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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cysteine cathepsins are a family of lysosomal proteases that are often upregulated in various human cancers, and have been implicated in distinct tumorigenic processes such as angiogenesis, proliferation, apoptosis and invasion. During cancer progression, cathepsins are often translocated to the cell surface of tumor cells or are secreted into the extracellular milieu, where they can promote tumor invasion through several possible mechanisms. First, they can directly cleave components of the extracellular matrix and basement membrane, essentially clearing a path for the migration of tumor cells away from the primary tumor mass. Second, at the cell membrane, cathepsins can direct a proteolytic cascade in which they activate other proteases such as matrix metalloproteinases and urokinase plasminogen activator, which in turn promote invasion. Finally, cleavage of the cell adhesion protein, E-cadherin, at the cell surface can disrupt adherens junctions and thus facilitate cancer cell migration and invasion. Therefore, cathepsins are now emerging as major players in tumor progression, making them potential drug targets for a wide range of human cancers.
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PMID:Cysteine cathepsins and the cutting edge of cancer invasion. 1724 12

Many human breast cancer cell lines have been in culture for several years, serving as model systems for studying aspects of breast cancer biology. Molecular alterations might occur in these cells during cultivation, and it remains unknown to which extent findings in these cell lines can be related to human disease. Hereby, we describe the establishment of a breast cancer cell line, MW1, from malignant pleural effusion. We compare expression patterns of several molecular markers in breast biopsy tissue, in cultivated tumor cells derived from pleural effusion reflecting the metastatic state, and in late passages of a lineage derived from the pleural culture. Our data show that expression of estrogen and progesterone receptors was lost in the cultivated tumor cells derived from pleural effusion as shown by immunohistochemical staining. Cytokeratin expression patterns remained luminal. During cultivation, the growth rate of MW1 cells increased dramatically and the morphology underwent alterations. As shown by Western blotting, E-cadherin expression remained unchanged whereas P-cadherin expression had increased after 4 years of cultivation of the cell line. Integrin beta4 expression was low in early passages of the pleural effusion whereas the cell line exhibited high expression levels of beta4. HGF receptor (c-Met), EGF receptor, VEGF and VEGF receptor-2 (KDR) expression was detectable by semiquantitative RT-PCR and remained unchanged during cultivation. In contrast, VEGF receptor-1 (flt-1) expression showed lower expression after 4 years of cultivation. The cell line migrated towards HGF, but not towards VEGF. This study provides exemplary insight into the molecular metamorphosis tumor cells undergo in vivo or in vitro on their way from the primary tumor via an equivalent of the metastatic state and during the development of a clonal cell line.
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PMID:A novel breast cancer cell line initially established from pleural effusion: evolution towards a more aggressive phenotype. 1727 57

Intratumoral hypoxia is an independent indicator of poor patient outcome and increasing evidence supports a role for hypoxia in the development of metastatic disease. Studies suggest that the acquisition of the metastatic phenotype is not simply the result of dysregulated signal transduction pathways, but instead is achieved through a stepwise selection process driven by hypoxia. Hypoxia facilitates disruption of tissue integrity through repression of E-cadherin expression, with concomitant gain of N-cadherin expression which allows cells to escape anoikis. Through upregulation of urokinase-type plasminogen activator receptor (uPAR) expression, hypoxia enhances proteolytic activity at the invasive front and alters the interactions between integrins and components of the extracellular matrix, thereby enabling cellular invasion through the basement membrane and the underlying stroma. Cell motility is increased through hypoxia-induced hepatocyte growth factor (HGF)-MET receptor signaling, resulting in cell migration towards the blood or lymphatic microcirculation. Hypoxia-induced vascular endothelial growth factor (VEGF) activity also plays a critical role in the dynamic tumor-stromal interactions required for the subsequent stages of metastasis. VEGF promotes angiogenesis and lymphangiogenesis in the primary tumor, providing the necessary routes for dissemination. VEGF-induced changes in vascular integrity and permeability promote both intravasation and extravasation, while VEGF-induced angiogenesis in the secondary tissue is essential for cell proliferation and establishment of metastatic lesions. Through regulation of these critical molecular targets, hypoxia promotes each step of the metastatic cascade and selects tumor cell populations that are able to escape the unfavorable microenvironment of the primary tumor.
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PMID:Hypoxia-driven selection of the metastatic phenotype. 1745 7

Squamous cell carcinoma of the head and neck (SCCHN) metastasizes to the lymph nodes and lungs. We have generated previously an orthotopic mouse model for head and neck metastasis and did in vivo selection of SCCHN cells through four rounds of serial metastases. A subpopulation of 686LN cells with high metastatic potential (686LN-Ms) was isolated. When the highly metastatic cells were compared with their low metastatic parental cells (686LN-Ps), we found that CXC chemokine receptor-4 (CXCR4) mRNA levels were significantly higher in the 686LN-Ms cells than the 686LN-Ps cells. Interestingly, the metastatic subclones had lost epithelial morphology and acquired mesenchymal features, which were maintained during cell expansion in vitro. This was featured by decreased E-cadherin and involucrin and increased vimentin and integrin beta(1). These results imply that CXCR4 and epithelial-mesenchymal transition markers can be potential biomarkers to identify the subpopulation of cells with high metastatic potential. Using the orthotopic SCCHN animal model, we showed that anti-CXCR4 treatment suppressed primary tumor growth by inhibiting tumor angiogenesis and prevented lung metastasis. Because the reduction of metastasis seen in the treated group could have resulted from 2-fold reduction in primary tumor size compared with that in the control group, we examined the effects of the CXCR4 antagonist in an experimental metastatic animal model in which 686LN-Ms cells were i.v. injected. 686LN-Ms cells failed to metastasize in the CXCR4 antagonist-treated group, whereas they metastasized to the lungs in the control group. Our data indicate that CXCR4 is an important target to inhibit tumor progression in SCCHN.
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PMID:CXC chemokine receptor-4 antagonist blocks both growth of primary tumor and metastasis of head and neck cancer in xenograft mouse models. 1767 Dec 23

Endometrial cancer is the most common gynecologic cancer in the developed world. The cell-adhesion protein E-cadherin acts as a tumor-suppressor protein and is down-regulated by the transcription factor Snail, whose expression was shown to be associated with estrogen receptor signaling. This study aimed to investigate the expression of E-cadherin, Snail, and estrogen-receptor alpha in 87 primary tumors and 26 metastases of endometroid endometrial carcinomas. Reduced E-cadherin immunoreactivity was seen in 44.8% of the primary tumors and 65.4% of the metastases with a statistical correlation to higher tumor grade (P=0.003) only in metastatic lesions. About 28.7% of primary tumor specimens showed a positive Snail immunoreactivity that was correlated with reduced estrogen-receptor alpha expression (P=0.047). Positive Snail immunoreactivity was also seen in 53.8% of the metastases where it was correlated with higher tumor grade (P=0.003) and abnormal E-cadherin expression (P=0.003). Interestingly, a Snail expressing endometrial carcinoma-cell line showed a higher migration potential than a variant of this cell line with low levels of Snail. Taken together, our data are in line with a proposed role for Snail in endometrial tumor progression.
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PMID:The E-cadherin repressor snail plays a role in tumor progression of endometrioid adenocarcinomas. 1804 86

The transcription factor, SNAI1 (Snail), has recently been proposed as an important mediator of tumor invasion because of its role in E-cadherin down-regulation and induction of epithelial-mesenchymal transition. In human breast cancer, the expression of SNAI1 and/or the homologous SNAI2 (Slug) has been associated with E-cadherin repression, local or distant metastasis, tumor recurrence, or poor prognosis in different tumor series. However, the specific contribution of either factor to breast tumor progression is still unclear. We have analyzed the role of SNAI1 in human breast cancer by loss of function studies and provide evidence of a major role for SNAI1 in both primary tumor growth and metastasis of human breast carcinoma MDA-MB-231 cells. Specific silencing of SNAI1 by short hairpin RNA induces a decrease in mesenchymal and proinvasive markers (MMP9, ID1, SPARC) in MDA-MB-231 cells, concomitant with reduced in vitro invasive behavior. More importantly, stable SNAI1 silencing in MDA-MB-231 cells leads to a dramatic reduction of in vivo tumor incidence and growth rate. Tumors induced by MDA-MB-231-SNAI1-silenced cells show extensive necrotic regions and a significant decrease in invasive and angiogenic markers. Moreover, SNAI1 silencing increases the sensitivity of MDA-MB-231 cells to chemotherapeutics relevant in breast cancer treatments, gemcitabine and docetaxel. Remarkably, analysis of cell lines derived from lymph node metastasis indicates that SNAI1 expression is required for metastatic dissemination.
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PMID:SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma MDA-MB-231 cells. 1808 2

Squamous cell carcinoma antigen (SCCA) has been used for the management of squamous cell carcinoma, especially in order to evaluate therapeutic effects and monitor recurrence. Recent studies have shown that SCCA performs several biological functions and can influence the behavior of cancer cells. It is well known that altered expression of E-cadherin is involved in the process of cancer invasion and metastasis. The present study was therefore undertaken to investigate the relationship between the expression of SCCA, E-cadherin and lymph node metastasis in advanced cervical squamous cell carcinoma patients. We studied 70 patients who had undergone radical hysterectomy and pelvic lymphadenectomy for stage IB, IIA and IIB of the disease, without pretreatments. Immunohistochemistry, using monoclonal antibodies against SCCA2 and E-cadherin, was performed to examine the relationship between SCCA2 and E-cadherin expression patterns in primary cancer lesions and lymph node metastasis. There was a significant positive relationship between the two expression patterns in primary cancer lesions (p<0.01). Both exhibited a heterogeneous expression pattern in the primary tumor which indicated a significant relationship with lymph node metastasis (p<0.01). Our data clearly show that SCCA2 expression is significantly related to E-cadherin expression and that the heterogeneous pattern of SCCA and E-cadherin in primary lesions is strongly associated with the high incidence of lymph node metastasis in cervical squamous cell carcinoma. These findings suggest that SCCA2 may be involved in cancer behavior such as metastasis, and as such can be a useful marker in predicting lymph node metastasis.
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PMID:Relationship between decreased expression of squamous cell carcinoma antigen 2 and E-cadherin in primary cervical cancer lesions and lymph node metastasis. 1809 81

E-cadherin is a major cell adhesion molecule implicated as a potent tumor suppressor, which is frequently altered in human tumors including hepatocellular carcinoma. Here, we report that hepatitis C virus Core downregulates E-cadherin expression at the transcription level. This effect was abolished after treatment of 5'-Aza-2'dC, a specific inhibitor of DNA methyltransferase (DNMT). In addition, this repression was strongly correlated with hypermethylation of CpG islands of E-cadherin promoter via concerted action of both DNMT1 and 3b in Core-expressing cells. The decreased E-cadherin expression results in dramatic morphological changes in Core-expressing cells. In addition, Core-expressing cells aggregate poorly in suspension culture, reflecting their altered cell-cell interactions. The biological significance was further demonstrated by the increased collagen invasion ability of Core-expressing cells. Therefore, our finding suggests that Core plays a role in hepatocellular carcinogenesis by favoring cell detachment from the surrounding cells and migration outside of the primary tumor site.
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PMID:Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. 1816 8

The presence of circulating tumor cells (CTC) is common in prostate cancer patients, however until recently their clinical significance was unknown. The CTC stage is essential for the formation of distant metastases, and their continuing presence after radical prostatectomy has been shown to predict recurrent or latent disease. Despite their mechanistic and prognostic importance, due both to their scarcity and difficulties in their isolation, little is known about the characteristics that enable their production and survival. The aim of this study was to investigate the molecular mechanisms underlying the survival of CTC cells. A novel CTC cell line from the bloodstream of an orthotopic mouse model of castration-resistant prostate cancer was established and compared with the primary tumor using attachment assays, detachment culture, Western blot, flow cytometry and 2D gel electrophoresis. Decreased adhesiveness and expression of adhesion molecules E-cadherin, beta4-integrin and gamma-catenin, together with resistance to detachment and drug-induced apoptosis and upregulation of Bcl-2 were integral to the development of CTC and their survival. Using proteomic studies, we observed that the GRP94 glycoprotein was suppressed in CTC. GRP94 was also shown to be suppressed in a tissue microarray study of 79 prostate cancer patients, indicating its possible role in prostate cancer progression. Overall, this study suggests molecular alterations accounting for the release and survival of CTC, which may be used as drug targets for either anti-metastatic therapy or the suppression of latent disease. We also indicate the novel involvement of GRP94 suppression in prostate cancer metastasis.
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PMID:Decreased adhesiveness, resistance to anoikis and suppression of GRP94 are integral to the survival of circulating tumor cells in prostate cancer. 1834 Apr 25

In this study, we analyzed the effect of the metastasis suppressor CD82/KAI-1, a member of the tetraspanin superfamily, on intercellular adhesion on cancer cells. The newly established invasion assay and the cell aggregation assay revealed that CD82 strengthens E-cadherin-mediated intercellular adhesion. Interestingly, ectopic expression of CD82 stabilized E-cadherin/beta-catenin complex formation. Furthermore, CD82 reduced tyrosine phosphorylation of beta-catenin on HGF stimulation. Taken together, CD82 may stabilize or strengthen E-cadherin-dependent intercellular adhesion by regulating beta-catenin-mediated signal transduction on cancer cells, and consequently, prevent cancer cells from seceding from the primary tumor site.
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PMID:A novel function of CD82/KAI-1 on E-cadherin-mediated homophilic cellular adhesion of cancer cells. 1839 72


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