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

Signaling via intercellular junctions plays an important role in the regulation of growth and differentiation of epithelial cells. Loss of cell-cell contacts has been implicated in carcinogenesis, tumor progression, and metastasis. Here, we investigated whether 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] was able to stimulate the assembly of adherens junctions and/or desmosomes in cultured human keratinocytes. After 4-day incubation, 1,25-(OH)2D3 caused assembly of adherens junctions, but not desmosomes. The adherens junctions were identified upon known ultrastructural criteria and evidence of the translocation of specific junctional proteins (E-cadherin, P-cadherin, alpha-catenin, and vinculin) to the cell-cell borders. The presence of alpha-catenin and vinculin at cell-cell borders indicated that the adherens junctions were functional. This was further supported by showing that anti E-cadherin antibody inhibited the 1,25-(OH)2D3-induced keratinocyte stratification. A relation between protein kinase C and adherens junction regulation was noticed. 1,25-(OH)2D3-dependent formation of junctions was blocked by the inhibitors of protein kinase C, bisindolylmaleimide and 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H-7), and treatment of keratinocytes with 1,25-(OH)2D3 caused a rapid activation of protein kinase C and its translocation to the membranes. Formation of intercellular contacts may be an important mechanism of 1,25-(OH)2D3 action in hyperproliferative and neoplastic diseases.
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PMID:1,25-dihydroxyvitamin D3 stimulates the assembly of adherens junctions in keratinocytes: involvement of protein kinase C. 916 7

Spatially-regulated P-cadherin expression is crucial for maintaining the normal epidermal architecture. P-cadherin expression in cutaneous squamous-cell carcinomas (SCC) is altered, and may participate in tumor progression. We therefore investigated how P-cadherin expression was regulated in a cultured cutaneous SCC cell line (DJM-1). At low calcium concentration (0.05 mM), DJM-1 cells expressed P-cadherin weakly in the cytoplasm. At a higher calcium concentration, P-cadherin was promptly translocated to the cell surface within 30 min, gradually increased on the cell surface for up to 48 hr, and was continuously expressed for at least 7 days. During this time course, the total amount of P-cadherin protein had increased, whereas the steady-state mRNA levels for P-cadherin had not changed. The inhibition of protein synthesis by cycloheximide, but not the inhibition of gene transcription by actinomycin-D, completely suppressed the expression of P-cadherin. The effect of calcium was inhibited by tyrphostins but not by H-7, cholera toxin, or dibutylic cyclic AMP. Increments in the extracellular calcium concentration did not mobilize the intracellular calcium pool, and were accompanied by the tyrosine phosphorylation of a 62-kDa protein. In addition, DJM-1 cells expressed mRNA for a calcium-sensing receptor originally demonstrated in the parathyroid gland. The results suggest an unique mechanism for regulating P-cadherin gene expression in DJM-1 cells by extracellular calcium, which stimulates the de novo synthesis of P-cadherin at the translational level through protein tyrosine phosphorylation.
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PMID:Human squamous-cell-carcinoma cell line (DJM-1) cells synthesize P-cadherin molecules via an elevation of extracellular calcium: calcium regulates P-cadherin-gene expression at the translational level via protein tyrosine phosphorylation. 935 92

Spatially regulated expression of E (epithelial)- and P (placental)-cadherins is crucial for maintaining normal epidermal architecture. In cutaneous squamous cell carcinomas (SCCs), aberrant P-cadherin expression is often observed in "squamoid" cancer cells, whereas E-cadherin expression in cancer cells is generally reduced. Therefore, it is plausible that SCC cells have acquired the ability to express P-cadherin and that P-cadherin plays a role in tumor progression. To address the issue, the in vitro effect of extracellular calcium on differentiation is a good model for investigating P-cadherin in normal and neoplastic skin. With elevations in extracellular calcium, human SCC cell line (DJM-1) cells initiate de novo synthesis of P-cadherin and express P-cadherin on the cell surface, whereas in normal human keratinocytes, P-cadherin expression on the cell surface is enhanced via the translocation from the cytosol to the cell membrane and/or the stabilization of P-cadherin at the cell surface. DJM-1 cells maintain P-cadherin expression on the cell surface at high levels for over 4 days after calcium elevation, whereas normal human keratinocytes cannot sustain cell surface P-cadherin when the cells are cultured in high calcium for more than 2 days. P-cadherin synthesis in DJM-1 cells is regulated at translational levels by extracellular calcium concentrations. SCC cells have the ability to produce P-cadherin by a mechanism not observed in normal keratinocytes, which might relate to the aberrant expression of P-cadherin in SCC of the skin.
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PMID:Distinct P-cadherin expression in cultured normal human keratinocytes and squamous cell carcinoma cell lines. 984 Jul 99

Epithelial ovarian carcinomas arise in a simple mesothelium (ovarian surface epithelium, OSE) but exhibit properties of oviductal and endometrial epithelia. Thus, during malignant progression, their differentiation proceeds from simple to complex, in contrast to carcinomas in other tissues. Related changes in OSE of women with a history of familial ovarian cancer indicate that this aberrant differentiation is initiated very early in neoplastic progression. The mechanisms underlying this process are not understood. Because cadherins are known regulators of differentiation, we investigated the relationship of the cadherins E, N and P to OSE morphology, growth patterns and differentiation in cultures of normal and metaplastic OSE from women with (FH-OSE) and without (NFH-OSE) a family history of ovarian cancer and in the ovarian carcinoma lines OVCAR-3 and CaOV3. We used immunofluorescence, RT-PCR, in situ hybridization and Western blotting. Our results define N-cadherin as the constitutively expressed cadherin of normal and metaplastic OSE and indicate that P-cadherin is undetectable while E-cadherin expression is conditional and related to genotype, stage of neoplastic progression and growth pattern. The altered expression of E-cadherin in apparently normal OSE of women with hereditary ovarian cancer syndromes in conjunction with the known capacity of E-cadherin to induce epithelial characteristics implicates this adhesion molecule as a possible inducer of the aberrant Mullerian differentiation which characterizes epithelial ovarian carcinomas. Abnormal differentiation in such (pre)-neoplastic tissues may represent an early, irreversible, non-mutational step in ovarian epithelial neoplastic progression.
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PMID:Constitutive and conditional cadherin expression in cultured human ovarian surface epithelium: influence of family history of ovarian cancer. 1018 16

We are investigating the hypothesis that cancer progression involves the formation of abnormal cadherin-catenin complexes. The detailed analysis of cadherins and catenins expressed in a panel of 17 human bladder-cancer cell lines revealed that E-cadherin was down-regulated at the mRNA level in 5 cell lines. Interestingly, plakoglobin was also down-regulated at the mRNA level in these 5 cell lines only. Furthermore, a slower migrating form of pp120 was detected in these cell lines and in 2 cell lines with heterogeneous E-cadherin expression. Cloning of the cadherins expressed in the bladder lines revealed that P-cadherin is expressed in the lines expressing E-cadherin and down-regulated at the mRNA level in lines devoid of E-cadherin. N-cadherin was expressed in the 5 lines with reduced E-cadherin expression, in the 2 lines with heterogeneous E-cadherin expression and in 2 other cell lines. Thus, we showed that catenin changes occur in correlation with lack of E-cadherin expression and that N-cadherin becomes predominantly expressed in cells that have lost E-cadherin expression. Our data suggest that co-regulation of the expression of genes encoding different members of the classical cadherins occurs during tumor progression and that expression of some catenins is also coordinated with cadherin expression.
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PMID:Changes in cadherin-catenin complexes in the progression of human bladder carcinoma. 1036 Aug 23

Changes in cell-cell interactions are critical in the process of cancer progression. Likewise, it has been shown that loss of expression of the cell adhesion molecule E-cadherin is associated with grade, stage, and prognosis in many carcinomas, including prostate cancer. Impaired E-cadherin-mediated interactions result in an invasive phenotype; however, the mere loss of cell-cell contact and communication is not the sole explanation for the observed correlation between loss of E-cadherin-mediated adhesion and poor clinical outcome. Using a degenerate cloning strategy for sequences that are highly conserved between the various cadherins, we found several other cadherins (N- and P-cadherin and cadherin-4, -6, and -11) to be expressed in human prostate cancer cells. Our data suggest that besides loss of E-cadherin function, also (upregulation of) expression of other cadherins is involved in the acquisition of an invasive and/or metastatic phenotype. Especially, changes in the expression of N-cadherin and cadherin-11 may play an important role in prostate cancer progression.
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PMID:Complex cadherin expression in human prostate cancer cells. 1065 39

Loss or reduced expression of E-cadherin has been shown to be associated with poor survival in patients with bladder cancer. In numerous cases, loss of E-cadherin expression in bladder tumors has been accompanied by continued association of catenins with the membrane, suggestive of the expression of an alternative cadherin member. In this study we examined 75 bladder tumors using immunohistochemistry for the expression of E-, P-cadherin, and alpha-, beta-, and gamma-catenins. As reported previously, loss or reduced E-cadherin expression is a frequent event in late stage bladder cancer, accompanied by less frequent alterations associated with different catenin family members. Analysis of 51 tumors for expression of E-, P-, and N-cadherin showed P-cadherin localized to the basal cell layers of normal urothelium, with retention of expression in the majority of tumors. In low-grade tumors P-cadherin was found localized to an expanded basal cell compartment, contrasting with the more extensive staining observed in late stage tumors. Membranous P-cadherin staining was often found in the absence of E-cadherin staining. N-cadherin is not expressed in normal bladder mucosa, but detection of this cadherin member was recorded in 39% (20/51) of bladder tumors. Unlike P-cadherin, membranous N-cadherin was detected in focal regions within tumors, representing novel expression in urothelial neoplastic progression. Although focal N-cadherin staining was observed in 3 noninvasive lesions, the majority of tumors expressing N-cadherin were invasive (17/20). Coexpression of E-, P-, and N-cadherin was recorded in 5 grade 2 bladder tumors. Expression of P-cadherin is maintained throughout bladder tumorigenesis, accompanied by aberrant expression of N-cadherin. Clearly, neither P- nor N-cadherin act in an invasive-suppressor mode in bladder cancer, but whether they have a primary role to play in urothelial neoplastic progression has yet to be established.
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PMID:Expression of classic cadherins type I in urothelial neoplastic progression. 1117 90

Breast carcinomas represent a heterogeneous group of tumors, with a diverse biologic behavior, outcome, and response to therapy. Recent studies have demonstrated that alterations in the expression of adhesion molecules in cancer cells are related to aggressiveness and poor prognosis. The aim of our study was to investigate the expression of P-cadherin in breast carcinomas and correlate it with estrogen receptor (ER) status. We selected 73 ductal carcinomas in situ (DCIS) and 149 invasive carcinomas of the breast, and assessed the expression of P-cadherin as well as other biologic markers. P-cadherin expression showed a strong inverse correlation with ER expression in both types of breast carcinoma (in situ and invasive). P-cadherin-positive and ER-negative tumors were related to a higher histologic grade, a high proliferation rate, and expression of c-erbB-2. We demonstrated that P-cadherin identifies a subgroup of breast carcinomas that lacks ER expression, and correlates with higher proliferation rates and other predictors of aggressive behavior. We believe that these tumors represent an advanced step in cancer progression, and our data support the hypothesis that an estrogen-independent pathway regulates P-cadherin expression.
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PMID:Aberrant P-cadherin expression: is it associated with estrogen-independent growth in breast cancer? 1260 56

P-Cadherin/CDH3 belongs to the family of classic cadherins that are engaged in various cellular activities including motility, invasion, and signaling of tumor cells, in addition to cell adhesion. However, the biological roles of P-cadherin itself are not fully characterized. Based on information derived from a previous genome-wide cDNA microarray analysis of microdissected pancreatic ductal adenocarcinoma (PDAC), we focused on P-cadherin as one of the genes most strongly overexpressed in the great majority of PDACs. To investigate the consequences of overexpression of P-cadherin in terms of pancreatic carcinogenesis and tumor progression, we used a P-cadherin-deficient PDAC cell line, Panc-1, to construct a cell line (Panc1-CDH3) that stably overexpressed P-cadherin. Induction of P-cadherin in Panc1-CDH3 increased the motility of the cancer cells, but a blocking antibody against P-cadherin suppressed the motility in vitro. Overexpression of P-cadherin was strongly associated with cytoplasmic accumulation of one of the catenins, p120ctn, and cadherin switching in PDAC cells. Moreover, P-cadherin-dependent activation of cell motility was associated with activation of Rho GTPases, Rac1 and Cdc42, through accumulation of p120ctn in cytoplasm and cadherin switching. These findings suggest that overexpression of P-cadherin is likely to be related to the biological aggressiveness of PDACs; blocking of P-cadherin activity or its associated signaling could be a novel therapeutic approach for treatment of aggressive pancreatic cancers.
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PMID:Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases. 1583 38

Cadherins are a superfamily of adhesion molecules that mediate Ca++ -dependent cell-cell adhesion necessary for normal morphogenesis and maintenance of tissue integrity. A classical cadherin molecule, such as E-cadherin, is a glycoprotein made up of three parts: an extracellular portion composed of five identical domains, a transmembrane portion composed of a single domain and a cytoplasmic portion composed of two domains. The cytoplasmic portion is anchored by means of cytoplasmic catenins to the cytoskeleton. The three amino acids sequence, histidine, alanine and valine (HAV motif) located at the most external domain of the extracellular portion, plays a key role in homophilic recognition between two cadherin molecules and cell-cell adhesion. Loss of cell-cell adhesion may be a prerequisite for malignant transformation and the invasive behavior of malignant tumors. Research of cadherin in malignancies has attracted much attention since cadherins may be proven to be reliable markers of biological behavior and prognosis The studies on cadherin in malignancies of the female genital tract have shown the following results: 1) in malignant transformation of the ovarian surface epithelium (OSE) and in epithelial ovarian carcinoma confined to the ovary (Stage I) there is a switch from N-cadherin expression to E-cadherin expression; 2) In advanced-stage epithelial ovarian carcinoma (Stages II-IV) the results are at odds: some investigators have shown a loss of E-cadherin expression most often because of hypermethylation of the promoter region of the gene, while others have demonstrated an increase in E-cadherin expression; 3) In endometrial carcinoma, E-cadherin expression is decreasing and P-cadherin expression is increasing with worsening of histologic type and differentiation, increased penetration into the myometrium, spread beyond the uterus and involvement of pelvic lymph nodes; 4) In squamous cell carcinoma of the uterine cervix E-cadherin expression is decreasing with tumor progression and in adenocarcinoma of the uterine cervix P-cadherin expression is increasing with tumor progression. It is hoped that the development of drugs that amend cell-cell adhesion will improve the prognosis of patients in whom tumor progression is associated with decrease or loss of cadherin expression.
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PMID:[Cadherins in malignancies of the female genital tract]. 1588 10


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