Blood concentration of soluble Fas antigen is higher in patients with benign and malignant tumors in comparison with healthy subjects, which probably suggests its involvement into tumorigenesis. Key Words: tumors; apoptosis; soluble Fas antigenApoptosis, programmed cell death, is an important mechanism maintaining homeostasis in multicellular organisms. Disturbances in cell elimination underlie various pathological states such as malignant tumors, Alzheimer disease, multiple sclerosis, amyotrophic lateral sclerosis, thyroiditis, hepatitis, and autoimmune diseases.Fas/APO-1/CD95 is a type I transmembrane glycoprotein belonging to the TNF/NDF receptor family [5]. Fas is expressed in various tissues, in particular in the thymus, liver, heart, lungs; it is present on activated lymphocytes, natural killers, virus-infected and tumor cells.Similarly to tumor necrosis factor p55, Fas not only induces cell apoptosis upon interaction with specific ligand FasL or agonistic monoclonal antibodies (MCA) to Fas, but also activate transcription factor NtkB [14]. The mechanism triggering cell death via Fas is studied in detail. The interaction of Fas with FasL or agonistic MCA induces activation of caspase-8 or caspase-2 proteases via adapter proteins FADD/ MORT-1 or RIP and RAIDD, respectively [11,14] Molecular cloning studies and nucleotide-sequence analysis have demonstrated that apart from transmembrane Fas receptor, cells produce also soluble Fas (sFas), a product of alternative spicing of full-length Fas mRNA, which inhibits cytotoxicity induced by anti-Fas MCA in vitro [2,3]. Thus, enhanced production of sFas can underlie cell resistance to apoptosis.Elevated blood concentration of sFas was observed in some autoimmune disease: systemic lupus erythematosus [15] The aim of the present study was to determine serum concentration of sFas in patients with malignant tumors of various morphology and localization and to explore the relationship between sFas and these diseases. MATERIALS AND METHODSHybrid cells producing MCA to recombinant full-length Fas (Coultronics) were obtained according to a standard protocol [9]. Splenocytes from immunized BALB/c mice (3 intraperitoneal injections with a 2-week interval) were fused with mouse myeloma cells NSO/1
A test system developed by the authors was used to measure serum concentrations of soluble Fas in patients with malignant and benign tumors of different location and morphology. Relationships between soluble Fas levels and the main clinical and morphological characteristics of cancer were evaluated. It is proven that the concentrations and incidence of detection of soluble Fas in the sera of patients with tumors are significantly higher than in normal subjects. No appreciable differences in the concentrations of soluble Fas were detected in malignant and benign tumors of the mammary gland, bones, ovaries, and adrenals. In thyroid cancer, soluble Fas levels were higher than in benign and hyperplastic processes in this organ. High level of soluble Fas is associated with late stages of the disease (ovarian cancer, cancer of the corpus uteri, adrenocortical and colorectal cancer) and with poor differentiation of the tumor (ovarian cancer and cancer of the corpus uteri), with local metastases (colorectal and adrenocortical cancer), and with tumor invasion into the myometrial tissue, intestinal wall, and adjacent tissues (cancer of the corpus uteri and colorectal cancer). A significantly high level of soluble Fas was detected in colorectal and adrenocortical cancer in the presence of at least 2 local metastases. Soluble Fas levels depended on tumor histogenesis in malignant and benign ovarian tumors. High concentration of soluble Fas was detected in large tumors in patients with ovarian cancer, cancer of the corpus uteri, colorectal cancer, thyroid cancer and adenoma, and in adrenocortical cancer. Initially high levels of soluble Fas are characteristic of patients whose tumors are little sensitive to nonadjuvant radiotherapy. The overall 5-year survival of patients with low levels of soluble Fas is better in osteosarcoma, cancer of the corpus uteri, ovarian and adrenocortical cancer.
The mean blood content of interleukin-6 in patients with adrenal tumors was much higher than in healthy donors. No correlations were revealed between interleukin-6 level, patients sex and age, stage and duration of the disease. Interleukin-6 concentration was maximum in patients with adrenocortical cancer. A negative correlation was found between interleukin-6 level and blood cortisol concentration in patients with cortisol-producing adenoma. In patients with aldosterone-producing adenoma, interleukin-6 level tended to correlate negatively with plasma renin activity.
Serum concentration of soluble Fas antigen (sFas) was measured in 60 normal subjects and 33 patients with colon cancer. The incidence of sFas detection and its serum content were higher in patients with colon cancer compared to normal subjects. No relationships between the incidence and level of sFas and patient's sex, age, duration and stage of the disease were found. Serum content of sFas tended to increase in patients with metastases to regional lymph nodes, liver, and lungs. The role of sFas as a marker predicting clinical course and outcome of colon cancer is discussed.
Serum levels of vascular endothelium growth factor were measured in 43 patients with adrenal tumors and 25 healthy subjects. The mean blood levels of the factor in patients with adrenal tumors significantly surpassed the control. No correlations between the level of vascular endothelium growth factor, patients age and sex were detected. The levels of this factor were maximum in patients with adrenocortical cancer, but its mean level differed negligibly from that in other morphological variants of tumors. The level of vascular endothelium growth factor tended to increase with increasing the stage of adrenocortical cancer. A direct correlation was revealed between the level of vascular endothelium growth factor and tumor size in adrenocortical cancer and aldosterone-producing adenoma. Presumably, vascular endothelium growth factor is involved into mechanisms of growth, invasion, and metastatic growth of adrenocortical cancer.
Overall and relapse-free survival of 238 patients with neuroendocrine tumors of the abdominal and retroperitoneal organs was evaluated with consideration for the presence of the carcinoid syndrome. The incidence of the carcinoid syndrome was 15.6%. The presence of the carcinoid syndrome was inessential for survival and relapse prognosis in patients with neuroendocrine tumors of the abdominal and retroperitoneal organs. A trend to the development of earlier relapses was noted in patients with this syndrome. Diarrhea was found to be a prognostically unfavorable factor. The time of the carcinoid syndrome development was prognostically significant in patients with malignant neuroendocrine tumors. The mean secretion of epinephrine, norepinephrine, and dopamine with daily urine was significantly higher in patients with the carcinoid syndrome. A significant positive correlation between urinary excretion of catecholamines was detected (r=0.53; p<0.05).
We compared plasma content of soluble Fas antigen (sFas) in 59 patients with tumors and tumor-like pathologies of the adrenal cortex and medulla and 60 healthy donors (control). The incidence and content of sFas in the plasma from patients with adrenal tumors was significantly higher than in healthy donors. A direct correlation was found between sFas content and patient's age. The maximum sFas concentrations were found in patients with pheochromocytoma and aldosterone-producing adenoma. In patients with adrenocortical cancer plasma content of sFas was lower than in patients with tumors of other morphological types. Plasma sFas content in patients with adrenocortical cancer directly correlated with the size of tumors. Our results suggest that sFas plays a role in the pathogenesis of primary adrenal tumors.
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