E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion

Zhang, Weitian; Alt-Holland, Addy; Margulis, Alexander R.; Shamis, Yulia; Fusenig, Norbert E.; Rodeck, Ulrich; Garlick, Jonathan A.

doi:10.1242/jcs.02738

Cited by 54 publications

(45 citation statements)

References 32 publications

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“…Experimental studies show that changes in cell-cell and cell-matrix adhesion are central to the conversion from premalignant lesions to early invasive carcinoma [13] . Syndecan-1 (CD138) is a member of the transmembrane heparin sulfate proteoglycan (HSPG) family, taking part in and improving adhesion between cell and extracellular matrix [14] , improving cell proliferation, maintaining the differentiation phenotype of cells and inhibiting the growth of tumor cells [15] .…”

Section: Discussionmentioning

confidence: 99%

“…The study of Ohta et al shows that over expression of the homeobox gene HOXD3 promotes the non-expression of E-cadherin and increased expression of integrin β3, which plays an important role in the quick migration and isolation of tumor cells [29] . Zhang et al [11] reported that E-cadherin loss in epithelial tumor progression was not only related to severing cell-cell adhesion but also associated with increased integrins expression, which induced cell-matrix adhesion of these cells [13] . The results of this study indicate that the expressions of syndecan-1 and E-cadherin in gastric tumor tissues are low and their levels are significantly correlated.…”

Section: Discussionmentioning

confidence: 99%

“…They are negatively correlated to the level of integrin β3 expression and this suggests that Integrins have different effects on the progression of gastric carcinoma. The functional consequence of enhanced cell-matrix adhesion is the initial attachment and retention of these cells at the epithelial-stromal interface, thus providing the appropriate microenvironmental conditions for incipient tumor cell invasion [13] . Basing on the biological characters of syndecan-1, E-cadherin and Integrins, on relevant documents and on the results of this study, the correlation of CAMs with the progression of gastric carcinoma can be summarized as follows: (1) at the early stage of gastric carcinoma, tumor cells have low E-cadherin and syndecan-1 expression, adhesion between cells is weak and tumor cells are isolated from primary tumor, which is the initial step of invasion and metastasis of gastric carcinoma; (2) the decrease of the expressions of E-cadherin and syndecan-1 reduces adhesion between tumor cells and BM or extracellular matrix mediated by them and this is propitious to local growth and dispersion of tumor.…”

Section: Discussionmentioning

confidence: 99%

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Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

Chu¹,

Ye²,

Tao³

et al. 2008

WJG

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analysis demonstrated that the mean survival time and 5-year survival rate were lower in the cases with low expressions of syndecan-1 and E-cadherin and high expression of integrin β3 (P < 0.01, in all cases). COX multivariate analysis showed that the expression level of syndecan-1 could be an independent prognostic index of gastric carcinoma (P < 0.01), whereas E-cadherin and integrin β3 could not be independent indexes (P > 0.05, P > 0.05 respectively). CONCLUSION:The low expression of syndecan-1 and E-cadherin and the high expression of integrin β3 are significantly correlated with the invasion and metastasis of gastric carcinoma, and they are highly correlated with each other. Therefore they may serve as important prognostic markers of gastric carcinoma. INTRODUCTIONGastric carcinoma is the most common malignant tumor of the digestive system. Two of the most important causes for the high mortality are invasion and metastasis. However, the mechanism of invasion and metastasis of gastric carcinoma is still not definitely clear at present [1] . Cell adhesion is one of the important steps in metastasis. Syndecan-1, E-cadherin and integrin β3 make up cell adhesion molecules (CAMs) and participate in the adhesion between the cell and the extracellular matrix [2] . Syndecan-1 is a set of transmembrane heparitin sulfate glycoproteins (HSPGS), which is present at the surface of most epithelia cells and take part in the adhesion between the cell and the extracellular matrix. The expression of syndecan-1 was augmented during epithelial regeneration and rearrangement in the stomach and other tissues [3,4] . E-cadherin is a calcium dependent intercellular Abstract AIM: To evaluate the relationship between the expression of cell adhesion molecules (CAMs) and the biological behavior of gastric carcinoma. METHODS:Expression of syndecan-1, E-cadherin and integrin β3 were evaluated by immunohistochemical study in a total of 118 gastric carcinomas and 20 nontumor gastric mucosas. RESULTS:T h e e x p r e s s i o n s o f s y n d e c a n -1 a n d E-cadherin were significantly lower in gastric carcinoma compared to non-tumor gastric mucosa, and the low expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). However, the expression of integrin β3 was significantly higher in gastric carcinoma compared to non-tumor gastric mucosa, and the high expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). In addition, the three protein expressions were correlated to the tumor growth pattern (P < 0.01, P < 0.01, and P < 0.05 respectively), but not correlated to tumor differentiation (P > 0.05, P > 0.05 and P > 0.05 respectively). Positive correlation was observed between the expressions of syndecan-1 and E-cadherin, but they which were negatively correlated to the expression of integrin β3 (P < 0.01 in all cases). Univariate

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

Chu¹,

Ye²,

Tao³

et al. 2008

WJG

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“…␣ 2 ␤ 1 integrin is a collagen-binding integrin, which engages in various biological functions, including collagen-induced platelet activation and aggregation (31), acting as a mediator for vascular endothelial growth factor-induced angiogenesis (32), and facilitating the invasion and adhesion of squamous cell carcinoma cells (33). The authors of several earlier studies have suggested that the increased level of ␣ 2 ␤ 1 integrin is mediated by the up-regulation of ␣ 2 integrin mRNA abundance (34 -36).…”

Section: Discussionmentioning

confidence: 99%

Elevated Expression of Cyr61 Enhances Peritoneal Dissemination of Gastric Cancer Cells through Integrin α2β1

Lin∥

Chang

Lin

et al. 2007

Journal of Biological Chemistry

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Cysteine-rich 61 (Cyr61/CCN1) is involved in human gastric cancer development and progression. Nonetheless, the role of Cyr61 as regards peritoneal dissemination of such cancers has not yet been completely characterized. We used liposome-mediated transfection to establish Cyr61, or antisense Cyr61, expression vectors into gastric cancer AGS or MKN45 cell lines. Transfectants were tested by means of a cancer-cell adhesion assay in vitro and ex vivo. Furthermore, a functional integrin fluorescence-activated cell sorting assay, reverse transcription-PCR, and an AP-1 reporter assay were performed to investigate the potential signaling pathway of Cyr61. It was shown that stable transfection of Cyr61 into the AGS cell line strongly enhanced its adhesion ability. The overexpression of Cyr61 within AGS cells significantly increased the functional expression of integrin ␣ 2 ␤ 1 . Function-neutralizing antibody to integrin ␣ 2 ␤ 1 effectively suppressed the Cyr61-mediated enhanced adhesion of AGS cells to peritoneal tissue. Promoter assays of integrin ␣2 gene further revealed that the AP-1 pathway was evidently activated within Cyr61-expressing AGS cells. Animal studies have revealed that mice injected with Cyr61-overexpressed AGS cells featured a greater number of peritoneal seeding nodules and a lower survival rate than the Neo control cell lines, and when such cells were treated with functional blocking antibody to integrin ␣ 2 ␤ 1 , they were able to elicit a decline in the peritoneal dissemination. The data suggest that Cyr61 may contribute to the peritoneal dissemination of gastric cancer by promoting tumor-cell adhesion ability through the up-regulation of the functional integrin ␣ 2 ␤ 1 via an AP-1-dependent pathway.

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“…Collectively, our results suggest that E-cadherin and GnT-III could be regulated by each other in a positive feedback. It has been reported that the association of E-cadherin with ␤1 integrin has an important role in cell-cell adhesion and intracellular signaling (40,41). In order to exclude the possible influence of ␤1 integrin on the regulation of GnT-III, GE11 cells were utilized as our experimental model.…”

Section: Figure 4 Enhanced Expression Of Gnt-iii In Cells Cultured Umentioning

confidence: 99%

Cell-Cell Interaction-dependent Regulation of N-Acetylglucosaminyltransferase III and the Bisected N-Glycans in GE11 Epithelial Cells

Iijima

Zhao

Isaji

et al. 2006

Journal of Biological Chemistry

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Changes in oligosaccharide structures are associated with numerous physiological and pathological events. In this study, the effects of cell-cell interactions on N-linked oligosaccharides (N-glycans) were investigated in GE11 epithelial cells. N-glycans were purified from whole cell lysates by hydrazinolysis and then detected by high performance liquid chromatography and mass spectrometry. Interestingly, the population of the bisecting GlcNAc-containing N-glycans, the formation of which is catalyzed by N-acetylglucosaminyltransferase III (GnT-III), was substantially increased in cells cultured under dense conditions compared with those cultured under sparse conditions. The expression levels and activities of GnT-III but not other glycosyltransferases, such as GnT-V and ␣1,6-fucosyltransferase, were also consistently increased in these cells. However, this was not observed in mouse embryonic fibroblasts or MDA-MB231 cells, in which E-cadherin is deficient. In contrast, perturbation of E-cadherin-mediated adhesion by treatment with EDTA or a neutralizing anti-E-cadherin antibody abolished the up-regulation of expression of GnT-III. Furthermore, we observed the significant increase in GnT-III activity under dense growth conditions after restoration of the expression of E-cadherin in MDA-MB231 cells. Our data together indicate that a E-cadherindependent pathway plays a critical role in regulation of GnT-III expression. Given the importance of GnT-III and the dynamic regulation of cell-cell interaction during tissue development and homeostasis, the changes in GnT-III expression presumably contribute to intracellular signaling transduction during such processes.It has been well known that sugar chains have various effects on the functional aspects of glycoproteins and play important roles in cell differentiation, adhesion, and proliferation (1, 2). The sugar chains of glycoproteins are produced via catalysis by various glycosyltransferases. As a result, a specific structure is determined by the expression pattern of these enzymes. The expression of glycosyltransferases is regulated not only by physiological conditions, such as developmental stages, but by pathological conditions, such as rheumatoid arthritis and tumorigenesis (3, 4). The increasing body of evidence suggests that the structures of the glycan components, such as sialyl Lewis antigens (5, 6), mucin-type O-glycans (7), or N-glycans (3, 8), which are controlled by glycosyltransferases, greatly contribute to cell adhesion, cell invasion, and cancer metastasis. A malignant phenotype has been reported to be highly associated with N-linked oligosaccharides (N-glycan) containing ␤1,6-branching, which is catalyzed by N-acetylglucosaminyltransferase V (GnT-V) 4 by transfer of GlcNAc from UDP-GlcNAc to a ␤1,6 mannose in N-glycans (8). It has also been reported that GnT-V activities and ␤1,6-branched N-glycan levels are increased in highly metastatic tumor cell lines (9, 10). Conversely, cancer metastasis is greatly suppressed in GnT-V knock-out mice (11). These re...

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E-cadherin loss promotes the initiation of squamous cell carcinoma invasion through modulation of integrin-mediated adhesion

Cited by 54 publications

References 32 publications

Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

Elevated Expression of Cyr61 Enhances Peritoneal Dissemination of Gastric Cancer Cells through Integrin α2β1

Cell-Cell Interaction-dependent Regulation of N-Acetylglucosaminyltransferase III and the Bisected N-Glycans in GE11 Epithelial Cells

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