The cadherin cell—cell adhesion pathway in prostate cancer progression

Abstract

Cadherins are a family of calcium-dependent cell-cell adhesion molecules involved in cell-cell aggregation and morphoregulatory cell function. Dysfunction of the cadherin pathway is involved in tumour invasiveness and disease progression for a variety of carcinomas. E-cadherin is a prognostic marker in prostatic cancer, based on the correlation of the grade of E-cadherin expression and tumour grade, stage, metastasis and survival, as well as recurrence after radical prostatectomy. P-cadherin was shown to be lost in all prostatic cancers, although this most likely reflects loss of the basal cell population rather than a transcriptional down-regulation, suggesting that loss of P-cadherin expression is an early event in the tumorigenesis of prostatic carcinomas. Catenins, particularly alpha-catenin, also play an important role in the dysfunction of the cell adhesion complex. Mechanisms of inactivation of the cadherin-catenin pathway include LOH, gene deletions and gene promoter hypermethylation. Therapeutic strategies have been investigated in tumour models, i.e. the use of demethylating agents for the hypermethylated promoter region of E-cadherin or gene transfer in PC-3 cells with homozygous deletion of the alpha-catenin gene. The complexity of neoplastic changes cannot be explained by alterations of cell adhesion molecules alone; but as demonstrated, cadherins and catenins play an important role in this process.

Detailed DNA methylation profiles of the E-cadherin promoter in the NCI-60 cancer cells

“…Both visualizations were generated by the MethMiner program package. 7 Figure 1A the non-CpG converted cytosines appear as vertical strips). 11 In Fig.…”

“…7 MethMiner is a multifunctional tool that (a) determines the levels of CpG and non-CpG cytosine methylation, (b) incorporates sequence information from nonconverted DNA into the assessment of methylation, (c) creates aligned sequence representations, (d) creates singlepage depictions of CpG and non-CpG methylation patterns, and (e) provides numerical representations of methylation status for statistical analysis. MethMiner therefore serves as an aid to the identification of patterns in the many hundreds of sequence reads generated by this project.…”

“…The methylation designation and cell line designation portions of the figure were created using the MethMiner program. 7 To determine whether the pattern of CpG site no. 4 methylation was statistically significant, we used the Kolmogorov-Smirnov test to evaluate the variance of all (29 Â 28 / 2) possible CpG site pairings.…”

“…E-cad is downregulated in a wide variety of tumors originating from epithelial cells (5, 8 -10). Its loss is an indicator of poor prognosis in both breast (11) and prostate (7,12) cancers.…”

“…It interacts with the intracellular a, h, and g catenins (2) and, through those molecules, is connected to the actin cytoskeleton. It acts as a tumor and invasion suppressor (3,4), the loss of which has been associated with tumorigenesis (5) and increased metastatic potential (6,7). E-cad is downregulated in a wide variety of tumors originating from epithelial cells (5, 8 -10).…”