Исследование компонентов инсулиноподобного сигнального пути в тканях почки при локальном и генерализованном светлоклеточном раке почки в зависимости от половой принадлежности больных. Объект исследованияусловно интактная ткань почки, опухолевая ткань и ткань перифокальной зоны, полученные при хирургическом лечении 100 больных с гистологически подтвержденным светлоклеточным вариантом рака почки (локальный рак (Т1-2N0М0) n=50, генерализованный (Т1-4N0М1) n=50). Методом ИФА с использованием стандартных тест-систем определяли уровень ростовых факторов-IGF-1, IGF-2, IGFBP-1, IGFBP-2 (Mediagnost, Германия) и СТГ-рилизинг (Peninsula Laboratories International, США). Статистический анализ результатов проводили с помощью пакета программ Statistica 6,0 (Stat-Soft, 2001). В условно интактной ткани IGFВР-2 и СТГ-рилизинг у женщин были ниже на 44% и 40%, чем у мужчин. В ткани перифокальной зоны уровень IGFВР-2 у женщин был выше, чем у мужчин на 38%, а СТГ-рилизинг ниже в 1,9 раза. В опухолевой ткани локального рака почки у женщин отмечалось статистически значимое снижение IGF-1 на 25%, IGFВР-1 на 29% и IGFВР-2 в 2 раза. При генерализованном процессе в условно интактной ткани у женщин по сравнению с мужчинами IGFBP-1 был ниже в 2 раза, IGFBP-2 в 2,7 раза. В ткани перифокальной зоны у женщин были повышены IGFBP-2 на 43,8% и СТГ-рилизинг на 44,6%. В опухолевой ткани генерализованного рака почки у женщин IGF-1 был выше в 1,7 раза, а IGF-2 ниже на 31%, IGFBP-2 ниже в 2,8 раза и СТГрилизинг на 36% по сравнению с мужчинами. Во всех исследуемых тканях почки при локальном и генерализованном процессах идентично изменяющимся показателем, характеризующим половые различия в реакции организма на опухолевый процесс, явился IGFBP-2. Ключевые слова: светлоклеточный рак почки, факторы роста, условно интактная ткань, перифокальная зона, половые различия.
Purpose of the study. To evaluate the prognostic significance of biological factors VEGF-A, sVEGF-R1, VEGF-D, FGF, EGF, EGFR, IGF-1, IGF-2, IGFBP-1, IGFBP-2, somatotropin-releasing factor (GHRH) in kidney tissues (tumour tissue, tissue of the perifocal zone and conditionally intact tissue) in local and generalized clear cell renal cancer using ROC analysis.Materials and methods. Two groups of patients were included in the study. Group 1 comprised 50 patients with local kidney cancer (T1–3N0M0), while group 2 comprised 50 patients with metastatic kidney cancer (T1–4N0M1). 10% cytosolic fractions of the kidney tumour tissue were examined. The content of growth factors — somatotropinreleasing factor (GHRH), somatotropin-releasing factor (GHRH) — was determined by the ELISA assay using standard test systems. An assessment of prognostically unfavourable factors that significantly affect the generalization of the tumour process was carried out using binary logistic regression and ROC analysis.Results. The performed ROC analysis revealed diagnostically significant progression biomarkers and their critical values for clear cell renal cancer (for conditionally intact tissue, these values were: VEGF-A ≤ 9107.9 pg/g of tissue; VEGF-R1 ≤ 122.8 ng/g of tissue; FGF ≤ 364.7 pg/g of tissue; IGF-2 ≤ 148 ng/g of tissue; for perifocal tissue, VEGF-A ≤ 5839.6 pg/g of tissue; for tumour tissue, VEGF-A > 9622.5 pg/g of tissue, FGF ≤ 435.1 pg/g of tissue, somatotropin-releasing factor (GHRH) ≤ 158.6 ng/g of tissue). The obtained data contribute to optimization of the disease prognosis.Conclusion. It is established that the most prognostically significant markers of clear cell renal cancer progression include VEGF-A, FGF, somatotropin-releasing factor (GHRH), which can serve as an additional criterion for the differential diagnosis of progression and monitoring of clear cell renal cancer.
Objective:study of components of an insulin-like signaling pathway in kidney tissues in local and advanced clear cell renal cell carcinoma depending on the gender of patients.Materials and methods:the object of the study was conditionally intact kidney tissue and tumor and perifocal tissues obtained during the surgical treatment of 100 patients with histologically confirmed clear cell kidney cancer (local cancer (Т1-2N0М0) n=50, advanced cancer (Т3-4N0М1) n=50). Levels of the IGF-1, IGF-2, IGFBP-1 and IGFBP-2 growth factors (Mediagnost, Germany) and STH-releasing (Peninsula Laboratories International, USA) were determined by ELISA using standard test systems. The results were analyzed using Statistica 6.0 (Stat-Soft, 2001).Results:levels of IGFВР-2 and STH-releasing in conditionally intact tissues in women were 44% and 40% lower than in men, respectively. The IGFВР-2 level in perifocal tissues of women was 38% higher than in men, while STH-releasing was lower by 1.9 times. Tumor tissues of local kidney cancer in women showed significant decrease in IGF-1 by 25%, IGFВР-1 by 29% and IGFВР-2 by 2 times. Levels of IGFBP-1 and IGFBP-2 in conditionally intact tissues of women with advanced cancer were 2 and 2.7 times lower, respectively, compared to men. IGFBP-2 and STH-releasing in perifocal tissues of women were increased by 43.8% and 44.6%, respectively. In tumor tissues of women with advanced kidney cancer, levels of IGF-1 were 1.7 times higher, IGF-2 – 31% lower, IGFBP-2 – 2.8 times lower and STH-releasing – 36% lower, compared to men.Conclusions:IGFBP-2 in all studied kidney tissues in local and advanced cancer was an identically variable index characterizing gender differences in the body’s reaction to the tumor process.
Purpose of the study. To conduct a comparative analysis of the expression of the following markers: Ki‑67, cyclin D1, E‑cadherin, CD44, MMP‑9, VEGF, P53, vimentin in renal tumor tissue in clear cell kidney cancer depending on the prevalence of the tumor process.Materials and methods. The material for the study was the operating material of 100 patients with light cell kidney cancer who were treated at the National Medical Reseaгch Centгe fог Oncology of the Russian Federation Health Ministry from 2015 to 2018. 50 patients were diagnosed with local cancer (T1–3an0m0), 50 – generalized cancer (T1–4N0M1). For the immunohistochemical (IHC) study, the material was fixed in 10% neutral formalin for 24 hours and encased in paraffin. Dewaxing and restoration of antigenic activity of the material was carried out in the RT module (Thermo Fisher Scientific) using Tris buffer pH=9, for 20 minutes at 98 °C. the Formulation of the IGC reaction was carried out in the immunohistostainer «Autostainer 480S» (Thermo Fisher Scientific). Used system detection UltraVision Quanto Detection System (Thermo Fisher Scientific), and the Chromogen DAB. Antibodies used: E‑cadherin (EP700Y) Cell Marque, 1: 100; CD 44 (EPR1013Y) Cell Marque 1:150; Ki‑67 (SP6) Spring Bio, 1:200; P53 (DO‑7) Cell Marque, 1:200; cyclin D1 (EP12) Dako, 1:200; VEGF Termo Fisher, 1:100; Vimentin (V9) Dako, 1:150; MMP‑9 (EP100902) Epitomics, 1:100. The results of the reactions with markers were evaluated by counting the number of colored cells in each 3rd field of view of the entire drug at magnification of the X200 lens in the AXIO Scope microscope. A1 (Carl Zeiss). The results were expressed as a percentage-the proportion of stained cells in relation to all tumor cells in the field of vision. Parametric methods of statistics were used for statistical processing of the results. The reliability of the difference between the two averages was determined by the student's t‑test for unrelated populations.Results. In clear cell kidney cancer, a low level of proliferative activity was observed in General, but in generalized, compared with local, it was significantly higher (P<0.05) (8±0.5% and 5±0.6%, respectively), and in generalized cancer, there was an overexpression of Cyclin D1–70±3.9%, compared to 14.4±2.3% in local stages, P<0.05. In generalized kidney cancer, epithelial-mesenchymal transformation processes are more pronounced in comparison with local cancer (a significant increase in Vimentin expression by 28% and CD44 by 16.6% (P<0.05), a decrease in E‑cadherin expression by 24% (P<0.05), and activation of neoangiogenesis processes (a significant increase in VEGF expression by 32%, P<0.05). The P53 protein was absent in local kidney cancer cells and was extremely low when generalized – 3.8±0.7%. One of the main markers of extracellular matrix degradation MMP‑9 was approximately at the same level at both stages: at local‑50±6% and 49.6±7.2% at generalized, the difference in indicators is not reliable (P<0.05).Conclusion. Progression of clear cell kidney cancer from local to generalized forms is accompanied by hyperexpression of cyclin D1, a decreased e‑cadherin expression while increasing vimentin expression (increasing signs of epithelial-mesenchymal transformation), an increase in CD44 and VEGF expression.
The aim of our study is to assess the local cytokine levels as prognostic factors for early relapse in NMIBC patients. 75 patients with NMIBC were enrolled in the study: 51 with primary NMIBC and 24 with initially recurrent NMIBC, LG and HG tumors were diagnosed in each group. Patients with primary NMIBC were monitored during 9 months after treatment: TURB and chemotherapy (No. 6). During TURB samples of tumors were taken, supernatants were obtained and tissue cytokine levels were measured (IL-1β, IL-6, IL-10, IL-18, TNFα, IFNγ, IL-8) by ELISA test. The results showed that in patients with primary NMIBC early relapses were diagnosed in 15 (46.8%) of LG tumors and in 11 (45%) of HG tumors matching that there was no difference depending upon tumor grade. In initially recurrent tumors of both LG and HG NMIBC the amounts of cytokines were maximal: in LG tumors they exceeded the primary ones from 7.1 (IFNγ) to 300 (IL-6) while in HG - from 2.0 (IL-10) to 9.7 (IL-6). The amounts of IL-1β, IL-6, IL-10, IFNγ, IL-8 were higher in those LG primary tumors which relapsed in 6-9 months compared to the ones which didn't, though their levels were much lower than in initially manifested relapse (from 2.6 times for IFNy to 150 times for IL-6). A similar trend, though not for all the same cytokines, was observed in HG tumors: tissue levels of IL-6, IL-10, IL-18 and TNFα were higher in tumors which relapsed in 6-9 months after treatment. The increase of 2 cytokines' levels were common for both LG and HG tumors (IL-6 and IL-10). This finding might be considered as a new prognostic factor of the early relapse. We conclude that relapse of LG and HG NMIBC is related to some immune mechanisms, namely to local hyperproduction of cytokines, especially IL-6 and IL-10, though IL-1β, IL-8, IFNγ could have an impact on LG and IL-18, TNFα — on HG tumors. Taking into account common signaling pathways of IL-6 and IL-10 like JAK/STAT, these transcription factors might be potential targets for new effective approaches to treatment.
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