Review of authors' results and the most representative literature data on the role of tumor-associated proteolitic systems involved in invasion, metastasizing and angiogenic processes in diagnostics and prognosis in various oncologic diseases is presented in this paper. The main attention is paid to the key matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) as well as to the plasminogen activation system components (uPA, Общие представления о роли ключевых, ассоциированных с опухолью, протеолитических систем в инвазии и метастазировании Способность к инвазии окружающих тканей и метаста-зированию в отдаленные органы -одно из фундаменталь-ных свойств злокачественных опухолей. На всех этапах инвазии и метастазирования опухолевая клетка находится в тесном контакте с внеклеточным матриксом (ВКМ), по-этому одним из главных молекулярных механизмов, лежа-щих в основе этих процессов, считается разрушение окру-жающей базальной мембраны ВКМ-ассоциированными
Analysis of long-term treatment results of 101 primary gastric cancer patients at various stages of the tumor process followed during 1 - 41 months (median - 6,4 months) from the onset of specific treatment are presented depending on the levels of soluble forms (s) of PD-1 receptor and its ligand PD-L1 in blood plasma. Overall survival assessed by Kaplan-Meyer analysis and with the help of Cox multiparametric regression model was applied as the criterion of prognostic value. It was found that at high (≥ 35 pg/ml) sPD-L1 levels in blood plasma, the overall survival of patients with gastric cancer was statistically significantly lower than at the marker’s levels below 35 pg / ml (p <0.045): 1-year survival comprised 78 and 96%, 2-year - 52 and 78%; 3-year - 40 and 61% at high and low sPD-L1 respectively. Median survival of patients with high plasma sPD-L1 comprised 29 months, of those with low sPD-L1 was not achieved during the whole follow-up period. This trend was observed not only in the total group of stage I-IV gastric cancer patients, but also in patients at the early stages of the disease, though sPD-L1 did not show an independent prognostic value in multiparametric model. At the same time, the overall survival of patients with gastric cancer did not depend on the baseline levels sPD-1 in blood plasma. Thus, soluble ligand sPD-L1 can be considered as a potentially valuable factor for prognosis of gastric cancer patients’ survival, and, probably, of anti-PD-1/PD-L1 treatment efficiency, but further studies and patients’ monitoring are required to prove this statement.
Results of comparative ELISA investigation of pretreatment sPD-1 and sPD-L1 content in blood plasma of 100 gastric cancer patients at various disease stages aged 25 to 81 years are presented. Control group included 60 practically healthy donors aged 18 - 68 years. Plasma sPD-L1 concentrations did not differ between gastric cancer patients and control group, and sPD-1 levels were statistically significantly lower in patients than in healthy donors (p<0.0001). Positive correlation (R=0.38; p=0.003) was revealed between plasma sPD-1 and sPD-L1 levels in control group and negative (R= -0.26; p=0,009) - in gastric cancer patients. ROC curve revealed the best sPD-1 cut-off level (< 21 pg/ml) with 77% sensitivity and 63.3% specificity, which is not sufficient for its application as diagnostic marker. Statistically significant increase of plasma sPD-L1 from stage I to stage IIIC (R=0.50; p=0.000011) was found. Analysis of associations between the evaluated markers’ levels and indices of gastric cancer expansion according to TNM system revealed statistically significant positive associations of plasma sPD-L1 levels with T (tumor invasion depth) and N (number of affected lymph nodes) indices: R=0.33; p=0.00093, and R=0.27; p=0.0099 respectively. sPD-L1 level was significantly increased in patients with low differentiated adenocarcinoma and cricoid-cell cancer as compared to highly differentiated adenocarcinoma (p=0.02 and p=0.004 respectively); in patients with cricoid-cell cancer it was also higher than in those with moderately differentiated adenocarcinoma (p=0.043) and undifferentiated cancer (p=0.049). Plasma sPD-1 level did not depend on disease stage, TNM system indices and tumor histological structure. Thus, soluble ligand sPD-L1, but not its receptor sPD-1, plasma level is increased in patients with unfavorable clinical and morphological characteristics, may be regarded as potentially valuable prognostic factor for gastric cancer patients’ survival, and probably as a predictor of anti - PD-1/PD-L1 treatment efficiency.
Владимирович-врач-уролог, соискатель лаборатории клинической биохимии 1 Короткова Екатерина Андреевнаканд. биол. наук, ст. науч. сотр., лаборатория клинической биохимии 1 Бежанова Светлана Дмитриевнааспирант отдела патологической анатомии опухолей человека 1 Морозов Алексей Андреевич-врачуролог, отделение урологии 2 Алферов Александр Андреевичаспирант лаборатории клинической биохимии 1 Казанцева Ирина Александровнад-р мед. наук, профессор, вед. науч. сотр., патологоанатомическое отделение 2 Кушлинский Николай Евгеньевичд-р мед. наук, профессор, членкорреспондент РАН, заведующий лабораторией клинической биохимии 1
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