IV, confirming that uPA appears to play a role in neoplastic progression. ...
... Furthermore, cases with cellular dissociation (n < 15) presented an overexpression of uPA. In OSCC, similar results were reported by Yoshizawa et al., 9 Nozaki et al., 24 and Inoue et al. 25 , who showed that uPA is associated with the worst pattern of invasion, characterized by a diffuse distribution of neoplastic cords. Thus, these authors suggested uPA could serve as a biomarker to assess the progression of this neoplasm. ...
Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) act in the proteolysis of basement membrane and extracellular matrix structures, facilitating tumor invasion. The purpose of this study was to evaluate the relationship between these proteins and clinicopathological parameters in squamous cell carcinoma of the oral tongue (SCCOT). Sixty cases of SCCOT were submitted to immunohistochemistry and analyzed semiquantitatively at the invasion front and in the tumor core. The results were associated with lymph node metastasis, clinical stage, locoregional recurrence, clinical outcome and histological grade of malignancy. A higher expression of uPA was observed in cases of tumors of high-grade versus low-grade malignancy (p = 0.010). Moreover, the cases with the worst pattern of invasion presented an overexpression of uPA (p = 0.011). The presence of locoregional recurrence was associated with uPAR (p = 0.039), and the expression of both biomarkers was much higher at the invasion front than in the tumor core (p < 0.001). The results suggest uPA and uPAR are involved in the progression and aggressiveness of SCCOT, mainly at the tumor-host interface.
... Our study confirms the findings in the latter study, as high uPAR expression only for the sub-group of well differentiated tumors was associated negatively with OS in the univariate analysis and reached borderline significance in the multivariate analysis. In two studies from the same Japanese group, containing 34 and 54 OSCC patients, respectively, high uPAR expression was associated with an aggressive mode of invasion [43,44]. Unfortunately, our study did not include the pattern of invasion (cohesive vs. non-cohesive invasive tumor front) as a histopathological variable, but further research in the relation between local tumor aggressiveness and uPAR activity in OSCC is warranted. ...
... In the survival analysis in the present study, enhanced uPAR expression was associated with a significant reduction in OS only, while no significant associations between expression of TF or EGFR and survival outcome could be demonstrated. Accordingly, our data supports findings in previous studies, that uPAR expression seems to be a prognostic factor for survival outcome in OSCC [31,42,44]. However, we did not find uPAR to be an independent prognostic factor in multivariate analysis. ...
... Interestingly, our study is the first to show that uPAR had impact on survival outcome across an entire cohort of patients, and not only in a subgroup analysis of patients defined by a specific clinicopathological variable [31,42] or a combination of biomarker expressions [44]. We did not find any significant association between EGFR expression and survival outcome, which is consistent with several previous studies, although some studies have associated enhanced EGFR expression with poor clinical outcome [12]. ...
Background
Tumor-specific biomarkers are a prerequisite for the development of targeted imaging and therapy in oral squamous cell carcinoma (OSCC). urokinase-type Plasminogen Activator Receptor (uPAR), Tissue Factor (TF) and Epidermal Growth Factor Receptor (EGFR) are three biomarkers that exhibit enhanced expression in many types of cancers, and have been investigated as potential biomarkers for targeted strategies and prognostication. The aim of the study was to investigate the expression patterns of uPAR, TF and EGFR and their potential prognostic value in OSCC.
Methods
Immunohistochemical expression of uPAR, TF and EGFR in tumor resection specimens from 191 patients with primary OSCC was analyzed. Overall (OS) and disease-free survival (DFS) was calculated. Associations between biomarker expression, clinicopathological factors and patient survival was analyzed using the Cox proportional hazards model for univariate and multivariate analysis, log rank and Kaplan-Meier statistics.
Results
uPAR and TF exhibited a highly tumor-specific expression pattern while EGFR also showed expression in normal tissues outside the tumor compartment. The overall positive expression rate of uPAR, TF and EGFR was 95%, 58% and 98%, respectively. High uPAR expression across the entire cohort was negatively associated with OS (p = 0.031, HR = 1.595 (95%CI 1.044–2.439)) in univariate analysis. The 5-year OS for high and low uPAR expression was 39% and 56%, respectively. The expression of TF and EGFR was not associated with survival outcome.
Conclusions
This study may suggest that uPAR and TF could potentially be attractive targets for molecular imaging and therapy in OSCC due to high positive expression rates and tumor-specific expression patterns. High uPAR expression was significantly associated with a reduced survival. uPAR seems to be a prognostic biomarker in oral cancer.
... Regarding this tumour entity, the interaction between malignant cells and TAMs occurs through the plasminogen activator urokinase (uPA) and its specific receptor uPAR, mainly through the activation of ERK1/2 and increase in the production of IL-4. In OSCC cells this receptor modifies several transduction pathways, affecting neoplastic cell behaviours and acts as a promoter of survival, proliferation, and metastasis [41][42][43]. The high levels of IL-4 produced modifies the tumour microenvironment and facilitates an increase in arginase-1 levels, considered a biomarker of TAMs [43]. ...
Background
Oral squamous cell carcinoma (OSCC) accounts over 90% of malignant neoplasms of the oral cavity. This pathological entity is associated to a high mortality rate that has remained unchanged over the past decades. Tumour-associated macrophages (TAMs) are believed to have potential involvement in OSCC progression. However, the molecular networks involved in communication between stroma and cancer cells have not yet been fully elucidated. Main bodyThe role of M2 polarized cells in oral carcinogenesis is supported by a correlation between TAMs accumulation into OSCC stroma and poor clinical outcome. Signalling pathways such as the NF-κB and cytokines released in the tumour microenvironment promote a bidirectional cross-talk between M2 and OSCC cells. These interactions consequently result in an increased proliferation of malignant cells and enhances aggressiveness, thus reducing patients’ survival time. Conclusions
Here, we present a comprehensive review of the role of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-10 and the receptor tyrosine kinase Axl in macrophage polarization to an M2 phenotype and OSCC progression. Understanding the molecular basis of oral carcinogenesis and metastatic spread of OSCC would promote the development of targeted treatment contributing to a more favourable prognosis.
... In oral cancer patients, uPAR is correlated with cancer invasion, secondary regional lymph node metastasis [15] and higher recurrence rates [15][16][17]. Various prognostic studies have related uPAR expression to worse disease-specific survival, 5-year overall survival and decreased overall survival in patients with early stage disease [18][19][20]. High endogenous levels of uPAR are found in hypoxic regions and invasive borders of solid tumours, including head-and-neck cancer, on both neoplastic as well as stromal cells, while in normal tissues and dysplastic epithelium little uPAR is present [11,16,21,22]. ...
... Maspin (mammary serine protease inhibitor), a member of the serine protease inhibitor/ non-inhibitor superfamily, has been shown to have tumor growth suppression activity in vitro and in vivo for a variety of cancers [24]. It has been reported that higher Maspin expression was associated with better overall survival rate and lower rate of lymph node metastasis; in contrast, in the OSCC patients, lower expression of Maspin was accompanied with larger tumors [25][26][27]. These findings suggest that Maspin could be a potential target in OSCC treatment. ...
... We further demonstrated that incubation of SAS and OECM-1 cells with iron chelators enhanced the expressions of NDRG3 dose-dependently (Figures 2 and 3). Maspin is a non-inhibitory serpin and has been reported as a potential tumor suppressor gene in several cancers including OSCC [24][25][26][27]37,38]. Our results indicate that Dp44mT treatment enhanced Maspin expressions in SAS and OECM-1 cells; however, DFO increased Maspin expressions only in SAS cells, and deferasirox treatment did not affect Maspin expressions in both OSCC cell lines. ...
Oral squamous cell carcinoma (OSCC) is a common malignancy with a growing worldwide incidence and prevalence. The N-myc downstream regulated gene (NDRG) family of NDRG1, 2, 3, and mammary serine protease inhibitor (Maspin) gene are well-known modulators in the neoplasia process. Current research has considered iron chelators as new anti-cancer agents; however, the anticancer activities of iron chelators and their target genes in OSCC have not been well investigated. We showed that iron chelators (Dp44mT, desferrioxamine (DFO), and deferasirox) all significantly inhibit SAS cell growth. Flow cytometry further indicated that Dp44mT inhibition of SAS cells growth was partly due to induction of G1 cell cycle arrest. Iron chelators enhanced expressions of NDRG1 and NDRG3 while repressing cyclin D1 expression in OSCC cells. The in vivo antitumor effect on OSCC and safety of Dp44mT were further confirmed through a xenograft animal model. The Dp44mT treatment also increased Maspin protein levels in SAS and OECM-1 cells. NDRG3 knockdown enhanced the growth of OECM-1 cells in vitro and in vivo. Our results indicated that NDRG3 is a tumor suppressor gene in OSCC cells, and Dp44mT could be a promising therapeutic agent for OSCC treatment.
