Loss of cellular polarity/cohesiveness in the invasive front of papillary thyroid carcinoma, a novel predictor for lymph node metastasis; possible morphological indicator of epithelial mesenchymal transition

Liu, Zhiyan; Kakudo, Kennichi; Bai, Yanhua; Li, Yaqiong; Ozaki, Takashi; Miyauchi, Akira; Taniguchi, Emiko; Mori, Ichiro

doi:10.1136/jcp.2010.083956

Cited by 44 publications

(63 citation statements)

References 26 publications

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“…This phenomenon was also reported by Liu et al (29) in larger PTCs. The authors of that study also demonstrated that E-cadherin loss was associated with a loss of cohesiveness and polarity, which was similar to our findings.…”

Section: Discussionsupporting

confidence: 68%

“…These results are in accordance with those of previous studies investigating E-cadherin expression in PTCs of all stages (23)(24)(25)(26)(27). Certain studies demonstrated a correlation between the loss of E-cadherin expression and disease progression or poorer prognosis in PTC (27,29); however, the results of the present study did not verify the clinical significance of E-cadherin expression in PTMC. The majority of PTMCs exhibited low Ki-67 indices, suggesting a low level of proliferation.…”

Section: Discussioncontrasting

confidence: 56%

“…The authors of that study also demonstrated that E-cadherin loss was associated with a loss of cohesiveness and polarity, which was similar to our findings. These phenotypical and morphological changes are characteristic of EMT (29). Furthermore, we observed that the tumors that had lost E-cadherin expression at the invasive front, commonly presented with lymph node involvement, suggesting clinical characteristics of EMT.…”

Section: Discussionmentioning

confidence: 70%

“…Seven tumors were surrounded by a thick fibrous capsule and the immune reactivity of E-cadherin at the invasive front was investigated in the remaining 86 tumors. The invasive front was defined as the interface (<0.1 cm) between the tumor and the adjacent non-neoplastic tissue (29).…”

Section: Patientsmentioning

confidence: 99%

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E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid microcarcinoma

Nakamura

Onoda

Noda

et al. 2013

Molecular and Clinical Oncology

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Abstract. Although papillary thyroid microcarcinoma (PTMC) has an excellent prognosis, certain cases exhibit aggressive clinical manifestations. In this study, we assessed the expression of E-cadherin and Ki-67 in primary PTMC tumors and metastatic lymph nodes, in order to investigate the mechanism underlying the mainly indolent but potentially malignant nature of PTMC. A total of 93 PTMC patients treated in our institute were included in this study. All primary tumors and 57 metastatic lymph nodes were immunohistochemically stained and a total of 73 tumors (78.5%) were positive for E-cadherin. E-cadherin expression was significantly less common at the invasive front (58.1%, P<0.01) compared to that at the center of the tumor. Tumors that had lost E-cadherin expression at the invasive front frequently presented with lymph node metastasis (70.6%). Small tumors (≤5 mm diameter) expressed E-cadherin significantly more frequently compared with larger tumors (P=0.04); however, no other particular characteristic was found to correlate with the status of E-cadherin expression in the primary tumors. E-cadherin expression was detected in 49 (86.0%) of the 57 metastatic foci and correlated significantly with the expression status at the invasive front of the tumor (P=0.02). The Ki-67 index was universally low and was not correlated with the clinicopathological characteristics or the E-cadherin expression of the tumors. These results suggested that cancer cells in the metastatic lymph nodes exhibit indolent characteristics, similar to those of the primary PTMC. However, the metastatic cancer cells may have already completed the process of epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET), suggesting an innate malignant potential. IntroductionAccording to the World Health Organization classification system for thyroid tumors, papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma (PTC) measuring ≤10 mm in its greatest dimension (1). The occurrence of PTMC is on the increase worldwide (2-4), along with the frequent application of neck ultrasonography (US) (5,6). PTMC is generally characterized by an indolent clinical course and has an excellent prognosis, with a disease-specific mortality of <0.5% (6). However, certain PTMC cases were found to be clinically aggressive (6,7). According to the observations of Sugitani et al (7), PTMC patients with bulky lymph node metastases or extrathyroidal invasion were at the highest risk for a cancer-specific fatal outcome. Those observations suggested that there is a group of PTMCs that have already acquired highly malignant potential. However, the basic mechanism underlying the development of aggressive characteristics in these tumors has not yet been identified.The reported risk factors for PTMC recurrence were shown to be male gender (8,9), extent of primary surgery (10), presence of lymph node metastases at initial diagnosis (3,(8)(9)(10)(11)(12), tumor multifocality (3,8,12) and capsular invasion (9,(11)(12)(13)(14...

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Section: Discussionsupporting

confidence: 68%

Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 70%

Section: Patientsmentioning

confidence: 99%

See 2 more Smart Citations

E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid microcarcinoma

Nakamura

Onoda

Noda

et al. 2013

Molecular and Clinical Oncology

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“…EMT was initially reported in embryonic development; however, it also occurs during tumor metastasis (14,15) and appears to be common in PTC invasion (16)(17)(18)(19). Transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) are inflammatory cytokines that are able to stimulate EMT in thyroid cancer cells or thyroid cells cultured ex vivo (20,21 of TNF-α and IFN-γ have been demonstrated to induce invasion and metastasis of cancer (11,12,(22)(23)(24) via mechanisms involving the SMAD, NF-κB, AKT/GSK-3β and JAK/STAT signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Inflammatory mediators, tumor necrosis factor-α and interferon-γ, induce EMT in human PTC cell lines

Gao

Guan

et al. 2015

Oncology Letters

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Abstract. Inflammatory mediators, tumor necrosis factor (TNF)-α and interferon (IFN)-γ, promote adverse outcomes in numerous types of cancer; however, their role in papillary thyroid cancer (PTC) remains unclear. The aim of the present study was to investigate the influence of TNF-α and IFN-γ on the migration, invasion and epithelial-mesenchymal transition (EMT) of the three PTC cell lines, TPC-1, BCPAP and K1. The effect of TNF-α and IFN-γ on cell migration and invasion was assessed by wound-healing and Transwell assays. In addition, the mRNA and protein expression levels of the EMT makers, E-cadherin, N-cadherin and vimentin, were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunoblot analysis. The wound-healing and Transwell experiments revealed that TNF-α and IFN-γ increased the migratory and invasive behavior of PTC cells (P<0.05). RT-qPCR revealed that TNF-α and IFN-γ downregulated E-cadherin mRNA, while they upregulated N-cadherin and vimentin mRNA expression levels. These results were further confirmed by the immunoblot analysis. The results of the present study suggest that TNF-α and IFN-γ induce EMT and malignant progression in human PTC cells.

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Aberrant expression of nuclear vimentin and related epithelial–mesenchymal transition markers in nasopharyngeal carcinoma

Luo

Fang

et al. 2012

Intl Journal of Cancer

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Expression of vimentin and the epithelial to mesenchymal transition (EMT) markers E-cadherin, b-catenin is essential for the progression of various human cancers. Our study aimed to investigate the aberrant localization E-cadherin, b-catenin and vimentin, and their prognostic significance in 122 nasopharyngeal carcinoma (NPC) patients by immunohistochemistry and immunofluorescence. Our results showed that both membranous and cytoplasmic localization of E-cadherin staining were associated with lymph node metastasis (p 5 0.000 and 0.005, respectively) and clinical stage (p 5 0.000 and 0.007, respectively). High cytoplasmic b-catenin correlated significantly with larger tumor size (p 5 0.020), lymph node metastasis (p 5 0.000) and advanced clinical stage (p 5 0.036). However, no significant difference was observed between membranous b-catenin and clinicopathologic features (p ! 0.05). High nuclear vimentin expression correlated significantly with positive lymph node metastasis (p 5 0.000) and advanced clinical stage (p 5 0.000). Multivariate analysis showed that nuclear vimentin and cytoplasmic E-cadherin were independent prognostic factors (p 5 0.016 and 0.001, respectively), as well as M classification (p 5 0.001). More importantly, patients with high coexpression of nuclear vimentin and cytoplasmic E-cadherin had shorter survival time (p 5 0.000). Furthermore, high coexpression of these two proteins was closely associated with lymph node metastasis (p 5 0.000) and advanced clinical stage (p 5 0.000). Our studies provide convincing evidence that EMT may play an important role in the biological progression of NPC, and nuclear vimentin and cytoplasmic E-cadherin might have independent prognostic value in NPC patients and serve as novel targets for prognostic therapeutics.Nasopharyngeal carcinoma (NPC) is a distinctive type of head and neck cancer with distinct ethnic and geographic distributions. It occurs with the highest frequency in Southern China, with an incidence rate of approximately 20-50 cases per 100,000 people each year.1 In contrast with other head and neck cancers, most cases of NPCs are undifferentiated squamous cell carcinomas with a high tendency to invade adjacent tissues and metastasize to regional lymph nodes at an early stage. Furthermore, the majority deaths of NPC patients are attributed to local recurrence and distant metastases. 2,3 It is known that genetic susceptibility, EpsteinBarr virus (EBV) infection and dietary factors play important roles in NPC pathogenesis. 4 However, the molecular mechanisms mediating the progression and metastasis of NPC have not been fully clarified.Epithelial-mesenchymal transition (EMT) is characterized as loss of epithelial morphology and development of a highly motile mesenchymal phenotype. 5,6 EMT is essential for embryonic development and has recently been demonstrated to be crucial for the invasion and metastasis of tumors, providing tumor cells with the capacity to escape from the primary site and invade the surrounding stroma. [7][8][9] It is well known...

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Loss of cellular polarity/cohesiveness in the invasive front of papillary thyroid carcinoma, a novel predictor for lymph node metastasis; possible morphological indicator of epithelial mesenchymal transition

Abstract: LOP/C may be a useful morphological feature of epithelial mesenchymal transition under H&E observation, and it is an important indicator of lymph node metastasis and aggressive clinical behaviour of PTC.

Cited by 44 publications

References 26 publications

E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid microcarcinoma

E-cadherin expression and cell proliferation in the primary tumor and metastatic lymph nodes of papillary thyroid microcarcinoma

Inflammatory mediators, tumor necrosis factor-α and interferon-γ, induce EMT in human PTC cell lines

Aberrant expression of nuclear vimentin and related epithelial–mesenchymal transition markers in nasopharyngeal carcinoma

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