E-cadherin and associated molecules in the invasion and progression of prostate cancer

Prostatic carcinoma is the most common type of male cancer found in the Western world and its distant metastasis becomes a life threatening event in tumour bearing patients. However, the biology of prostate cancer and metastasis is poorly understood. We review the progress made in the last decade on the molecular and cellular biology of cell-cell adhesion molecules in the invasion and progression of prostate cancer, with emphasis being placed on E-cadherin and its associated molecules.     

Predictive value of p53 mutations analyzed in bladder washings for progression of high-risk superficial bladder cancer

To assess the value of p53 mutations in predicting the progression of superficial bladder cancer [transitional cell carcinoma (TCC)] and to define exactly when p53 mutations occur in the process of tumor progression, 80 consecutive bladder washings from 26 high-risk (indicated by quantitative karyometric analysis) superficial TCC patients were examined by single-strand conformation polymorphism. Six of 13 patients who experienced clinical progression (progression to T2 or higher) were found to have a p53 mutation in one or more of their bladder washings. In the control group (no progression to invasive disease), only 1 of 13 patients had a p53 mutation. For these high-risk superficial TCC patients, the occurrence of a p53 mutation has a positive predictive value of 86% for the progression of disease. A negative predictive value of 63% was observed. Moreover, because p53 mutations were found in samples prior to progression (mean, 8 months), they could identify patients who need changes in their treatment strategies to prevent progression to invasive disease. Despite these promising results, it is obvious that to increase not only the positive predictive value but especially the negative predictive value of this procedure to predict progression, additional prognostic markers are still needed.     

Immunosuppressive factors: role in cancer development and progression

The concept of the immunological surveillance against neoplastic cells was initially proposed by Erlich in 1909 and later elaborated by Burnet. This hypothesis states that the normal function of the immune system, in particular the cell-mediated immunity, is to recognize and destroy the transformed and proliferating tumor cells. The role of cell-mediated immunity during the first steps of tumorigenesis remains controversial. However, there is certain evidence about its importance in the progression and dissemination of cancer. The frequent immunosuppressed condition of cancer patients at tumor relapse or recurrence of secondary tumors is a clinical sign supporting this hypothesis, and many studies have demonstrated a defective immune response in patients diagnosed with advanced cancer. Several mechanisms of escape from the immune surveillance have been described, including the immunoselection of tumor antigen-negative variants, the downregulation of MHC class I expression, suppressive T cells, and the elaboration of immunosuppressive cytokines and other factors. Because of the technical difficulty of isolating the very small amounts from culture supernatants or body fluids, only a few of these substances have been characterized and studied with respect to their biological activity: transforming growth factor-beta (TGF-beta), the protein p15E, interleukin 10 (IL-10), prostaglandin E2 (PGE2), mucins, suppressive E-receptor (SER), immunosuppressive acidic protein (IAP), and adhesion molecules. The possibility of monitoring cancer patients by testing biochemical factors related to cancer growth led to a proposal to measure a number of these factors as tumor markers. Some of them, e.g. mucins, enjoy the consensus of the oncologic community, as for some indications they can help the clinician in the management of cancer patients. Except for the class of mucins, the other above-mentioned immunosuppressive factors have not found any clinical application in the laboratory routine because the information deriving from their measurement, although of speculative and scientific interest, has limited clinical value at present. Nevertheless, even if they have no impact on patient management, these substances do have a potential role to play in the study of cancer patients, and should be taken into account when developing new therapeutic strategies.     

The current role of radiotherapy in the treatment of invasive bladder cancer

Invasive bladder cancer remains a therapeutic challenge. Approximately 50% of patients treated with radical cystectomy die of metastatic disease. External beam radiation therapy when given alone has results inferior to that of surgery, and although it has shown some benefit when given in the preoperative setting, this was not verified by randomized trials. Altered fractionation radiation schemes and combined modality using a cisplatin-based combination chemotherapy with radiation have resulted in up to 60% bladder preservation.     

Association of PTPmu with catenins in cancer cells: a possible role for E-cadherin

Protein tyrosine phosphorylation and dephosphorylation is regulated by the action of protein tyrosine kinases (PTK) and phosphatases (PTP) respectively. The receptor type phosphatase, PTPmu, is located at the cell surface where it may function to regulate the phosphoryl status of members of the cadherin adhesion complex and thus cadherin function. We have investigated the association of PTPmu with E-cadherin and catenin molecules in human tumour cells and report that PTPmu; is associated with E-cadherin and alpha and beta-catenin in E-cadherin-positive cell lines. However, no association between PTPmu and catenin members could be detected in E-cadherin negative cells. These observations suggest that the association of PTPmu with catenin molecules may occur via E-cadherin rather than a direct interaction.     

A critical review of the role of definitive radiation therapy in bladder cancer

The role of radiation therapy in the management of bladder cancer continues to be controversial. Attention to the issue of response to treatment, instead of overall survival, ultimate local control and quality of life, has hampered progress in determining the optimal-treatment strategy for patients with bladder cancer. Although the heterogeneity of bladder cancer has been recognized for some time now, the trend has been to seek one cure for all, rather than to use the available modalities selectively and optimally. The use of continent urinary diversion has made cystectomy more acceptable, but no form of diversion is as satisfying as a natural, well functioning bladder. The case against definitive XRT has been built on the lack of total radiosensitivity of transitional cell carcinoma. It is interesting that the lack of total chemosensitivity of bladder cancer and total curability with surgery has not prevented those modalities from being widely used. The recognition of the systemic nature of invasive bladder cancer has appropriately led to increased attention to the control of systemic disease. However, this has led to, at times, compromised local therapy. The use of primary or adjuvant chemotherapy should not impede the pursuit of optimal local therapy in patients with bladder cancer with the emphasis on the optimal quality of life. In parallel, the goal of bladder preservation and improved quality of life should not overshadow the importance of local tumor control. Because metastatic bladder cancer currently is an almost universally lethal disease, we should optimize the use of effective treatment modalities to achieve modest improvements in cure rate. The idea that definitive radiation therapy has no role in the management of bladder cancer exists in the minds of those who hold strong convictions and see an alternative view to their own as being controversial. We believe that attention should not focus on this controversy but on the recognition of the reality that the best management of bladder cancer is a shared responsibility among the oncologists of all disciplines. With this recognition, clinical research toward improving outcome for patients with bladder cancer will move forward.     

E-cadherin germline mutations in familial gastric cancer

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide, and about 10% of cases show familial clustering. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.     

Expression of E-cadherin in primary and metastatic prostate cancer

Immunohistochemical studies have suggested that E-cadherin may be a useful prognostic marker in prostate cancer. Previous studies have depended on cryostat sections of tissues selected grossly. Many prostate cancers, even when extensive, are not visible grossly; many others cannot be demarcated sharply grossly. The wide applicability of prognostic markers after total prostatectomy will depend upon methods that can be applied to tissue selected based upon the histopathological examination of the entire prostate. Our purpose was to investigate the possibility that E-cadherin could be demonstrated in paraffin-embedded whole prostates and metastatic prostate cancer. Microwaving in citrate buffer was the best of five methods tested for the demonstration of E-cadherin in paraffin-embedded prostate and was used to investigate 53 primary prostate cancers from 44 patients and lymph node metastases from 14 patients. Metastases of prostate cancer to lymph nodes expressed less (P = 0.008) E-cadherin than primary prostate cancers. The expression of E-cadherin correlated with the histopathological differentiation (Gleason grade) of primary prostate cancers (P = 0.03, Ptrend = 0.003). The use of monoclonal anti-human E-cadherin (HECD-1) with microwaving in citrate buffer followed by immunoperoxidase staining with heavy metal enhancement for the demonstration of E-cadherin in paraffin-embedded tissue will, for the first time, allow the use of archival tissue for prognostic studies of E-cadherin in prostate cancer and other tissue. Our results are consistent with the hypothesis that aggressive prostate cancers exhibit decreased expression of E-cadherin and demonstrate the feasibility of long-term prognostic studies of this molecule in the usually multiple prostate cancers found in whole, formalin-fixed, paraffin-embedded resected prostates.     

BCG in bladder cancer

BCG is usually thought of as a vaccine for tuberculosis. This paper describes how it can be used as an alternative to cytotoxic agents in the treatment of bladder cancer.     

PyNPase expression and cancer progression in the colorectum

We analyzed PyNPase expression discriminating between cancer and tumor stroma of the colorectum by Western blotting using a newly developed extraction method from microdissected tissue sections fixed with buffered formalin. Analysis of 98 colorectal cancers revealed that PyNPase was as high as 70.2 +/- 18.5 unit/mg protein in the stroma fraction (SF), whereas it was 45.1 +/- 10.5 in the cancer fraction (CF) (p < 0.0001). Vessel density was correlated with PyNPase in the SF but not in the CF. In stage IIIb, 11 cases expressing a high level of PyNPase in the CF showed poorer prognosis than 10 cases with low-level PyNPase expression (p < 0.05), although the level of PyNPase expression in the SF did not affected the patients prognosis. Immunohistochemical examination indicated that PyNPase in the SF was mainly produced by macrophages (M phi), and therefore we investigated the profile of PyNPase production by M phi. In in vitro experiments PyNPase production by M phi was greatly enhanced by stimulation with OK-432, and the culture supernatant had the ability to convert 5'DFUR to 5-FU.     

Growth factors in bladder cancer

This article is an overview of peptide growth factors, their receptors, and signal-transduction pathways that play a role in bladder cancer. Included in this overview are epidermal growth factor receptor and its ligands, erbB2, fibroblast growth factors, insulin-like growth factor, the transferrin receptor, and transforming growth factor-beta. The use of growth factors or growth factor receptors for diagnostic and therapeutic interventions is also discussed.     

Electropermeabilization in bladder cancer chemotherapy

PURPOSE: Electropermeabilization has been used for the introduction of genes into cells. Using this technique, we introduced the cytotoxic drug bleomycin (BLM) into cells and examined whether the technique might be useful for the treatment of bladder cancer. MATERIALS AND METHODS: For electropermeabilization in vitro, we used YTS-1 cells, a human transitional cell carcinoma line. Aliquots of cell suspension were mixed with a solution of BLM and immediately exposed to electric pulses. A high-power pulse generator was used to supply square-shaped pulses of 1250 V/cm (100 micros, eight pulses). After a 2-h post-shock incubation, cells were washed and incubated for one further hour. Then the concentration of BLM in the cells was measured using a bioassay. For electropermeabilization of tissue, we used normal male Wistar rats. The bladder was exposed and 10 mg/kg BLM was injected into the caudal vein. A series of eight pulses with a time constant of 100 micros at an electric field intensity of 1000 V/cm was applied. The bladder, liver and lungs were extracted 1 h later and prepared for quantification of the BLM concentration using the bioassay. RESULTS: Electrotreated cells contained significantly higher concentrations of BLM than nonelectrotreated cells. The concentration of BLM 1 h after electrotreatment in bladder tissue was 2.7 times higher than that in nonelectrotreated bladder tissue. CONCLUSION: The electropermeabilization technique has the potential to serve as a new and effective modality for the treatment of bladder cancer.     

Prognostic factors in bladder cancer

Prognostic factors in bladder cancer are used to determine the prognosis of patients and select the method of treatment. Clinical stage, the number of tumors, size of the main tumor, mode of proliferation, cell type, histological grade, histological stage, mode of spread, and intramural lymphatic and venous invasion are well-known prognostic factors. They are closely related to survival or the disease-free interval. Most prognostic factors are histopathological findings. Now, study of new prognostic factors in bladder cancer related to molecular biological or immunohistochemical technique is ongoing.     

Genetics of bladder cancer

Bladder cancer manifests many different forms, ranging from superficial to aggressive muscle invasion, which suggests that various genetic alterations are responsible. Several attempts have been made to establish correlations between specific genetic alterations and various grades of the disease. Numerous types of chromosomal abnormalities have been observed, involving [1p, 1q, 2q, 3p, 4p, 5q, i(5p), +7, +8, 8p, 9p, 9q, 10q23-25, 11p, 11q, +11, 13q, 14q, 17p, 18q, 21q, and Y]. In addition, p53 mutations and loss of heterozygosity on various chromosomes have recently begun to shed light on the molecular pathways of transitional cell carcinomas of the bladder. We have begun to focus on specific genomic sites (especially 9q), although the heterogeneity of the disease and the variable presentation suggests divergent progression pathways. When the genetic basis of bladder cancer is fully understood, new diagnostic and therapeutic strategies will be developed, which in turn may promote better clinical management by pathologists and urologists.     

The role of genetically-based metabolic polymorphisms in human cancer: an ecological study of bladder cancer and N-acetyltransferase in 23 populations

Intrathecally applied alpha2-adrenoceptor antagonists atipamezole, idazoxan and yohimbine had no significant effect on any neuronal response in normal animals. In contrast, all three antagonists (100 microg) significantly increased the area under the curve of the total response to formalin, especially the second phase. Our results suggest the alpha2-adrenoceptor-mediated noradrenergic inhibitory system in the spinal cord is dormant under normal conditions, but controls both the magnitude and duration of the neuronal responses to subcutaneous injection of formalin.     

Adherens junctions in the Drosophila embryo: the role of E-cadherin in their establishment and morphogenetic function

The integrity of epithelia depends largely on specialised adhesive structures, the adherens junctions. Several of the components required for building these structures are highly conserved between vertebrates and insects (e.g. E-cadherin and alpha- and beta-catenin), while others have so far been found only in invertebrates (e.g. crumbs). Two recent papers(1,2) show that the Drosophila E-cadherin is encoded by the gene shotgun. Phenotypic analyses of shotgun as well as armadillo (beta-catenin) and crumbs mutants provide new insights into the mechanisms by which adherens junctions are built and, further, show that the requirement for E-cadherin largely depends on the morphogenetic activity of an epithelium.     

The role of dog bladder mucosa in the N-oxidation of arylamines

The in vitro metabolic N-oxidation of 1- and 1-napthylamine, 4-biphenylamine, 2-fluorenylamine and 3-dibenzolfuranylamine has been investigated with intact dog bladder, whole intact bladder mucosa and microsomes prepared from this tissue. Very low levels of metabolic N-oxidation of these carcinogenic amines were detected with these tissue preparations using ferrihemoglobin formation in dog erythrocytes. No N-oxidation by these tissue preparations was observed using gas-liquid chromatography. The concentrations of the N-oxidized metabolites observed in the urine of dogs in vivo exposed to thse amines suggests that N-oxidation takes place predominately in the liver and that the bladder plays, at most, a minor role in the formation of these presumed proximate urinary carcinogens.