Significance Of Epithelial-mesenchymal Transition Research Articles

True significance of N-acetylglucosaminyltransferases GnT-III, V and α1,6 fucosyltransferase in epithelial-mesenchymal transition and cancer

It is well known that numerous cancer-related changes occur in glycans that are attached to glycoproteins, glycolipids and proteoglycans on the cell surface and these changes in structure and the expression of the glycans are largely regulated by glycosyl-transferases, glycosidases, nucleotide sugars and their related genes. Such structural changes in glycans on cell surface proteins may accelerate the progression, invasion and metastasis of cancer cells. Among the over 200 known glycosyltransferases and related genes, β 1,6 N-acetylglucosaminyltransferase V (GnT-V) (the MGAT5 gene) and α 1,6 fucosyltransferase (FUT8) (the FUT8 gene) are representative enzymes in this respect because changes in glycans caused by these genes appear to be related to cancer metastasis and invasion in vitro as well as in vivo, and a number of reports on these genes in related to epithelial-mesenchymal transition (EMT) have also appeared. Another enzyme, one of the N-glycan branching enzymes, β1,4 N-acetylglucosaminyltransferase III (GnT-III) (the MGAT3 gene) has been reported to suppress EMT. However, there are intermediate states between EMT and mesenchymal-epithelial transition (MET) and some of these genes have been implicated in both EMT and MET and are also probably in an intermediate state. Therefore, it would be difficult to clearly define which specific glycosyltransferase is involved in EMT or MET or an intermediate state. The significance of EMT and N-glycan branching glycosyltransferases needs to be reconsidered and the inhibition of their corresponding genes would also be desirable in therapeutics. This review mainly focuses on GnT-III, GnT-V and FUT8, major players as N-glycan branching enzymes in cancer in relation to EMT programs, and also discusses the catalytic mechanisms of GnT-V and FUT8 whose crystal structures have now been obtained.

P1.17-002 Clinicopathological Significance of Epithelial Mesenchymal Transition in Thymic Cancer

The epithelial to mesenchymal transition (EMT) is a fundamental biological process during which epithelial cells change to a mesenchymal phenotype which has a profound impact on cancer progression. It has been proposed that increased expressions of EMT markers, loss of epithelial markers such as E-cadherin, and altered expressions of mesenchymal markers such as N-cadherin are called as cadherin switching and associated with poor prognosis in cancer case. We analyzed the expression of E-cadherin and N-cadherin in thymic cancer to determine the relationship to clinicopthological factors and prognosis. We collected the data of 31 patients with thymic cancer from our institution between 2000 and 2014. Immunohistochemistry was used to examine the expression of EMT markers, E-cadherin and N-cadherin in tumor specimens. We evaluated the correlation between EMT and prognosis in patients with thymic cancer. We also compared expressions of the cadherins in tumor specimens obtained both before and after preoperative chemoradiotherapy or chemotherapy from 14 patients with thymic cancer who underwent preoperative biopsy in our hospital. Eighteen patients underwent preoperative treatment. The resection was extended to the surrounding organs in addition to thymectomy including thymic tumor and anterior mediastinal lymphadenectomy. Twenty-six patients had a R0 resection. Pathological findings revealed that one patient had Masaoka stage I disease, one had II, 20 had III, one had IVa, and 8 had IVb. The histological diagnosis was squamous cell carcinoma in 24, undifferentiated carcinoma in 4, and others in 3 patients. Immunohistochemically, decreased expression of E-cadherin or upregulation of N-cadherin was detected in surgically resected specimens in 15 patients whose tumor was classified as EMT marker-positive. According to a clinicopathological comparison of these groups, EMT status was not related to preoperative therapy, Masaoka staging, or histology. The 5-year survival rate for all patients was 86%, 63% for EMT marker-positive, and 100% for EMT marker-negative. The survival rate of patients with EMT marker-positive tumors was significantly lower than that of those with EMT marker-negative tumors. Decreased expression of E-cadherin or upregulation of N-cadheirn was detected in surgically resected specimens after preoperative treatment compared with biopsy specimens obtained before treatment in 10 of 14 patients. EMT marker expression such as cadherin switching was detected in thymic cancer tumor and was more often detected after preoperative treatment, indicating that EMT may affect the degree of malignant potential in thymic cancer and make them insensitive to treatment.

Predictive value for lymph node metastasis of epithelial-mesenchymal transition and cancer stem cell marker expression in early gastric cancer

BackgroundMinimally invasive therapies, including endoscopic mucosal resection or sentinel node navigation surgery, have been widely applied in early gastric cancer because of their benefits in promoting patient quality of life. However, lymph node dissection is beyond the capability of endoscopic therapy, and in sentinel node navigation surgery, the potential for skip metastasis is not negligible. Therefore, the possibility of lymph node metastasis is the most important factor to consider when deciding whether to apply the minimally invasive therapies. In the present study, the significance of epithelial mesenchymal transition and stem cell marker expression in lymph node metastasis in early gastric cancer was investigated. MethodsWe evaluated the significance of the expression of 5 epithelial mesenchymal transition-related markers (E-cadherin, MMP7, S100A, Snail-1, and HGF) and 6 stem cell markers (ALDH1, SOX2, CD24, CD44, CD54, and CD133) in 119 early gastric cancer specimens using immunohistochemistry. Because protein expression is heterogeneous in gastric cancer, we analyzed the expression of these markers in two selected regions (one each at the superficial zone and the deep invasive front). ResultsExpression of E-cadherin, MMP7, HGF, and CD133 at the deep invasive front was associated with the absence of lymph node metastasis (P=0.013, 0.018, <0.001, and 0.026, respectively). Presence of diffuse-type component, lymphatic invasion, and lack of expression of HGF and CD133 at the deep invasive front were independent predictive markers of lymph node metastasis (P=0.019, <0.001, 0.015, and 0.047, respectively). ConclusionsLymph node metastasis is strongly associated with expression status of HGF and CD133 at the deep invasive front, suggesting the usefulness of these proteins as independent predictive markers of lymph node metastasis in early gastric cancer.

胸腺癌における上皮間葉移行の臨床病理学的意義に関する解析

胸腺癌における上皮間葉移行の臨床病理学的意義に関する解析

Expression and significance of markers from lung epithelium cells in neonatal rats with bronchopulmonary dysplasia

Objective To investigate the dynamic expression of mRNA and protein of surfactant protein C (SPC), E-cadherin (E-cad), N-cadherin (N-cad) and α-smooth muscle actin (α-SMA) and elucidate the significance of epithelial-mesenchymal transition (EMT) in a newborn rat model of Bronchopulmonary dysplasia(BPD). Methods A newborn rat model of BPD in hyperoxia was established, and a control group exposed to air was established.Lung tissue was collected on days 3, 7, 14, and 21, respectively.Alveolar development was evaluated by radical alveolar counts(RAC), including thickness of alveolar septum, ratio of alveolar and septa.Real-time PCR and Western-blot were used to detect levels of markers of epithelial cells (SPC, E-cad) and interstitial cells (N-cad, α-SMA) in AT2 and protein expression. Results On day 7, 14, and 21, compared with the control group, RAC(7.38±0.92, 9.25±0.70, 9.88±0.99) and alveolar area/pulmonary septal area ratios(A/S)(2.53±0.02, 3.34±0.09, 3.96±0.13) were all higher in BPD group[RAC(5.88±0.83, 5.14±0.83, 4.38±0.52) and A/S (1.88±0.03, 1.95±0.03, 1.89±0.02)](all P<0.05); the alveolar septum(8.53±0.04, 10.75±0.46, 13.55±0.84) in BPD group were thicker than those (5.77±0.09, 4.40±0.12, 3.67±0.18) in the control group (all P<0.01). The expressions of SPC and α-SMA in BPD group were significantly higher than those in the control group on day 14 and 21(all P<0.05). The level of E-cad mRNA(2.43±0.60, 2.59±0.48, 3.37±0.53) and protein(18.39±1.77, 18.29±1.52, 11.48±1.72) for E-cad were higher in the control group than those(mRNA: 1.48±0.55, 1.57±0.48, 1.12±0.45; protein: 9.50±1.38, 8.57±1.06, 8.22±1.31) in BPD group was lower(P<0.05), while the level of N-cad was significantly higher(P<0.05) on day 7, 14, and 21. Conclusions In the development of BPD, the markers of lung epithelial cells were down regulation, while the markers of interstitial cells were up-regulation, and these findings suggest that EMT from lung epithelial cells contributes to the occurrence of BPD. Key words: Alveolar epithelial type Ⅱ cell; Special marker; Epithelial-mesenchymal transition; Bronchopulmonary dysplasia; Rat, newborn

Clinical significance of epithelial mesenchymal transition (EMT) in chronic obstructive pulmonary disease (COPD): potential target for prevention of airway fibrosis and lung cancer.

Unfortunately, the research effort directed into chronic obstructive pulmonary disease (COPD) has been disproportionately weak compared to its social importance, and indeed it is the least researched of all common chronic conditions. Tobacco smoking is the major etiological factor. Only 25% of smokers will develop “classic” COPD; in these vulnerable individuals the progression of airways disease to symptomatic COPD occurs over two or more decades. We know surprisingly little about the pathobiology of COPD airway disease, though small airway fibrosis and obliteration are likely to be the main contributors to physiological airway dysfunction and these features occur earlier than any subsequent development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration and change in extracellular matrix (ECM) is epithelial mesenchymal transition (EMT), so called Type-II EMT. When associated with angiogenesis (Type-III EMT) it may well also be a link with the development of lung (airway) cancer which is closely associated with COPD. Active EMT in COPD may help to explain why lung cancer is so common in smokers and also the core pathophysiology of small airway fibrosis. Better understanding may lead to new markers for incipient neoplasia, and better preventive management of patients. There is serious need to understand key components of airway EMT in smokers and COPD, and to demarcate novel drug targets for the prevention of lung cancer and airway fibrosis, as well as better secondary management of COPD. Since over 90% of human cancer arises in epithelia and the involvement of EMT in all of these may be a central paradigm, insights gained in COPD may have important generalizable value.

Unusual Patterns of Endometrial Carcinoma Including MELF and its Relation to Epithelial Mesenchymal Transition

Although most of Dr Scully's research addressed diseases of the ovary, about 10% of his published manuscripts focused on endometrial lesions, most often consisting of observations about unusual types or deceptive patterns of endometrial carcinoma that had not previously been described, or lesions for which the behavior had been unknown. He characterized and clarified the entity of clear cell carcinoma of the endometrium, and wrote about endometrial carcinomas with argyrophil, oxyphil, and giant cells, and those simulating microglandular hyperplasia of the cervix, as well as uterine papillary serous, squamous cell, and small cell carcinoma,. He provided a useful classification of precancers of the endometrium and also emphasized the relationship between estrogens and the development of some forms of uterine carcinoma. This article addresses the importance of his careful observations, focusing primarily on the potential relationship of 1 pattern of endometrial carcinoma that he described which has areas of microcystic, elongated, fragmented glands (MELF), frequently accompanied by a fibromyxoid or inflammatory stroma, to the recently described concept of epithelial mesenchymal transition. Endometrioid carcinomas with MELF frequently display a variety of immunohistochemical changes including reduced expression of E-cadherin, B-catenin, estrogen and progesterone receptors, Ki67, and overexpression of fascin, galactin-3, cyclin D1, and p16, as might be expected with epithelial mesenchymal transition. Additional studies will be needed to explain the significance of epithelial mesenchymal transition that occurs in carcinomas with regions of MELF.

Abstract 5003: The functional interplay between activated Stat5 and Stat3 in breast cancer formation and progression.

Abstract Cancer cells with stem cell-like characteristics are defined as cancer stem cells (CSCs) that are proposed to drive tumor initiation, progression and recurrence. Recent studies show the significance of epithelial-mesenchymal transition (EMT) in the induction of CSCs and their metastatic dissemination. Growth and colonization of the migrating stem cells require their re-differentiation and the reversal of EMT, mesenchymal to epithelial transition (MET), at the site of distant metastasis. We study the functional interplay between two related transcription factors, signal transducer and activator of transcription 5 (Stat5) and Stat3 in the genetic and epigenetic regulation of non-metastatic and metastatic breast cancer cells. Simultaneous activity of both Stats is observed in high percentage of human luminal breast cancers. In both normal and malignant cells, Stat5 activity is associated with cell proliferation, differentiation and survival, however, its activity in tumors is defined as a good prognostic marker due to response to antiestrogen therapy. During postlactational gland regression, called involution, P-Stat3 regulates lysosomal-mediated cell death, which is in contrast to its strong oncogenic function during mammary tumorigenesis. To gain insights into oncogenic functions of Stat5, we established a new mouse model which allows the investigation of genetic and epigenetic contributions in the initiation and progression of mammary tumors. In this model we used genetic manipulation of mammary stem cells (MaSCs) derived from primary tissue and the reconstitution of functional epithelium through transplantation into cleared fat pads to generate transgenic glands. The persistent activation of Stat5 during post-lactational involution resulted in the induction of non-metastatic adenocarcinomas, resembling human luminal-A breast cancer subtype. These tumors could be serially transplanted in BALB/c wild-type recipient mice and contain a small fraction of Lin-CD24lowCD44high tumor initiating cells. Both primary and secondary tumors show simultaneous activity of Stat5 and Stat3 and express estrogen and progesterone receptors (ER+PR+) and their downstream target genes like amphiregulin, RANKL and Wnt4. We performed microarray gene expression analysis of tumor tissues and P-Stat5 transgenic grafts and studied potential target genes, which can explain Stat5 oncogenic functions in tumor formation in contrast to its suppression effects on tumor cell migration. We are now studying the relative contribution of Stat5 and Stat3 in the regulation of metastatic process and transient EMT-MET changes. Our tumor model allows the identification of new genetic and epigenetic biomarkers, which are necessary for a better diagnosis and treatment of breast cancer and the prediction of invasive relapse. Citation Format: Vida Vafaizadeh, Bernd Groner. The functional interplay between activated Stat5 and Stat3 in breast cancer formation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5003. doi:10.1158/1538-7445.AM2013-5003

Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer

Background:Circulating tumour cells (CTC) have a crucial role in metastasis formation and can consistently provide information on patient prognosis. Epithelial-mesenchymal transition (EMT) is considered as an essential process in the metastatic cascade, but there is currently very few data demonstrating directly the existence of the EMT process in CTCs.Methods:CTCs were enriched by blood filtration using ISET (isolation by size of epithelial tumour cells), triply labelled with fluorescent anti-vimentin, anti-pan-keratin antibodies and SYTOX orange nuclear dye, and examined by confocal microscopy in six patients with metastatic non-small cell lung cancer (NSCLC). In parallel, CTCs were morphocytologically identified by an experienced cytopathologist.Results:Isolated or clusters of dual CTCs strongly co-expressing vimentin and keratin were evidenced in all patients (range 5–88/5 ml). CTCs expressing only vimentin were detected in three patients, but were less frequent (range 3–15/5 ml). No CTC expressing only keratin was detected.Conclusion:We showed for the first time the existence of hybrid CTCs with an epithelial/mesenchymal phenotype in patients with NSCLC. Their characterisation should provide further insight on the significance of EMT in CTCs and on the mechanism of metastasis in patients with NSCLC.

Significance of Epithelial-Mesenchymal Transition in Cancer

Significance of Epithelial-Mesenchymal Transition in Cancer