Neoplastic spindle cells in nasopharyngeal carcinoma show features of epithelial–mesenchymal transition

Luo, Weiren; Chen, Xiaoyi; Li, Siyi; Wu, Aibing; Yao, Kangde

doi:10.1111/j.1365-2559.2012.04205.x

Cited by 43 publications

(47 citation statements)

References 37 publications

(39 reference statements)

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“…Particularly, we found that distributions of SOX2, OCT4 and Nanog staining were more frequently located in the invasive front of tumors, and these cells often exhibited a fibroblast-like, spindle-shaped phenotype. Recently, we have demonstrated that these spindle cells in the invasive tumor front correlated strongly with EMT in NPC tissues [41]. Taken together, our findings strongly indicate that these stem cells-like cancer cells might strongly resemble cells that have undergone an EMT.…”

Section: Discussionsupporting

confidence: 74%

Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma

et al. 2013

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Expression of embryonic stem cells (ESCs) markers (SOX2, OCT4, Nanog and Nestin) is crucial for progression of various human malignancies. The purpose of this study was to investigate the expression and prognostic impact of these molecules in nasopharyngeal carcinoma (NPC) patients by immunohistochemistry and immunofluorescence. In the present study, we found that the expression levels of SOX2, OCT4 and Nanog were highly expressed in NPC compared with the non-tumorous tissues. Furthermore, these proteins correlated significantly with several clinicalpathological factors and epithelial-mesenchymal transition (EMT)-associated indicators (E-cadherin/N-cadherin and Snail). In multivariate analyses, high expression of OCT4 (P = 0.013) and Nanog (P = 0.040), but not that of SOX2, was associated with worse survival and had strongly independent prognostic effects. Of note, OCT4 and Nanog were more frequently located at the invasive front of tumors, and correlated significantly with various aggressive behaviors including T classification, N classification, M classification and clinical stage. Furthermore, patients with co-expression of OCT4 and Nanog in the invasive front had significantly worse survival (P = 0.005). Interestingly, at the invasive front, these molecules correlated significantly with Nestin expression in endothelial cells (P<0.001). These findings provide evidence that ESCs biomarkers OCT4 and Nanog serves as independent prognostic factors for NPC. Additionally, cancer cells in the invasive front of NPC acquiring ESCs-like features should be maintained by vascular niches.

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Section: Discussionsupporting

confidence: 74%

Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma

et al. 2013

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“…Previous reports have shown that NPC cells have undergone the process of EMT [39-41], in particular the neoplastic spindle cells in NPC [40]. Our present results showed that knockdown of STAB1 expression by SATB1 specific siRNA led to an obvious up-regulation of E-cadherin and a down-regulation of Vinmentin, the marker for EMT (Additional file 2: Figure S1).…”

Section: Discussionsupporting

confidence: 64%

Over-expression of the special AT rich sequence binding protein 1 (SATB1) promotes the progression of nasopharyngeal carcinoma: association with EBV LMP-1 expression

et al. 2013

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BackgroundSpecial AT rich sequence binding protein 1 (SATB1) plays a crucial role in the biology of various types of human cancer. However, the role of SATB1 in human nasopharyngeal carcinoma (NPC) remains unknown. In the present study, we sought to investigate the contribution of aberrant SATB1 expression in the progression of NPC and its association with the Epstein Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1).MethodsImmunohistochemical analysis was performed to detect SATB1 and LMP-1 protein in clinical samples, and the association of SATB1 protein expression with patient clinicopathological characteristics and LMP-1 expression were analyzed. SATB1 expression profiles were evaluated in well-differentiated NPC cell line CNE1, poorly-differentiated CNE2Z, undifferentiated C666-1 and immortalized nasopharyngeal epithelia NP-69 cells using quantitative RT-PCR, western blotting and fluorescent staining. After inhibition the SATB1 expression by using SATB1 specific small interfering RNA in these cell lines, the change of cell proliferation was investigated by western blotting analysis of PCNA (proliferating cell nuclear antigen) expression and CCK-8 assay, and the cell migration was assessed by Transwell migration assay. Finally, the expressions of SATB1 and PCNA were examined in CNE1 cells that forced LMP-1 expression by fluorescent staining and RT-PCR.ResultsImmunohistochemical analysis revealed that SATB1 protein expression was elevated in NPC tissues compared to benign nasopharyngeal tissues (P = 0.005). Moreover, high levels of SATB1 protein expression were positively correlated with clinical stage (P = 0.025), the status of lymph node metastasis (N classification) (P = 0.018), distant metastasis (M classification) (P = 0.041) and LMP-1 expression status (r = 2.35, P < 0.01) in NPC patients. In vitro experiments demonstrated that an inverse relationship between SATB1 expression and NPC differentiation status, with SATB1 weakly expressed in NP-69 cells and CNE1 cells, and significant increasingly expressed in CNE-2Z and C666-1 cells. Targeted knockdown of SATB1 expression obviously attenuated the proliferation and migration of highly SATB1-expressing CNE2Z and C666-1 cells, but not NP-69 and CNE1 cells. Interestingly, forced LMP-1 expression in CNE1 cells led to a surprisingly increasing SATB1 expression and nuclear location, companying with an up-regulated PCNA expression.ConclusionsOur results reveal that EBV LMP-1-mediated over-expression of SATB1 is associated with NPC progression, suggesting SATB1 may represent a promising biomarker and therapeutic target for NPC.

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“…It is noteworthy that either the differentiated or the undifferentiated subtype generally comprises a certain content of mesenchymal-like cell (that is “neoplastic spindle cells”), which is predominantly observed in the invasive front (tumor-host interface) and tumor stroma [14-17]. Recently, our findings show hat EMT markers E-cadherin expression was mostly inhibited in the spindle cells, whereas the expression of vimentin, fibronectin, Snail and Slug was upregulated [16]. We suggest that EMT may be crucial for the pathogenesis of neoplastic spindle cells in NPC, and spindle cells should be considered as the more aggressive subtype.…”

Section: Introductionmentioning

confidence: 89%

“…Additionally, 29 of the UDC tumors also comprised non-spindled neoplastic epithelial cells. In total, there was a neoplastic spindle cells component in 115 cases (range, 10% to 90%), and a non-spindled cells component in 47 cases (range, 5% to 85%) [16]. …”

Section: Methodsmentioning

confidence: 99%

Molecular Characterization and Clinical Implications of Spindle Cells in Nasopharyngeal Carcinoma: A Novel Molecule-Morphology Model of Tumor Progression Proposed

Luo

Yao

2013

PLoS ONE

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Up to now, the precise molecular and morphological changes underlying the invasive and metastatic properties of nasopharyngeal carcinoma (NPC) remain largely unresolved. We speculate that neoplastic spindle cells, which are prominently found in the invasive tumor front and the surrounding stroma, might be responsible for the aggressive patterns. Expression profiling of various biomarkers relevant to cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) was performed by tissue microarray-based immunohistochemistry in NPC samples. The expression of EBER and LMP1 was detected by in situ hybridization and immunohistochemistry, respectively. We found that overexpression of CSCs-related markers (ALDH1, Nanog and ABCG2) and up-regulation of EMT markers (Fibronectin, MMP-2, Periostin, SPARC, Snail and Slug), together with E- to N-cadherin switching, occurred preferentially in tumors containing a large proportion of spindle-shaped malignant cells. Furthermore, CSCs-like properties were highly present in spindle cells compared with non-spindle cells of tumors, and correlated strongly with EMT features. In addition, EBV-related factors EBER and LMP1 were highly expressed and correlated strongly with CSCs and EMT characteristics in neoplastic spindle cells. Importantly, high proportion of spindle cells (≥20%) correlated significantly with various aggressive aspects including lymph node metastasis (P = 0.031) and local recurrence (P = 0.014). Patients with high proportion of spindle cells had poor survival (P = 0.004), though it was not an independent value. In conclusion, we demonstrate that spindle cells could be valuable morphological indicators of tumor progression and unfavorable prognosis of NPC. An integrated molecule-morphology model of NPC firstly constructed may shed significant light on the metastatic cascade and clinical relevance of patients.

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Neoplastic spindle cells in nasopharyngeal carcinoma show features of epithelial–mesenchymal transition

Abstract: Our findings demonstrate for the first time that EMT might play an important role in the development of neoplastic spindle cells in NPC.

Cited by 43 publications

References 37 publications

Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma

Embryonic Stem Cells Markers SOX2, OCT4 and Nanog Expression and Their Correlations with Epithelial-Mesenchymal Transition in Nasopharyngeal Carcinoma

Over-expression of the special AT rich sequence binding protein 1 (SATB1) promotes the progression of nasopharyngeal carcinoma: association with EBV LMP-1 expression

Molecular Characterization and Clinical Implications of Spindle Cells in Nasopharyngeal Carcinoma: A Novel Molecule-Morphology Model of Tumor Progression Proposed

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