Identification of high mobility group protein I(Y) as potential progression marker for prostate cancer by differential hybridization analysis.

One of the major problems in the diagnosis of localized prostatic tumors is to predict the aggressiveness of an individual tumor, which is presumably associated with chance to progression. In an attempt to find molecular markers that are specific for aggressive prostatic cancer cells, we compared steady-state mRNA levels of progressionally related prostatic tumors. The Dunning R-3327-H subline, a relatively benign rat prostatic tumor, was compared to the therefrom derived highly aggressive MatLyLu tumor by differential hybridization analysis. The differential screening revealed 26 complementary DNA clones that detected transcripts overexpressed in MatLyLu. Upon further screening on the entire panel of Dunning R-3327 sublines, it appeared that three clones (pBUS1, pBUS19, and pBUS30), detected transcripts specifically expressed in metastatic rat prostatic tumors. The expression pattern of pBUS19 and pBUS30 suggested a relation between these complementary DNAs. Nucleotide sequence analysis, however, could not yet substantiate this. Computer-assisted comparison of the DNA sequences revealed the presence of rat long terminal repeat-like repetitive elements in pBUS19. The differential expression of repetitive elements in progressionally related tumors is interesting, yet similar findings have not been reported in human malignancies. Nucleotide sequence analysis of pBUS1 indicated that this clone is identical or related to high mobility group protein I(Y), a non-histone nuclear protein. From recent studies it appeared that this protein might be implicated in replication and/or transcription processes and is induced in fast proliferating/undifferentiated cells. The overexpression of high mobility group protein I(Y) correlates rather with metastatic ability than with growth rate; hence it may serve as a valuable marker to identify progressionally advanced prostate cancer cells.

Cadherin-11 is expressed in invasive breast cancer cell lines.

In several cancers, including breast cancer, loss of E-cadherin expression is correlated with a loss of the epithelial phenotype and with a gain of invasiveness. Cells that have lost E-cadherin expression are either poorly invasive with a rounded phenotype, or highly invasive, with a mesenchymal phenotype. Most cells lacking E-cadherin still retain weak calcium-dependent adhesion, indicating the presence of another cadherin family member. We have now examined the expression of the mesenchymal cadherin, cadherin-11, in breast cancer cell lines. Cadherin-11 mRNA and protein, as well as a variant form, are expressed in the most invasive cell lines but not in any of the noninvasive cell lines. Cadherin-11 is localized to a detergent-soluble pool and is associated with both alpha- and beta-catenin. Immunocytochemistry shows that cadherin-11 is localized to the cell membrane at sites of cell-cell contact as well as at lamellipodia-like projections, which do not interact with other cells. These results suggest that cadherin-11 expression may be well correlated with the invasive phenotype in cancer cells and may serve as a molecular marker for the more aggressive, invasive subset of tumors. Cadherin-11 may mediate the interaction between malignant tumor cells and other cell types that normally express cadherin-11, such as stromal cells or osteoblasts or perhaps even with the surrounding extracellular matrix, thus facilitating tumor cell invasion and metastasis.

DD3: a new prostate-specific gene, highly overexpressed in prostate cancer.

Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer-related deaths in the Western male population. Despite the tremendous efforts that have been made to improve the early detection of this disease and to design new treatment modalities, there is still an urgent need for new markers and therapeutic targets for the management of prostate cancer patients. Using differential display analysis to compare the mRNA expression patterns of normal versus tumor tissue of the human prostate, we identified a cDNA, DD3, which is highly overexpressed in 53 of 56 prostatic tumors in comparison to nonneoplastic prostatic tissue of the same patients. Reverse transcription-PCR analysis using DD3-specific primers indicated that the expression of DD3 is very prostate specific because no product could be amplified in 18 different normal human tissues studied. Also, in a sampling of other tumor types and a large number of cell lines, no expression of DD3 could be detected. Molecular characterization of the DD3 transcription unit revealed that alternative splicing and alternative polyadenylation occur. The fact that no extensive open reading frame could be found suggests that DD3 may function as a noncoding RNA. The DD3 gene was mapped to chromosome 9q21-22, and no homology of DD3 to any gene present in the computer databases was found. Our data indicate that DD3 is one of the most prostate cancer-specific genes yet described, and this makes DD3 a promising marker for the early diagnosis of prostate cancer and provides a powerful tool for the development of new treatment strategies for prostate cancer patients.

Down modulation of fibronectin messenger RNA in metastasizing rat prostatic cancer cells revealed by differential hybridization analysis.

To identify genes whose expression is down modulated in the process of metastasis, gene expression was analyzed in cell lines derived from Dunning R-3327 rat prostatic tumor sublines. A complementary DNA (cDNA) library from the anaplastic nonmetastasizing subline AT-1 was used for a differential hybridization analysis, using probes derived from mRNAs of the AT-1 and the metastasizing MAT-LyLu subline. In this way 14 cDNA clones were isolated representing 6 differentially expressed genes. The expression levels in a panel of tumor sublines measured with these cDNA clones were tested for correlation with the anaplastic non-metastasizing phenotype. One cDNA clone, designated pSE-1, whose expression was high in all tested sublines with that phenotype, appeared to represent the gene for fibronectin. To further investigate the down modulation of this gene, we studied its expression in AT-2 (anaplastic, nonmetastasizing tumor) and lines derived therefrom that exhibited a high metastatic potential after transfection with the v-Ha-ras oncogene. In the genetically manipulated metastasizing tumor sublines, fibronectin mRNA levels were approximately 4- to 8-fold lowered compared to the nonmetastasizing parental AT-2 line.

Homozygous deletion and frequent allelic loss of chromosome 8p22 loci in human prostate cancer.

Allelic loss studies have been instrumental in identifying tumor suppressor gene loci in a variety of cancers. In this study we analyzed prostate cancer specimens from 52 patients for allelic loss using 8 polymorphic probes for the short arm of chromosome 8. Overall, 32 of 51 (63%) informative tumors showed loss of at least one locus on chromosome 8p. The most frequently deleted region is observed at chromosome 8p22-8p21.2. Loss of one allele is identified in 14 of 23 (61%) tumors at D8S163, in 15 of 32 (47%) tumors at lipoprotein lipase, and in 20 of 29 (69%) tumors at MSR, all on 8p22. Loss of one allele is identified in 16 of 27 (59%) tumors at D8S220 at 8p21.3-8p21.2. In addition to frequent loss of one allele at the MSR locus, one metastatic prostate cancer sample demonstrated homozygous deletion of MSR sequences. Loci telomeric and centromeric to this region are largely retained. A chromosome 8p deletion map is constructed and defines the smallest region of overlap to a 14-cM interval at 8p22 between D8S163 and lipoprotein lipase, flanking the MSR locus. Evidence of chromosome 8q multiplication at locus D8S39 was detected in 5 of 32 (16%) tumors, all of which demonstrated loss with at least one probe on chromosome 8p. This study extends the previous finding of frequent loss of chromosome 8p in prostate cancer by defining a common region of loss of heterozygosity at 8p22 and a homozygous deletion of the MSR locus contained within this region. This is the first homozygous deletion identified in the genome of a human prostate cancer and the highest rate of loss yet reported on chromosome 8p in cancer. These results strongly suggest the presence of a tumor suppressor gene in this region which is frequently inactivated in prostate cancer.

Decreased expression of E-cadherin in the progression of rat prostatic cancer.

Cadherins represent a family of Ca(2+)-dependent cell adhesion molecules involved in homotypic, homophilic cell-cell interactions. Recent studies have shown that the cadherins can play a role in invasive and metastatic behavior. Using the established Dunning R-3327 model system of serially transplantable rat prostate cancers, the expression of E- and P-cadherin in rat prostatic cancer was studied. Analysis within this system demonstrated that whereas E-cadherin was expressed in the normal rat prostate and the well- or moderately differentiated, noninvasive Dunning tumors, no expression, either at the mRNA or at the protein level, could be detected in the invasive sublines. Since not all invasive Dunning tumors studied have metastatic ability, these results suggest that a decreased expression of E-cadherin is correlated with invasive behavior rather than with metastatic ability. Recently, genetic instability occurred in an animal bearing the well differentiated, androgen-responsive, slow growing, nonmetastatic Dunning R-3327-H rat prostate cancer resulting in the progression to an anaplastic, androgen-independent, fast growing, highly metastatic state. This spontaneously arising tumor, termed the AT6 subline, in its original host was heterogeneously composed of both a well differentiated and an anaplastic population of cancer cells in which areas of squamous cell differentiation were occasionally observed. The original animal bearing this heterogeneous AT6 cancer developed multiple metastases, the lung metastases being heterogeneously composed of anaplastic and squamous cell populations. Cytogenetic analysis demonstrated that the lung metastases were derived from a specific subpopulation of cancer cells present in the original AT6 primary tumor. Immunohistochemical studies demonstrated that only the area of lung metastases displaying squamous morphology were positive for E-cadherin. In contrast, the anaplastic areas of the lung metastases and the metastases in other organs were E-cadherin negative. By the first passage of the AT6 tumor only the anaplastic cells were present and no detectable E-cadherin mRNA or protein was found in the primary tumor and metastatic deposits. These results suggest that a decreased expression of E-cadherin is associated with the progression of prostatic cancer.

Cadherin switching in human prostate cancer progression.

The progression of carcinomas is associated with the loss of epithelial morphology and a concomitant acquisition of a more mesenchymal phenotype, which in turn is thought to contribute to the invasive and/or metastatic behavior of the malignant process. Changes in the expression of cadherins, "cadherin switching," plays a critical role during embryogenesis, particularly in morphogenetic processes. Loss of E-cadherin is reported to be associated with a poor prognosis; however, thus far, evidence (R. Umbas, et al., Cancer Res. 54: 3929-3933, 1994) for up-regulation of other cadherins has only been reported in vitro, ie., we have found evidence (M. J. G. Bussemakers et al., Int. J. Cancer, 85: 446-450, 2000) for cadherin switching in prostate cancer cell lines (up-regulation of N-cadherin and cadherin-11, two mesenchymal cadherins, in cell lines that lack a functional E-cadherin-catenin adhesion complex). Here, we report on the immunohistochemical analysis of the expression of N-cadherin and cadherin-11 in human prostate cancer specimens. N-cadherin was not expressed in normal prostate tissue; however, in prostatic cancer, N-cadherin was found to be expressed in the poorly differentiated areas, which showed mainly aberrant or negative E-cadherin staining. Cadherin-11 is expressed in the stroma of all prostatic tumors, in the area where stromal and epithelial cells are found. In addition, cadherin-11 is also expressed in a dotted pattern or at the membrane of the epithelial cells of high-grade cancers. In a number of metastatic lesions, N-cadherin and cadherin-11 are expressed homogeneously. These data raise the possibility that cadherin switching plays an important role in prostate cancer metastasis.

Regional loss of imprinting of the insulin-like growth factor II gene occurs in human prostate tissues.

In most tissues, the insulin-like growth factor II gene (IGF-II) demonstrates imprinting, being expressed exclusively from the paternal allele. Recently, a loss of IGF-II imprinting (i.e., biallelic expression) has been found in sporadic Wilm's tumors and lung carcinomas, and this molecular event may contribute to the pathogenesis of these tumors. Here, we report that in prostates removed at radical surgery for localized adenocarcinoma, both the cancer and the associated normal peripheral zone tissue have a pronounced biallelic expression of the IGF-II gene. However, this pattern of gene expression is uncommon in periurethral samples of benign prostatic hyperplasia (BPH) from the same specimens. We analyzed the status of genomic imprinting at the IGF-II locus in prostate specimens removed for carcinoma using an ApaI polymorphism in the 3' untranslated exon of the IGF-II gene. First-strand cDNA synthesis and subsequent PCR amplification were performed on 13 of 35 radical prostatectomy specimens found to be informative for analysis of allele-specific expression. Biallelic expression for IGF-II RNA was demonstrated in 10 (83%) of 12 tumor samples and 8 (73%) of 11 matched peripheral zone prostate samples but in only 2 (18%) of 11 BPH samples. RNA transcripts were readily demonstrated by Northern blot analysis, and differences in expression were not noted among normal, BPH, and tumor prostate tissues. In situ hybridization revealed production of IGF-II by both the epithelium and stroma. The finding of a frequent biallelic expression of IGF-II in peripheral prostate specimens suggests a regional pattern of IGF-II gene regulation exists in prostate tissue. We hypothesize that this tissue-specific pattern of gene expression may participate in the marked predilection of peripheral prostatic tissue for the development of carcinogenesis.

P-Cadherin is a basal cell-specific epithelial marker that is not expressed in prostate cancer.

P-Cadherin is a member of the cadherin family of cell surface glycoproteins that mediate Ca2+-dependent cell-cell adhesion and is expressed in a differential fashion in normal epithelial tissues. The expression of P-cadherin in human prostate cancer development has not been investigated previously. By immunohistochemistry, we show that P-cadherin expression is restricted to the cell-cell border of basal epithelial cells in 30 normal prostate samples. This staining is down-regulated in prostatic intraepithelial neoplasia and is absent in all 25 of the well to poorly differentiated prostate cancer specimens analyzed. To examine potential P-cadherin-regulatory elements, we sequenced the 5'-flanking region of this gene. Similar to the mouse gene, the human P-cadherin promoter is TATA-less, contains an Sp-1 binding site and, analogous to the human E-cadherin sequence, demonstrates a GC-rich region characteristic of a CpG island. Cytosine methylation of this region occurs in P-cadherin-negative prostate cancer cell lines but not in cell lines expressing this gene. In vivo, a lack of expression in 12 clinical prostate cancer specimens is not associated with methylation of the P-cadherin promoter. These results demonstrate that the expression of the basal cell marker P-cadherin is lost in prostate cancer development and that in vivo mechanisms other than cytosine methylation regulate this consistent loss of expression.

Molecular biology of prostate cancer.

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16 appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha catenin mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers, and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are underway and will hopefully elucidate critical early events in prostatic carcinogenesis.

The prognostic value of E-cadherin and the cadherin-associated molecules alpha-, beta-, gamma-catenin and p120ctn in prostate cancer specific survival: a long-term follow-up study.

OBJECTIVES: To determine the value of loss of expression of E-cadherin and cadherin associated molecules as prognostic markers for prostate cancer patients in a long-term follow-up study. METHODS: Sixty-five prostate cancer specimens, obtained from patients with different stages of prostate cancer who underwent a radical prostatectomy or TUR-P between 1987 and 1991, were used for immunohistochemical analysis of the expression pattern of E-cadherin, alpha-, beta-, gamma-catenin and p120(ctn). Clinical records of these patients were studied for follow-up data and the prognostic value of expression of these adhesion molecules was determined by Kaplan-Meier survival analyses and multivariable proportional hazard regression analysis. RESULTS: Normal staining patterns were found in 36 cases (55.4%) for E-cadherin, 37 cases (56.9%) for alpha-catenin, 40 cases (61.5%) for beta-catenin, 25 cases (38.5%) for gamma-catenin, and 40 cases (61.5%) for p120(ctn). Overall, a strong correlation was found between the expression of E-cadherin and other cadherin-associated molecules. The 5-year survival rates for each staining were as follows: E-cadherin (normal 79.2%, aberrant 26.8%), alpha-catenin (normal 79.2%, aberrant 26.8%), beta-catenin (normal 73.1%, aberrant 27.3%), gamma-catenin (normal 86.4%, aberrant 37.1%), and p120(ctn) (normal 72.8%, aberrant 30.0%). There was a significant difference in survival between normal and aberrant expression in each staining (log rank P < 0.0001). The proportional hazard regression model including tumor stage and Gleason score revealed alpha-catenin expression as the best prognostic marker for patients with prostate cancer. CONCLUSIONS: Our data revealed a strong correlation between E-cadherin expression and other cadherin-associated molecules. Among these markers, alpha-catenin seems the best prognostic marker for prostate cancer specific survival. Larger studies are needed to confirm this result.

Changes in gene expression and targets for therapy.

A better understanding of the molecular changes associated with the onset and progression of prostate cancer may provide us with a rational basis for the development of new diagnostic and therapeutic tools. Likewise, the recent identification of critical biochemical pathways, including angiogenesis, programmed cell death, cell adhesion and signal transduction, provide us with promising targets for therapeutic approaches. Furthermore, the identification and characterization of new tumor-specific antigens or prostate-cancer-specific gene promoters could be instrumental for the development of new treatment modalities. Many research groups are trying to identify genes that are involved in prostate cancer development and which may serve as new tumor markers and potential targets for therapy. In addition to prostate-specific antigen, prostate-specific membrane antigen and human kallikrein-2, the recently identified prostate stem cell antigen may also provide us with a new tool for the diagnosis and treatment of prostate cancer. Our own studies led to the identification of DD3, a gene that is strongly overexpressed in human prostatic cancers and the expression of which appears to be restricted to the prostate. Further studies are necessary to establish the clinical usefulness of these new prostate-cancer-specific genes for the management of prostate cancer patients.

The role of cell adhesion molecules and proteases in tumor invasion and metastasis.

Over the past 10 years it has become apparent that invasion and metastasis are extremely complex processes; neoplastic cells must escape from the primary tumor, degrade the extracellular matrix, migrate to distant sites, arrest in the capillaries, and migrate through the basement membrane and underlying connective tissue to the metastatic site. Therefore, tumor cells must exhibit considerable flexibility in their adhesive interactions, and this is reflected in a complex and dynamic expression pattern of cell adhesion molecules, proteases, protease inhibitors, motility factors, and growth factors. Despite the recent explosion of information regarding adhesion-related molecules, questions as to their possible roles in normal tissue architecture and as to how alterations in their expression or structure may be responsible for the progression from a single malignant cell to a lethal metastatic disease need further investigation. Moreover, efforts should be made to use the obtained knowledge to contribute to improvements in the clinical management of cancer. In this review the different classes of cell adhesion molecules and proteases are summarized, with special emphasis being placed on molecules that have been shown to correlate with invasion and metastasis. Furthermore, the role of E-cadherin in cell adhesion and invasive processes is discussed in more detail, since E-cadherin may be considered promising as a candidate among cell-adhesion-regulating molecules to be used as a biomarker for malignancy. We also elaborate on the role of the catenins, which associate with and are important for the functioning of E-cadherin.

Oncogene expression in prostate cancer.

Molecular biology has proven to be instrumental in studies on the onset and progression of cancer. Reasoning that tumorigenesis can be considered as a multistep process in which a normal cell gradually escapes from its delicately regulated growth pattern, one might describe this process in terms of gene expression. The group of genes that are good candidates for investigation in this context are the proto-oncogenes. Recent progress in oncogene research, has led us to believe that the group of oncogenes is much greater in number than the fifty so far characterized, since all growth factor-, growth factor receptor-, signal transducer- and transcription regulating genes have a potency to become oncogenic. Recessive genes, such as tumor suppressor genes might be equally relevant to the onset and progression of cancer. In this paper we confine ourselves to the role of protooncogenes in urological cancers, in particular prostate cancer. The usefulness of these genes as markers of progression in prostate cancer will be discussed.

Molecular cloning and characterization of the human E-cadherin cDNA.

E-cadherin is a Ca(2+)-dependent cell adhesion molecule involved in cell-cell interaction. In its normal physiological function it plays an important role in embryonic development and tissue morphogenesis. Recent studies have shown that in cancer development E-cadherin can act as a suppressor of invasion. Indeed, in several kinds of carcinomas allelic loss of the E-cadherin/Uvomorulin locus and decreased E-cadherin expression have been described. The importance of E-cadherin in human cancer development may be substantiated by molecular analysis of the E-cadherin transcript. Therefore, we isolated and characterized the human E-cadherin cDNA. Comparison of the nucleotide and deduced amino acid sequences revealed that the human E-cadherin is highly homologous to the mouse E-cadherin (uvomorulin) and to other members of the cadherin family.

Structural analysis of the entire proopiomelanocortin gene of Xenopus laevis.

In the pars intermedia of the pituitary the prohormone proopiomelanocortin (POMC) is tissue-specifically processed to, among other peptides, alpha-melanotropin (alpha MSH). In the South African clawed toad Xenopus laevis this hormone mediates the process of background adaptation: release of alpha-MSH causes darkening of the animal, while inhibition of alpha-MSH release results in a pale toad. Elevated release of alpha-MSH coincides with a higher rate of POMC gene transcription. The present study aims to find possible transcriptional regulatory elements in the Xenopus POMC gene. For that purpose the complete nucleotide sequence of the POMC gene and its 5'- and 3'- flanking regions were determined and analyzed. The Xenopus POMC gene promoter contains several regions which may be regulatory DNA elements in view of their similarity with corresponding regions of mammalian POMC gene promoters. In the rat POMC gene promoter, many of these regions represent protein-binding sequences. Besides the promoter sequence and the protein-coding sequences, no other segments with significant identity between the Xenopus and human POMC genes were found. Intron A of the Xenopus POMC gene contains a simple sequence, (TATC)76, and a JH12 repetitive element, while the 3'-flanking region contains a repetitive-EcoRI-monomer-2 element. Comparison of the JH12 sequence of the POMC gene with JH12 sequences from other Xenopus genes revealed a 335-bp consensus sequence which is flanked by a 30-bp inverted repeat. This JH12 consensus sequence is significantly larger than the previously reported JH12 core region. Alignment of intron B of the Xenopus POMC gene with database sequences revealed a consensus sequence of a novel Xenopus repetitive element of 330 bp flanked by a nearly perfect inverted repeat, indicating that this element may be a transposon-like element.

Transcriptional regulation of the human E-cadherin gene in human prostate cancer cell lines: characterization of the human E-cadherin gene promoter.

Decreased expression of the Ca(2+)-dependent cell adhesion molecule E-cadherin is observed in several poorly differentiated carcinomas and is presumably associated with an invasive phenotype of these tumors. Evidence accumulated so far indicates that decreased transcription is a major mechanism leading to defective E-cadherin function. Therefore, we isolated and characterized the human E-cadherin gene promoter and studied the transcriptional regulation of this gene in two human prostate cancer cell lines, one expressing E-cadherin (PC-3), the other one not expressing E-cadherin (TSU-pr1). We show that the E-cadherin promoter is not active in the non-expressing cells and that this may be due to the binding of a repressor protein to the promoter.

The genes for the calcium-dependent cell adhesion molecules P- and E-cadherin are tandemly arranged in the human genome.

Cadherins constitute a gene family of Ca(2+)-dependent cell-cell adhesion molecules involved in the morphogenesis and maintenance of tissue integrity. E- and P-cadherin are members of the cadherin family that are both expressed in epithelial tissues. Here we present the localization of the human P-cadherin gene at 32 kb upstream of the human E-cadherin gene, mapping it to chromosome 16q22.1. Tandem arrangement of two cell-cell adhesion molecules from the cadherin family has also been reported in chicken. This is the first evidence for the direct linkage of two cadherins in mammals. The evolutionary conservation of the tandem arrangement of two genes encoding cell adhesion molecules suggests that the close proximity of the genes may be important for the regulation of the genes.

Coordinate recruitment of E-cadherin and ALCAM to cell-cell contacts by alpha-catenin.

Here we report on the role of alpha-catenin in the cellular localization of activated leukocyte cell adhesion molecule, ALCAM, and cadherin-mediated cell adhesion in human prostate cancer cells. Cell lines that have a functional E-cadherin-mediated cell adhesion (DU-145 and LNCaP) show ALCAM staining at cell-cell contacts. In contrast, in cell lines that lack alpha-catenin expression (ALVA-31, PC-3, and PPC-1), E-cadherin-mediated adhesion is disturbed and ALCAM staining is cytoplasmic. A role of alpha-catenin in the recruitment of E-cadherin and ALCAM to cell-cell contacts was established by transfection of an alpha-N-catenin construct into cell lines ALVA-31 and PC-3. This resulted not only in the correct assembly of E-cadherin/alpha-catenin complexes at the cell membrane but also in localization of ALCAM to cell-cell contacts, indicating that indeed alpha-catenin affects ALCAM localization.

Complex cadherin expression in human prostate cancer cells.

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.