Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling.

The Wnt signaling pathway is involved in normal embryonic development and controls the homeostatic self-renewal of stem cells in adult tissues. Constitutive activation of Wnt signaling contributes to cancer development and progression. We identified a CXXC4 homozygous deletion at 4q24 in an aggressive renal cell carcinoma (RCC) using single-nucleotide polymorphism (SNP) arrays. CXXC4 encodes Idax, which negatively regulates Wnt signaling by binding to the PDZ domain of Dishevelled. CXXC4 mRNA levels in tumor samples were significantly lower in patients with metastases compared with those without (P=0.0016). Patients whose tumors had lower CXXC4 expression than normal kidney showed a poorer cause-specific survival outcome than those with higher expression (P=0.0095). Decreased expression of CXXC4 also correlated with cytoplasmic staining of beta-catenin. Knockdown of CXXC4 induced the nuclear translocation of beta-catenin and altered expression of a set of genes involved in cell proliferation, invasion and survival. Furthermore, reduced expression of CXXC4 by small interfering RNAs promoted cell proliferation and inhibited apoptosis after 5-FU and doxorubicin treatment in RCC cells. These data suggest that CXXC4 plays a critical role in tumor progression of RCC through Wnt signaling. Wnt signaling could thus be a potential molecular target in RCC indicating decreased CXXC4 expression.

[A case of transitional cell carcinoma of the urinary bladder with high serum level of CEA and CA19-9].

An 85-year-old male with asymptomatic gross hematuria was diagnosed with invasive bladder tumor, transitional cell carcinoma grade 3. Serum levels of CEA and CA19-9 were elevated and histological examination revealed expression of both markers in the cytoplasm of cancer cells. Out of therapeutic options, intra-arterial chemotherapy and radiotherapy were selected because of his age. During the treatment, serum levels of CEA and CA19-9 decreased along with reduction of tumor size. These serum markers have been reported to be elevated in 10 to 60% of patients with bladder tumor and are useful markers for evaluation of the treatment as suggested in the present case.

AgNOR count in resting cells (resting NOR) is a new prognostic marker in invasive bladder tumor.

PURPOSE: We have previously demonstrated that the AgNOR count in proliferating cells is a predictor of tumor recurrence in superficial bladder tumor (J. Urol. 162 (1999), 63-68). In the present study, we evaluate the type of AgNOR associated with cell cycles as a prognostic factor in invasive bladder tumor using a double staining technique employing both AgNOR and MIB-1 labelling. MATERIALS AND METHODS: Forty-four paraffin sections of invasive bladder tumors were stained simultaneously with AgNOR and MIB-1. The number of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed. RESULTS: The AgNOR count in proliferating cells (proliferating NOR) was significantly higher than that in resting cells (resting NOR) (p<0.01). The resting NOR in tumors with distant metastases was significantly higher than that in tumors without metastases (p<0.05). Patients with a low resting NOR tumor had a better prognosis than those with a high resting NOR tumor, whereas the proliferating NOR was not associated with survival. Survival analysis revealed that the resting NOR was the most powerful prognostic marker in patients with invasive bladder tumor (p<0.05). CONCLUSIONS: Resting NOR had a predictive value in the prognosis of patients with invasive bladder tumor.

Genetic heterogeneity of surgically resected prostate carcinomas and their biopsy specimens is related to their histologic differentiation.

BACKGROUND: In human prostate carcinogenesis, many genetic analyses including conventional loss of heterozygosity (LOH) studies and microsatellite LOH analyses using the polymerase chain reaction method have revealed frequent LOH events at specific regions on chromosomes 3p, 7q, 8p, 10q, 16q, 17q, and 18q. METHODS: Using the laser-captured microdissection method, the authors extracted genomic DNA from 23 cases of prostate carcinomas including 59 different lesions and 8 biopsy specimens. Using (32)P-labeled primers, the authors analyzed six microsatellite loci (D3S647, D3S1228, D7S522, D8S137, NEFL, and D10S190) at which frequent LOH events have been reported. RESULTS: Of 10 cases in which the authors found LOH at any of the loci, 8 cases showed a heterogeneous LOH pattern. In four cases, the authors also found replication error (RER) at some of the loci examined. There was no significant relation between histologic differentiation and frequency of LOH or RER events. The overall LOH rate was found to be significantly lower in foci at classification pT2 (1 of 28 foci, 3%) compared with those at classification pT3 (13 of 44 foci, 30%). In pT3 samples, LOH events in extraglandular foci (9 of 23 foci, 39%) tended to be more frequent compared with those in intraglandular foci (8 of 41 foci, 20%). The patterns of LOH events in biopsy specimens correlated well with those in foci from surgical material showing the same histologic characteristics. CONCLUSIONS: Prostate carcinoma is a genetically multicentric carcinoma, and the genetic heterogeneity is well correlated with histologic differentiation. The frequency of LOH events increased according to the degree of tumor progression.

Classical cadherins in urological cancers.

Decreased E-cadherin expression assessed by immunohistochemistry correlates with poor survival of bladder and prostate cancer patients. The clinical usefulness of this parameter should therefore be evaluated in a large scale prospective study. In proximal kidney tubule and in its derived tumours cadherin-6 seems to take over E-cadherin function. Impaired E-cadherin function leads to increased invasive capacity of the cells. It has been shown that defective function can result from several mechanisms: mutation of the gene, alteration of transcription, post translational modifications or changes in the interaction of E-cadherin with cytoskeleton anchoring proteins: the catenins. A major mechanism leading to decreased E-cadherin expression in tumours lies in decreased transcription of the gene. Hence, a better understanding of the regulation of E-cadherin transcription might open avenues for therapy by restoring a normal expression.

Alterations in expression of cadherin-6 and E-cadherin during kidney development and in renal cell carcinoma.

OBJECTIVES: Cell-cell adhesion mediated by cadherins is tight and stable and preserves tissue integrity. However, during tissue remodeling, e.g., development, adhesion may be modified for morphogenic movement. Similarly, during carcinogenesis, cell-cell adhesion might alter leading to a more aggressive phenotype. Here we describe cadherin expression patterns in developing, adult, and neoplastic kidney. METHODS: Fetal kidneys were obtained from voluntary terminations of pregnancy and 43 renal cell carcinomas (RCC) and normal kidneys were obtained at nephrectomy. Frozen sections of these specimens were stained immunohistochemically using antibodies against E-cadherin (ECD), cadherin-6 (CAD6) and alpha-catenin (alpha-cat). RESULTS: CAD6 was expressed in lower and middle limbs of the S-shaped bodies, structures that will develop into renal proximal tubules, which also express CAD6. Similarly, ECD was expressed in the upper limb of S-shaped bodies, structures which will develop into distal and collecting tubules which also express ECD. Twenty-four out of 43 RCC (55.8%) displayed a CAD6 (+)/ECD (-)/alpha-cat (+) phenotype. The other RCC had a CAD6 (+)/ECD (+)/alpha-cat (+) phenotype (10/43, 23.2%), CAD6 (-)/ECD (+)/alpha-cat (+) phenotype (3/43, 7.0%) or CAD6 (-)/ECD (-)/alpha-cat (+) phenotype (6/43, 14.0%), respectively. On the other hand, normal, heterogeneous, or absent expression of CAD6 was seen in 19, 15, and 9 tumors, whereas in 11, 2, and 30 tumors, respectively, ECD expression was seen. Survival curves showed that abnormal CAD6 expression correlated with a poor prognosis rather than abnormal ECD expression. CONCLUSIONS: The combination of cadherin expression appeared to be fixed relatively early during kidney organogenesis. Since almost all RCC originate from proximal tubular epithelial cells (CAD6 (+)/ECD (-)/alpha-cat (+)), only 55. 8% of RCC retained the original cadherin phenotype. Alterations in expression of these molecules may be a reflection of the degree of dedifferentiation from the primary organ. In addition, scoring of expression patterns including heterogeneous expression could be a useful tool to estimate the malignancy potential of the tumor.

High-dose chemotherapy with peripheral blood stem cell transplantation for advanced testicular cancer.

BACKGROUND: The present study was performed in order to investigate the efficacy and safety of high-dose chemotherapy for the treatment of patients with advanced testicular cancer. METHODS: Seven patients were treated with high-dose carboplatin, etoposide and cyclophosphamide followed by peripheral blood stem cell transplantation. Five patients received one cycle and two patients received two cycles of the high-dose chemotherapy. RESULTS: Of the seven patients, one achieved a complete response and four achieved partial responses with markers negative. As a result of subsequent surgery for residual tumors, three of the four partial responders showed no residual cancer cells. One patient who did not undergo surgery received radiotherapy after the high-dose chemotherapy and the residual tumors disappeared. All five patients who had either a complete or partial response are still alive and without evidence of disease at 12, 27, 30, 37 and 40 months. One patient is alive with disease at 7 months and one died of progressive disease at 6 months. The hematologic recovery after high-dose chemotherapy was rapid and non-hematologic toxicities were usually mild and manageable. CONCLUSIONS: High-dose chemotherapy followed by peripheral blood stem cell transplantation is safe and effective for use in patients with far-advanced testicular cancer, particularly when the high-dose chemotherapy is conducted as the initial treatment. Further larger and long-term follow-up studies are needed to define the role of high-dose chemotherapy on testicular cancer.

A bladder preservation regimen using intra-arterial chemotherapy and radiotherapy for invasive bladder cancer: a prospective study.

BACKGROUND: A prospective study was performed to investigate combined treatment with intra-arterial chemotherapy and radiation therapy for bladder preservation in locally invasive bladder cancer. METHODS: Patients with invasive bladder cancer, stage T2-3N0M0, were included in the study. Intra-arterial chemotherapy was performed with three injections of methotrexate and cisplatin at 3-week intervals. Simultaneously, the patients underwent X-ray irradiation (40 Gy) of the small pelvic space. Where a post-treatment transurethral resection (TUR) biopsy showed no residual tumor, the tumor site was irradiated by a 30 Gy proton beam and the bladder was preserved. Where tumors remained, radical cystectomy was performed. RESULTS: Between 1990 and 1996, 42 patients were treated according to this protocol. Post-treatment TUR biopsy and urine cytology showed no residual tumors in 39 of 42 cases (93%). The bladder was preserved in accordance with the study protocol in 36 cases. A median follow-up of 38 months showed 3-year non-recurrence in 72% of bladder-preserved patients and the rate of bladder preservation was 84%. The nine recurrences included eight cases of superficial bladder recurrence. One cancer death occurred among the bladder-preservation patients, giving 3-year survival and cause-specific survival rates of 84% and 100%, respectively. Although bladder function decreased slightly in compliance, bladder capacity was retained in almost all cases. CONCLUSIONS: This regimen is useful for bladder preservation in T2-3 locally invasive bladder cancer. Information from more cases and the results of more long-term observations are needed, as is an evaluation of appropriate subject selection and factors associated with quality of life issues, particularly regarding bladder function.

Promoting effects of antiandrogenic agents on rat ventral prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB).

The objective of this study was to determine the effects of androgen depletion by 5alpha-reductase inhibitor (eg epristeride), pure antiandrogen (eg casodex) or C17-20 lyase inhibitor (eg YM116) on rat prostate carcinogenesis induced by administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB was subcutaneously administered on male F344 rats for the first 20 weeks. Epristeride (10 and 50 mg/kg, three times per week), casodex (15 and 30 mg/kg, three times per week) or YM116 (15 and 30 mg/kg, three times per week) were administered orally for 40 consecutive. Then, all accessory sex organs were studied for the formation of neoplastic lesions by histological examination. All carcinoma lesions were produced only in the ventral lobe of the prostate. The incidence of carcinoma developing in the ventral lobe of the prostate was 9.5% in the control group on which DMAB alone was administered, whereas it was 31.6% in the epristeride 10 mg/kg group. 45.0% in the epristeride 50 mg/kg group, 47.8% in the casodex 15 mg/kg group, 63.2% in the casodex 30 mg/kg group, 10.5% in the YM116 15 mg/kg group and 5.0% in the YM116 30 mg/kg group. The incidences of carcinoma in the epristeride 10 mg/kg group, casodex 15 mg/kg group and casodex 30 mg/kg group were significantly higher than that of the control group. In this experimental model, all ventral prostate carcinomas were in situ adenocarcinomas that did not form palpable nodules or distant metastasis. Epristeride and casodex showed a dose-dependent promoting effect on rat ventral prostate carcinogenesis. These results were contradictory to the results of our previous studies; exogenous testosterone in combination with DMAB produced palpable, and metastatic tumors in other portions of accessory sex organs of F344 rats but no carcinoma in ventral prostate, and those invasive carcinomas were significantly inhibited by 5alpha-reductase inhibitor and nonsteroidal anti-androgen. The action mechanisms of androgen and the effects of androgen-regulatory drugs on prostate carcinogenesis should be further studied. Prostate Cancer and Prostatic Diseases (2000) 3, 115-119

Mechanisms associated with abnormal E-cadherin immunoreactivity in human bladder tumors.

The involvement of E-cadherin in the progression of carcinoma is supported by a large number of studies showing an inverse relationship between E-cadherin immunoreactivity and tumor aggressiveness. However, the mechanisms leading to decreased E-cadherin immunoreactivity are still unclear. Comparison of Northern blotting and immunohistochemistry in a series of 49 frozen bladder tumors revealed that, in 16 of 23 tumors with abnormal staining, clear mRNA down-regulation occurred. In the 7 cases without mRNA down-regulation, no structural anomalies of E-cadherin could be detected by Southern blotting, Western blotting or PCR-SSCP. Western blotting confirmed that, in 6 of these tumors, E-cadherin was down-regulated at the protein level. This down-regulation was accompanied by down-regulation of alpha-catenin and, to a lesser extent, of beta- or gamma-catenin. However, Northern-blot analysis indicated that expression of the 3 catenins is maintained at the mRNA level. Thus our data show that, in bladder tumors, mRNA down-regulation accounts for about two thirds (16/23) of tumors with abnormal staining and that post-transcriptional down-regulation of E-cadherin occurs in 6/23 of these tumors.

[Short- and long-term outcome after urethroplasty in the patients with hypospadias treated by Hodgson III method].

Between 1977 and 1997, 29 patients with hypospadias were surgically treated by Hodgson type III urethroplasty at Tsukuba University Hospital. The duration of surgery ranged from 150 to 535 minutes with an average of 269.3 minutes and the urethral catheter was removed between 4 and 14 days (average 8.7 day) after surgery. The postoperative hospital stay ranged from 10 to 29 days with an average of 18.4 days. The overall success rate of initial surgery was observed in 18 of the 29 patients (62.1%). As early postoperative complications, urethral fistula and stricture were seen in 10 (34%) and 3 (10%) patients, respectively; of these four fistulas persisted. As late complications revealed by questionnaire, erectile disorder was observed in one case. To obtain a higher success rate on initial treatment, skillful surgical technique and selection of appropriate cases are required.

Argyrophilic nucleolar organizer region in proliferating cell has a predictive value for local recurrence in superficial bladder tumor.

PURPOSE: It has been shown in many carcinomas that the proliferation rate and number of argyrophilic nucleolar organizer regions (AgNOR) are associated with tumor aggressiveness. However, in bladder tumor the significance of the correlation between the number of AgNOR and tumor behavior remains controversial. Therefore, it would be helpful if a new technique could be developed that would allow for more accurate AgNOR counting in association with tumor behavior. We established the simultaneous staining technique of AgNOR with Ki-67 labeling to reveal the significance of AgNOR count in superficial bladder tumor. MATERIALS AND METHODS: A total of 50 paraffin sections of superficial bladder tumor were stained with AgNOR and Ki-67 (MIB-1). The numbers of AgNORs in proliferating (MIB-1 positive) or resting (MIB-1 negative) cells were counted from a total of 100 nuclei. Correlations between MIB-1 associated AgNOR count and clinicopathological parameters were statistically analyzed. RESULTS: The AgNOR count in proliferating cells was significantly higher than that in resting cells (p<0.01), and the count significantly increased with tumor grade (p<0.01). Based on recurrence-free survival analyses the local recurrence rate was significantly higher in patients with high proliferating cell NOR but not for those with resting or whole cells. However, no AgNOR score helped to select patients at high risk for disease progression. CONCLUSIONS: Proliferating cell NOR had a predictive value for local recurrence in patients with superficial bladder tumor.

Changes in cadherin-catenin complexes in the progression of human bladder carcinoma.

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.

[A case of synchronous multifocal urothelial tumors in a patient with phenacetin abuse].

A 79-year-old male with phenacetin abuse was admitted to our University Hospital for treatment of asymptomatic gross hematuria. Intravenous urograpdy and computed tomography revealed synchronous right renal pelvic carcinoma and bladder carcinoma. Right nephroureterectomy and transurethral resection of bladder tumor (TUR-Bt) were performed. Histologically, right renal pelvic tumor and bladder tumor were both transitional cell carcinomas of grade 2, pT1, and grade 1 = 2, Ta, respectively. Additionally, pathological examination revealed two distal ureteral tumors, which were transitional cell carcinomas of grade 2, pTa. He also had a history of heavy tobacco-smoking (20 cigarettes per day for 50 years). We discuss the relationship between transitional cell carcinoma and phenacetin abuse as well as the influence of tobacco-smoking, and review the literature.

[Recent progress of prognostic factors in renal cell carcinoma].

Although it has been considered that the pathological stage is the most powerful prognostic marker for a patient with renal cell carcinoma, many investigations have been performed to discover a new predictive marker of this tumor. Recent studies have shown that nuclear morphometry, cell proliferation analyses, (Ki-67 and AgNOR), expression of cell adhesion molecule, (cadherin-6 and alpha-catenin), and protease expression, expression and serum level of growth factors (VEGF and bFGF), might be among the new candidates for a useful prognostic marker. However, proliferating cell nuclear antigen, genetic alterations or DNA ploidy are unlikely to be reliable markers to predict the prognosis of the patient. In further analysis, multivariate analyses for these markers and new molecular markers will be needed to establish a new diagnostic tool that is more useful than classical pathological stage classification of the tumor.

Evaluation of nucleolar organizer regions in human bladder cancers by light- and electron-microscopic morphometry.

The number of nucleolar organizer regions (NOR) of human bladder cancers was evaluated at the light- and electron-microscopic level. The average number of argyrophilic NOR (AgNOR), stained by the one-step silver colloid method, was measured in benign and malignant urothelial cells in the human urinary bladder using a light microscope. The average number of nucleolar fibrillar centers (FC) per nucleus was also calculated by quantitative ultrastructural morphometry in the specimens from the same patients. Statistical evaluations revealed that the average number of AgNOR per nucleus was significantly correlated with the elevation of tumor grade and stage (p < 0.05). An average FC number per nucleus also increased in association with tumor grade and stage (p < 0.05). Although the average number of FC was 5.6 times higher than that of AgNOR, the correlation between the average number of FC and AgNOR was statistically significant. In conclusion, these results suggested that the silver staining method was a useful and convenient tool for the evaluation of the differentiation and invasive potential of bladder cancer cells at the light-microscopic level.

Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma.

In many carcinomas, E-cadherin is considered to be a prognostic marker for patient survivals, and its decreased expression is associated with metastatic disease. Among renal cell carcinomas (RCCs), however, only 20% of tumors express E-cadherin, whereas a much higher percentage express other cadherins, e.g., N-cadherin and cadherin-6 (T. Shimazui et al, Cancer Res., 56: 3234-3237, 1996). Among these cadherins expressed in RCCs, cadherin-6 has been identified as a major cadherin in the renal proximal tubules and in the tumors themselves. Hence, we have investigated the relationship between prognosis and cadherin-6 expression in tumor cells in 43 patients with RCC. Expression of cadherin-6, E-cadherin, and alpha-catenin was detected immunohistochemically and evaluated microscopically as normal, heterogeneous, or absent. Normal, heterogeneous, and absent expression of cadherin-6 were observed in 19, 16, and 8 of 43 cases, respectively. Coexpression of E-cadherin and cadherin-6 was detected in only 10 cases. Among 30 tumors in which E-cadherin expression was absent, 24 expressed cadherin-6. In addition, the expression pattern of alpha-catenin correlated more highly with that of cadherin-6 than it did with E-cadherin (P = 0.0003 versus 0.025). In survival analyses, aberrant expression of cadherin-6 correlated with poor survivals both among all patients (P = 0.0009) and in those with E-cadherin-absent RCC (P = 0.0008). These results suggest that cadherin-6 is a major cadherin playing an essential role in cell-cell adhesion in E-cadherin-absent RCC.

[Effect of UFT on treatment of urological cancer--effect of UFT on treatment of invasive bladder cancer and advanced prostate cancer. Ibaraki Urological Cancer Chemotherapy Study Group].

A prospective randomized joint study was conducted to evaluate the usefulness of UFT 1) as a postoperative adjuvant therapy in patients with invasive bladder cancer who had undergone curative combination therapy with operation and/or chemotherapy and/or radiation therapy, 2) as an endocrine chemotherapy in patients with newly diagnosed stage C/D prostate cancer, for a period of 3 years from January, 1992. For bladder cancer, of 36 patients with invasive bladder cancer, clinically cured by combination therapy, 20 patients were treated with UFT as an adjuvant chemotherapy over 12 months, and they were compared to 16 patients with no adjuvant therapy. After excluding 10 inappropriate patients, 12 patients in the UFT treatment group and 14 patients with no adjuvant treatment group were observed. For prostate cancer, of 29 patients with clinically stage C/D prostate cancer, 13 were treated with endocrine therapy in combination with UFT, and 16 patients were treated with endocrine therapy alone. After excluding 7 inappropriate patients, 10 patients with endocrine chemotherapy and 12 patients with hormonal therapy were observed. The non-recurrence rate, survival rate and side effects of UFT were evaluated. In the study of bladder cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. In the study of prostate cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. These findings suggest UFT is less useful as an adjuvant therapy for the invasive bladder cancer and as an endocrine chemotherapy for newly diagnosed advanced prostate cancer.

[Molecular biological aspect].

Although adenocarcinoma of the prostate is recently becoming one of most common malignancies in Japanese men, it still poses many questions regarding its etiology, pathology, pathogenesis and clinical management. Many reports have been made on oncogene and tumor suppressor gene, however, frequent genetic alterations have not been identified during prostate cancer development. Loss of heterozygosity (LOH) on 8p might be an important event in the early stage of prostatic carcinogenesis, whereas alteration in 17p is now considered a late event. Numerous reports about the androgen receptor (AR) gene have revealed that mutations in the coding region of AR possibly results in an acquired resistance to androgen blockade therapy and anti-androgen withdrawal syndrome. It has been also shown that shorter CAG repeats of AR gene are associated with a higher risk of prostate cancer. Regarding molecular diagnosis, prostate-specific membrane antigen (PSM) appears to be a new molecule with many potentially valuable applications. PSM-reverse transcriptase-polymerase chain reaction (RT-PCR) is probably more sensitive and specific than PSA-RT-PCR to predict micrometastatic disease. Gene therapy based on the above molecular aspect is currently under investigation but not generally used yet.

Decreased expression of alpha-catenin is associated with poor prognosis of patients with localized renal cell carcinoma.

During the progression of many cancers, cell-cell adhesion molecules, e.g., E-cadherin (EC), may be down-regulated. In a number of carcinomas, EC has been described as an independent prognostic variable. We have studied the expression of adhesion molecules participating in cadherin-catenin complexes in renal cell carcinoma (RCC) specimens. Expression of EC, catenins and p120cas protein was examined in frozen tissue of 90 RCC specimens by immunohistochemistry, and these molecules were evaluated for their significance as prognostic markers. Staining was scored as normal (homogeneously positive at cell-cell borders) or abnormal (heterogeneous or absent). A significant correlation between poor survival and decreased expression of alpha-, beta- or gamma-catenin was observed, whereas no association between survival and EC or p120cas expression was seen. Cox's proportional hazard regression analysis showed that in patients with pT1-3N0M0 disease, reduced alpha-catenin expression correlated with poor survival, suggesting that alpha-catenin expression might be an independent prognostic indicator for patients of this group.