Tumor necrosis factor-alpha-promoted expression of Bcl-2 and inhibition of mitochondrial cytochrome c release mediate resistance of mature dendritic cells to melanoma-induced apoptosis.

Melanoma escapes host defenses through a variety of means, including the elimination of immune effector cells within the tumor microenvironment. We have reported recently that murine and human tumors including melanoma induce premature apoptosis of dendritic cells both in vitro and in vivo. In this study, we have demonstrated that overexpression of the Bcl-2 protein family member Bcl-xL rescued murine dendritic cells (DCs) from melanoma-induced death in vitro. Another successful protection approach was tumor necrosis factor (TNF)-alpha-promoted sustained expression of the antiapoptotic protein Bcl-2 within dendritic cells. This effect of TNF-alpha was mediated by inhibition of mitochondrial cytochrome c release. Thus, both Bcl-xL and Bcl-2 enhance survival of dendritic cells within the tumor microenvironment. In addition, mature DCs were more resistant to melanoma-induced apoptosis than immature dendritic cells. This finding suggests a stage-dependent sensitivity of DCs to tumor-induced cell death. We conclude that: (a) mature DCs might be more suitable for the use of cancer vaccination; and (b) Bcl-2 protein family members such as Bcl-xL and Bcl-2 rescue DCs from tumor-induced premature apoptosis.

Human prostate cancer regulates generation and maturation of monocyte-derived dendritic cells.

BACKGROUND: The progression of prostate cancer is accompanied by a marked suppression of the immune system, including the apoptotic death of dendritic cells (DC) responsible for the induction of antitumor immunity. In this study, we evaluated whether prostate cancer might inhibit DC generation and maturation in vitro. METHODS: DC were generated from peripheral blood monocytes in the presence of the human prostate cell line LNCaP or nonmalignant cells, and characterized by light microscopy, FACScan analysis, and ability to stimulate T-cell proliferation. RESULTS: Prostate cancer significantly inhibited the conversion of monocytes into DC, which was assessed by the expression of DC markers CD1a and CD83. These cells were weak stimulators of T-cell proliferation, suggesting that DC generated in the prostate cancer microenvironment are functionally inhibited. CONCLUSIONS: Prostate cancer not only kills mature DC, but also inhibits their generation and maturation, resulting in decreased production of antigen-presenting cells and inhibition of their functional activity.

TNF-alpha protects dendritic cells from prostate cancer-induced apoptosis.

We have recently shown that human prostate cancer (PCa) cells induced apoptotic death of the most potent antigen-presenting cells, dendritic cells (DC), which are responsible for the induction of specific antitumor immune responses. Here we have evaluated the effect of murine PCa cells RM-1 on the survival of immature and tumor necrosis factor-alpha (TNF-alpha)-stimulated mature DC. PCa cells and DC were co-incubated for 24-48 h and DC apoptosis was assessed by morphologic criteria, Annexin V assay, and TUNEL staining. We have shown that co-incubation of RM-1 cells with DC is accompanied by an increased level of DC apoptosis, which was mediated by decreased expression of anti-apoptotic protein Bcl-2. Stimulation of DC maturation by TNF-alpha resulted in increased resistance of DC to PCa-induced apoptosis. In TNF-alpha treated mature DC, but not in immature DC, the expression of Bcl-2 was not blocked after exposure to RM-1-derived factors. Thus, these data suggest that TNF-alpha-induced maturation of DC increases their resistance to PCa induced apoptosis. This is likely to be due to the stabilizing of the expression of anti-apoptotic protein Bcl-2. The difference in the sensitivity of mature and immature DC to PCa-induced cell death should be considered during the design of DC-based clinical trials for PCa patients.Prostate Cancer and Prostatic Diseases (2001) 4, 221-227.

Detection of tumorigenesis in rat bladders with optical coherence tomography.

Optical coherence tomography (OCT) is a novel technique that enables noninvasive cross-sectional imaging of biological tissues. Because of its high resolution (approximately 10 microm), superior dynamic range (140 dB in our case) and up to 2-3 mm penetration depth, OCT is potentially useful for noninvasive screening of superficial lesions. Bladder cancer arises within the transitional epithelium. Despite the ability to visualize the epithelium via cystoscopy, it is often difficult to detect early epithelial cancers and to determine their penetration to the underlying layers. To investigate the potential of OCT to enhance imaging of bladder cancers and other epithelial lesions, we applied OCT to normal and diseased bladder epithelium, and correlated the results with histological findings. OCT images of porcine bladder (a close homolog of human bladder) confirm the ability of this method to image human tissues. To determine whether OCT can track the course of bladder cancer, a standard rat model of bladder cancer in which Fisher rats are exposed to methyl-nitroso-urea (MNU), was followed both with OCT and histological studies. Our results show that the micro morphology of porcine bladder such as the urothelium, submucosa and muscles is identified by OCT and well correlated with the histological evaluations. OCT detected edema, inflammatory infiltrates, and submucosal blood congestion as well as the abnormal growth of urothelium (e.g., papillary hyperplasia and carcinomas). By contrast, surface imaging, which resembles cystoscopy, provided far less sensitivity and resolution than OCT. This is the first OCT study of any tumor documented in a systematic fashion, and the results suggest the potential of OCT for the noninvasive diagnosis of both bladder inflammatory lesions and early urothelial abnormalities, which conventional cystoscopy often misses, by imaging characterization of the increases in urothelial thickening and backscattering. However, because of the depth limitation, OCT may have limited applications in staging the invasion of higher-state urothelial cancers, especially for papillary carcinomas.

The treatment of prostate cancer: an overview of current options.

PURPOSE: The purpose of this report is to discuss the current treatment options available to the patient with prostate cancer in all stages of the disease. OVERVIEW: With the exception of skin cancer, prostate cancer is the most common cancer in men in the United States. Most patients in the current era will present with organ-confined disease, amenable to curative treatment. Treatment for organ-confined disease includes watchful waiting, radical prostatectomy, radiation therapy, and cryosurgery in selective cases. Hormone therapy is the cornerstone of treatment of patients with advanced prostate cancer. There is no curative treatment for hormone-refractory prostate cancer. CLINICAL IMPLICATIONS: The availability of several therapeutic options for localized prostate cancer warrants careful consideration when planning treatment with curative intent. Patients need to be active participants in decision making, and they must be aware of the benefits and possible complications of the different types of treatment. Patients with advanced prostate cancer need to be aware that hormone treatment will provide temporization and palliation in the majority of cases. Hormone-resistant prostate cancer is refractory to most forms of conventional and experimental therapy.

Transduction of dendritic cells with Bcl-xL increases their resistance to prostate cancer-induced apoptosis and antitumor effect in mice.

We have shown that prostate cancer (PCa) causes apoptosis of dendritic cells (DC), which might block the development of specific antitumor immune responses. Analysis of murine prostatic carcinoma tissues revealed the significant decrease in intratumoral DC number during tumor progression. We demonstrated that the cytokine-mediated increase in DC survival was accompanied by an elevated expression of the anti-apoptotic protein Bcl-xL. Next, we evaluated the resistance to tumor-induced apoptosis and the antitumor efficiency of genetically engineered DC overexpressing Bcl-xL. DC were transduced with an adenoviral vector encoding the murine Bcl-xL gene and injected intratumorally. Data analysis revealed that treatment of PCa-bearing mice with Bcl-xL-transduced DC resulted in significant inhibition of tumor growth compared with the administration of nontransduced DC. Thus, our data suggest that the protection of DC from PCa-induced apoptosis might significantly increase the efficacy of DC-based therapies in cancer even in the absence of available tumor-specific Ags.

Cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins.

Prostate cancer is the most common cancer in men in the United States, and second in cancer-induced mortality. It is likely that tumour-induced immunosuppression is one of the reasons for low treatment efficacy in patients with advanced prostate cancer. It has been recently demonstrated that prostate cancer tissue is almost devoid of dendritic cells (DC), the major antigen-presenting cells responsible for the induction of specific antitumour immune responses. In this study, we have tested the hypothesis that prostate cancer induces progressive suppression of the DC system. We found that co-incubation of human DC with three prostate cancer cell lines led to the high levels of premature apoptosis of DC, which were significantly higher than in DC cultures co-incubated with normal prostate cells or blood leucocytes. Stimulation of DC for 24 hours with CD40 ligand (CD154), IL-12 or IL-15 prior to their co-incubation with prostate cancer cells resulted in a significant increase in DC survival in the tumour microenvironment. Furthermore, activation of DC with these cytokines was also accompanied by increased expression of the anti-apoptotic protein Bcl-x(L) in DC, suggesting a possible mechanism involved in DC protection from apoptotic death. In summary, our data demonstrate that prostate cancer induces active elimination of DC in the tumour microenvironment. Stimulation of DC by CD154, IL-12 or IL-15 leads to an increased expression of the anti-apoptotic protein Bcl-x(L) and increased resistance of DC to prostate cancer-induced apoptosis. These results suggest a new mechanism of tumour escape from immune recognition and demonstrate the cytokine-based approaches which might significantly increase the efficacy of DC-based therapies for cancer.

Endothelium-derived factors as paracrine mediators of prostate cancer progression.

BACKGROUND: Vascular endothelium represents a complex network of cells producing a large number of active substrates affecting physiologic, metabolic, and immunologic properties of the whole organism, as well as particular organs or tissues. The potential influence of endothelium-derived paracrine factors on prostate cancer progression has only begun to be examined. METHODS: This review summarizes recent literature on endothelium-derived factors, including vasoactive agents, peptide growth factors, cytokines, and colony-stimulating factors, involved in the development and progression of prostate cancer. RESULTS: Endothelial cells produce an array of active substrates, many of which have been shown to influence prostate cancer growth. Available data demonstrate the positive impact of such molecules as endothelin-1, basic FGF, TGF-beta, IL-6, and IL-8 on prostate cancer progression. Many other endothelium-derived factors NO, IGF, PDGF, IL-1, G-CSF, and GM-CSF (Nitric Oxide, Insulin-Like Growth Factor, Platelet-Derived Growth Factor, Interleukin-1, Granulocyte Colony Stimulating Factor, and Granulocyte-Macrophage Colony Stimulating Factor) are, at best, implicated in prostate cancer growth, and in most cases support cancer progression. CONCLUSIONS: A better understanding of endothelium-derived factors, as paracrine mediators of prostate carcinogenesis and progression, should aid in the development of novel therapeutic strategies.

Abdominal reservoirs for continent urinary diversion.

PURPOSE: Abdominal reservoirs with a continent stoma were constructed. MATERIALS AND METHODS: Different types of artificial valves were fashioned. Our original modification for construction of the Kock pouch is described. The main principle of our suggested version is the embedded and plicated valve, foregoing the antireflux afferent loop, with direct ureteral implantation into the reservoir. RESULTS: Of 69 patients 7 died in the postoperative period. Continence was achieved in 58 of the remaining 62 patients (93.5%). All 7 patients with the embedded valve were continent. CONCLUSIONS: The described modifications led to a shorter operating time and simplified certain portions of the operation.

Continent urinary diversion (Gotsadze Pouch) after pelvic exenteration for gynaecological malignancies.

The problem of urinary diversion is of major importance in patients requiring pelvic exenteration for advanced gynaecological malignancies. Eight patients underwent pelvic exenteration (4-total and 4-anterior) at the Georgian Oncologic Centre, 7 of them for recurrent cervical carcinoma after combined treatment and 1--for primary advanced cervical carcinoma. The original surgical technique for construction of detubalarized ileal reservoir with continent umbilical stoma (Gotsadze Pouch) is described. Six patients underwent this type of urinary diversion with successful results. Urination is patient-controlled via self-catheterization every 5 to 6 hours. The results obtained by operation can be considered as optimal for their functional and rehabilitational properties.

[The causes of mortality following cystectomy for bladder tumor]. / Prichiny letal'nosti posle tsistéktomii po povodu opukholi mochevogo puzyria.

The analysis of the treatment results is given for 183 patients with bladder cancer following cystectomy under various methods of urine derivation. Ureterocutaneostomy, Brickers operation, ureteral implantation into an isolated segment of the sigmoid, ureteral implantation into the colonic reservoir with controlled evacuation, radical cystectomy with ureteral implantation into an isolated rectal bladder with formation of sigmostoma, ureterosigmoanastomosis were performed in 94, 15, 10, 35, 12 and 17 patients, respectively. As shown by the follow-up available for 151 patients, 55 patients died of the tumor progression, 22 of renal complications, 11 of other causes. Within 2 postoperative years the disease progression and renal failure caused death in 65 (73.9%) out of 88 patients. The least lethality due to renal failure (3.2%) was recorded in patients with colonic reservoir.

[The quality of life of patients after cystectomy for cancer]. / Kachestvo zhizni bol'nykh posle tsistéktomii po povodu raka.

Quality of life was assessed in 60 cystectomized patients with bladder cancer versus method of urine derivation. Surgery had been ended with formation of "wet" stoma in 39 cases (ureterocutaneostomy--in 30 patients and operation after Bricker--in 9) whereas in 21 cases "dry" stoma had been formed with derivation of the urine into large bowel reservoir assuring controlled voiding. Only as few as 9 (23.1%) "wet" stoma patients retained the pretreatment activity as compared to 100% of those in the other treatment group. One-third of the "wet" stoma patients were unsatisfied with functional results of surgery and preferred formation of the reservoir which assured controlled voiding and allowed freedom from urinal.

[The lack of knowledgeability of men about testicular tumors as a cause for the late diagnosis of this disease]. / Plokhaia osvedomlennost' muzhchin ob opukholiakh iaichka kak prichina pozdnei diagnostiki étogo zabolevaniia.

Five hundred and sixty-two males, aged 15-50 years, were questionnaired to assess their knowledge about testicular cancer, its early symptoms, treatment and role of self-examination in early diagnosis of tumor. Only 25 (4.5%) respondents answered all 9 questions correctly whereas 93 (16.6i%) failed completely. On the average, each respondent gave a correct answer to four questions out of nine. The study pointed to very poor knowledge about testicular cancer among young males. This calls for making educational effort to improve the situation.

[Ways toward improvement of the results of cystectomy in bladder cancer]. / Puti uluchsheniia rezul'tatov tsistéktomii pri rake mochevogo puzyria.

Cystectomy with derivation of urine into large bowel reservoir was performed in 35 cases of bladder cancer including five females. Four patients (11.4%) died postoperatively. In patients with partial or complete ileocecal valve failure, the best functional results were obtained with formation of intussusceptum in the area of the ileum stoma. The reservoir volume increased with time, reaching 750 +/- 57.9 ml by the end of the second year. Within the same period, pressure in the totally filled reservoir decreased from 32 +/- 1.7 to 18 +/- 4.3 un. Postoperative monitoring of anatomic structure of the kidneys showed improvement in urine passage. Wide integration of the procedure discussed with practice will improve results of bladder cancer treatment.

[The results of cystectomy in bladder cancer]. / Rezul'taty tsistéktomii pri rake mochevogo puzyria.

Long-term results were assessed in 173 bladder cancer patients subjected to cystectomy. Twenty-eight (16.2%) patients died postoperatively. End results were evaluated in 142 patients. The patients were followed up for 1-17 years. Within that period, 50 patients (35.2%) died of tumor progression whereas 20--from renal failure (14.1%). Overall three- and five-year survival was 54.8 +/- 5.1 and 50.0 +/- 5.6%, respectively. Treatment results were studied versus stage, histologic pattern, type of treatment, tumor growth pattern and age. A significant correlation was established for stage and effectiveness of cystectomy only.

[The incidence of bladder tumor recurrences after transurethral resection during combined treatment]. / Chastota retsidivov opukholei mochevogo puzyria posle transuretral'noi rezektsii pri kombinirovannom lechenii.

A total of 231 patients undergoing transurethral resection combined with intravesical chemotherapy were examined for incidence of vesical tumor relapses. Some patients were subjected only to transurethral resection (Group I), those had the resection followed by intravesical adriamycin (Group II), those underwent the resection followed by thiophosphamide chemical prevention (Group III), and those had surgeries after intravesical chemotherapy (Group IV). The incidence of the relapses was 44, 43.1, 29.6, and 52.9%, respectively. The incidence of relapses was examined in relation to the type, malignancy, and multiple foci of the tumor.