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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previously, we demonstrated that connexins (Cxs) showed aberrant localization and expression in most endometrial hyperplasia and carcinoma samples, indicating that during endometrial carcinogenesis, loss of gap junctional intercellular communication (GJIC) may occur at relatively early stages. In the present study, we focused on the correlations between GJIC and the expression of the E-cadherin and its 5' CpG island methylation in endometrial cancer cells and tissues to investigate their roles in the carcinogenesis and tumor progression of endometrial cancer. In this study, three of the 10 cell lines investigated, Ishikawa, RL-952 and KLE, in which both Cxs and E-cadherin mRNA were expressed, exhibited GJIC by scrape-loading/dye transfer. On the other hand, the other seven cell lines, in which either or both Cxs and E-cadherin mRNA were negative or weakly expressed, did not show GJIC. HEC-50, HEC-1B and HEC-108, in which Cxs were positively expressed but E-cadherin was negatively expressed, showed cytoplasmic localization of Cxs by immunohistochemistry. All five lines, which showed the weak expression of E-cadherin, had E-cadherin 5' CpG island methylation. By immunohistochemistry of 56 endometrial carcinomas, 13 of 27 methylated samples showed weak expression of Cx26 and the other 14 showed diffuse localization in cytoplasm. On the other hand, of 29 unmethylated samples, two showed cell-cell localization, 25 weak expression and two diffuse localization. Furthermore, E-cadherin expression was revealed to be drastically down-regulated by E-cadherin antisense oligonucleotides that post-transcriptionally down-regulated E-cadherin expression and in the cell, the localization of Cxs were changed from the cell-cell borders to the cytoplasm, and GJIC also decreased. The results indicated that 5' CpG island methylation, which caused loss of E-cadherin expression, indirectly caused the suppression of GJIC by aberrant localization of Cxs in endometrial carcinoma cells.
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PMID:Suppression of gap junctional intercellular communication via 5' CpG island methylation in promoter region of E-cadherin gene in endometrial cancer cells. 1289 2

Glypican-3 (GPC3), a proteoglycan bound to the cell membrane through a GPI anchor, is widely expressed in the embryo but down regulated in most adult tissues, with some exceptions as mammary cells. GPC3 is involved in the regulation of cell proliferation and survival in specific cell types. LM3, a murine mammary tumor cell line unable to express GPC3, was stably transfected with the rat GPC3 gene to analyze its role in tumor progression. Upon injection into syngeneic BALB/c mice LM3-GPC3 clones showed less local invasiveness and developed fewer spontaneous and experimental lung metastasis than controls. GPC3-expressing cells were more sensitive to apoptosis induced by serum depletion, exhibited a delay in the first steps of spreading and were less motile than controls. On the other hand, LM3-GPC3 cells were significantly more adherent to FN than control ones. We observed that GPC3 transfectants presented a higher expression of E-cadherin and beta-catenin, molecules whose down regulation has been associated with tumor progression. Exogenous TGF-beta increased MMP-9 activity in both control and GPC3-expressing cells, but did not modulate MMP-2. Contrarily, GPC3 expression prevented the increase of MMP-2 activity induced by IGF-II. Our results suggest that GPC3 has a protective role against mammary cancer progression.
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PMID:Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model. 1290 26

beta-catenin plays an important role in the Wnt signaling pathway and the E-cadherin-catenin complex plays a critical role in the maintenance of normal tissue architecture. An alteration of any of the components of the E-cadherin-catenin complex is believed to result in the loss of cell-cell adhesion and to contribute to carcinogenesis. In order to evaluate such alterations in the gastric adenoma-carcinoma sequence, the abnormal expression of beta-catenin and E-cadherin and the mutations of beta-catenin exon 3 were studied. In the case of beta-catenin, nuclear immunoreactivity was noted in 17 (11.3%) out of 150 adenomas and 19 (17.1%) out of 111 carcinomas (p = 0.18). Among 51 gastric adenomas, no mutations were detected by direct sequencing analysis. The loss of membranous expression of both beta-catenin and E-cadherin linearly increased with tumor progression, however, beta-catenin loss was more frequent than E-cadherin. Our results show that the nuclear expression and membranous loss of beta-catenin without exon 3 mutation is relatively frequent in gastric adenomas. These suggest that alteration of other genes is primarily responsible for the nuclear translocation of beta-catenin in gastric adenomas.
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PMID:Expression of beta-catenin and E-cadherin in the adenoma-carcinoma sequence of the stomach. 1292 24

The function of the predisposition gene to multiple endocrine neoplasia type 1 (MEN1) syndrome remains largely unknown. Previous studies demonstrated that null mutation of the Men1 gene caused mid-gestation lethality in mice, whereas heterozygous Men1 knockout mice developed multiple endocrine tumors late in life. To seek direct evidence on the causal role of menin in suppressing tumor development, we generated mice in which the Men1 gene was disrupted specifically in pancreatic beta cells. These mice began to develop hyperplastic islets at as early as 2 months of age and insulinomas at 6 months of age. The islet lesions exhibited features of multistage tumor progression, including beta-cell dedifferentiation, angiogenesis, and altered expression of both E-cadherin and beta-catenin. Additionally, disturbance of blood insulin and glucose levels correlated with tumor development, mimicking human MEN1 symptoms. Our data indicate that this strain of mice provides a powerful tool for the study of the mechanisms of tumorigenesis related to MEN1 disease.
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PMID:Pancreatic beta-cell-specific ablation of the multiple endocrine neoplasia type 1 (MEN1) gene causes full penetrance of insulinoma development in mice. 1294 3

Ionizing radiation (IR) is a known human breast carcinogen. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. As a consequence, we have proposed that an additional factor contributing to IR carcinogenesis is the potential disruption of critical constraints that are imposed by normal cell interactions. To test this hypothesis, we asked whether IR affected the ability of nonmalignant human mammary epithelial cells (HMEC) to undergo tissue-specific morphogenesis in culture by using confocal microscopy and imaging bioinformatics. We found that irradiated single HMEC gave rise to colonies exhibiting decreased localization of E-cadherin, beta-catenin, and connexin-43, proteins necessary for the establishment of polarity and communication. Severely compromised acinar organization was manifested by the majority of irradiated HMEC progeny as quantified by image analysis. Disrupted cell-cell communication, aberrant cell-extracellular matrix interactions, and loss of tissue-specific architecture observed in the daughters of irradiated HMEC are characteristic of neoplastic progression. These data point to a heritable, nonmutational mechanism whereby IR compromises cell polarity and multicellular organization.
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PMID:Ionizing radiation induces heritable disruption of epithelial cell interactions. 1296 Mar 93

Since ovarian carcinoma cells detach from the primary lesion and metastasize via peritoneal dissemination, we hypothesized that these cells are exposed to hypoxia, which may affect cell attachment and invasiveness. To address this hypothesis, we first examined in vivo the immunohistochemical expression of hypoxia-inducible factor-1alpha (HIF-1alpha) and its topological correlation with E-cadherin expression in ovarian carcinomas. We then examined in vitro the effect of hypoxia on the mRNA and protein expressions of E-cadherin using two ovarian cancer cell lines, SKOV3 and OVCAR3, and normal ovarian surface epithelial (OSE) cells. In addition, hypoxia-induced change in the expression of SNAIL, a transcriptional factor repressing E-cadherin expression, was also analyzed. Finally, we examined the facilitation of invasiveness of ovarian cancer cells under hypoxia using Matrigel invasion assay. Immunohistochemically, nuclear localization of HIF-1alpha was observed in 32 of the 76 (42%) carcinomas studied, and showed a topological correlation with loss of E-cadherin expression. Northern blotting, real-time PCR and Western blotting demonstrated that E-cadherin expression was remarkably decreased under hypoxia in both SKOV3 and OVCAR3 cells, but not in normal OSE cells. mRNA expression of SNAIL was increased under hypoxia in both ovarian cancer cell lines. Invasion assay revealed that hypoxia increases the invasiveness of ovarian cancer cells. Accordingly, the present study demonstrated that hypoxia induces down-regulation of E-cadherin in ovarian carcinoma cells, via up-regulation of the transcriptional repressor SNAIL. These findings suggest that hypoxia plays an important role in the change in intercellular attachment, which may be involved in the initiation of tumor progression of ovarian cancer cells.
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PMID:Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells. 1450 51

The etiology of gastric cancer (GC) is multifactorial, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. This article reviews the considerable progress that has been achieved in understanding the genetics of GC. The genetic effects consist of inherited genetic factors that predispose to GC, and the genetic targets of neoplastic progression that confer altered growth capacity to neoplastic cells. Inherited genotypes include germline mutations of high-penetrance genes directly associated with hereditary GC syndromes and genetic polymorphisms that indirectly affect the susceptibility to GC after exposure to carcinogens or Helicobacter pylori infection. Based on accumulation of different oncogenes or tumor suppressor genes alterations, 2 broad classes of genetic pathways called suppressor and mutator phenotypes are defined that participate in the development and progression of GC. Examples of genes involved in pathogenesis of GC include p53, adenomatous polyposis coli (APC), beta-catenin, E-cadherin, transforming growth factor (TGF)-betaRII, and hMLH1. Delineating genes involved in different subtypes of GC can reflect the heterogeneity and biologic characteristics of GC. Elucidation of the role of inherited genotypes and genetic alterations at different stages of gastrocarcinogenesis may provide a more coherent picture of the mechanism of this devastating disease and facilitate the development of novel approaches to effective prevention and intervention. Advances in high throughput technologies and functional genomics have rapidly increased our understanding of gene structure and function and its role in disease.
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PMID:Genetic alterations and polymorphisms in gastric cancer. 1451 82

Carbonic anhydrase IX (CA IX) is a cancer-associated transmembrane isoform of zinc metalloenzymes that catalyse interconversion between carbon dioxide and bicarbonate. CA IX is strongly induced by tumor hypoxia and has been proposed to participate in acidification of tumor microenvironment and in cell adhesion. To elucidate the cell adhesion-related role of CA IX, we investigated its subcellular localization and relationship to E-cadherin, a key adhesion molecule whose loss or destabilization is linked to tumor invasion. For this purpose, we generated MDCK cells with constitutive expression of human CA IX protein. During the monolayer formation, CA IX was localized to cell-cell contacts and its distribution in lateral membranes overlapped with E-cadherin. Calcium switch-triggered disruption and reconstitution of cell contacts resulted in relocalization of both CA IX and E-cadherin to cytoplasm and back to plasma membrane. A similar phenomenon was observed in hypoxia-treated and reoxygenated cells. Moreover, CA IX-expressing MDCK cells exhibited reduced cell adhesion capacity and lower levels of Triton-insoluble E-cadherin. Finally, CA IX was found to coprecipitate with beta-catenin. We conclude that CA IX has a capacity to modulate E-cadherin-mediated cell adhesion via interaction with beta-catenin, which could be of potential significance in hypoxia-induced tumor progression.
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PMID:Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. 1456 91

Perturbation in E-cadherin expression leads to loss of cellular adhesion with possible consequence of cellular transformation and tumor progression. The aims of this study were to determine E-cadherin expression in each subtype of gastric cancer classified by different classification systems, and to investigate the role of E-cadherin in cell differentiation, cancer invasion and metastasis. Expression of E-cadherin was analyzed in 84 patients with gastric adenocarcinoma by immunohistochemistry and correlated with clinicopahotlogical parameters. Our results showed loss of E-cadherin expression in 0% (0/3), 20.0% (9/45), 48% (15/31), 100% (3/3) and 100% (2/2) of papillary, tubular, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma by Japanese histological classification. The reduction of E-cadherin expression was inversely correlated with the grade of differentiation. According to the histological classification of Lauren and Ming, the frequency of lost E-cadherin expression was higher in diffuse type (65%) and infiltrative type (64%) gastric cancer than in intestinal type (20%, P<0.001) and expanding type cancer (22%, P<0.001), respectively. The loss of E-cadherin expression was significantly associated with tumor invasion (P<0.05). Furthermore, there was a borderline association between the loss of E-cadherin expression and poor survival (P=0.109). These data demonstrated a striking correlation between E-cadherin expression and the differentiation of gastric carcinoma. The loss of E-cadherin expression may contribute to gastric cancer invasion to adjacent organs.
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PMID:Loss of E-cadherin expression correlates with poor differentiation and invasion into adjacent organs in gastric adenocarcinomas. 1458 Jun 91

Carcinoembryonic antigen (CEA) has been suggested as a metastatic activator in colorectal carcinoma, whereas the E-cadherin expression is downregulated in a variety of carcinomas. CEA and E-cadherin expressions were simultaneously assessed with regard to tumor progression in the various sites of colorectal carcinomas with liver metastasis. Twenty-six consecutive patients who had colorectal carcinoma with liver metastasis underwent curative surgery for primary tumor and liver metastasis. CEA and E-cadherin expression were identified on immunohistochemical staining using the labeled streptavidin-biotin method. Their mRNA expression was also detected by RT in situ PCR using one-step reverse transcription-polymerase chain reaction (RT-PCR). CEA and E-cadherin expression scores in the tumor center were greater than those in the tumor margin in both primary tumor and liver metastasis (P<0.001 to 0.006). CEA expression scores were closely associated with E-cadherin expression scores on the corresponding tumor site (P<0.001 to 0.017). CEA and E-cadherin mRNA expression was greatest in the hepatocytes adjacent to liver metastasis, next greatest in the primary tumor, and least in the liver metastasis (P<0.001 to 0.002). CEA mRNA expression was also closely correlated with E-cadherin mRNA expression in the primary tumor (P<0.001) and in the adjacent hepatocytes of the liver metastasis (P=0.018). Patients with a lesser CEA expression score in the liver metastasis margin appeared to have a longer disease-free survival period than did those with a greater CEA expression score. Expression of CEA and E-cadherin was closely correlated with the mRNA levels. Furthermore, these correlations may be implicated in the tumor progression of colorectal carcinoma considering their biological properties.
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PMID:Coexpression of carcinoembryonic antigen and E-cadherin in colorectal adenocarcinoma with liver metastasis. 1459 71


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