Search

Autophagy plays a dual role in oncogenesis processes. On one hand, autophagy enhances the cell resistance to oncogenic factors, and on the other hand, it participates in the tumor progression. The aim of the study was to find the associations between the effectiveness of the FLOT regimen in resectable gastric cancers (GCs) with the key autophagy-related proteins. Materials and Methods: The study included 34 patients with morphologically verified gastric cancer. All patients had FLOT neoadjunvant chemotherapy (NACT) (fluorouracil, leucovorin, oxaliplatin, and docetaxel) followed by gastrectomy. The studied tissue material was the non-transformed and tumor tissues obtained during diagnostic video gastroscopy in patients before the start of the combined treatment and after surgical treatment, frozen after collection. The LC3B, mTOR, and AMPK expression was determined by real-time PCR. The content of the LC3B protein was determined by Western blotting analysis. Results: The mRNA level and the content of the LC3B protein were associated with the tumor stage and the presence of signet ring cells. The AMPK mRNA level was increased in patients with the T4N0-2M0 stage by 37.7 and 7.33 times, which was consequently compared with patients with the T2N0M0 and T3N0-1M0 stages. The opposite changes in the mTOR and AMPK in the GCs before anti-cancer therapy were noted. The tumor size and regional lymph node affections were associated with a decrease in the mTOR mRNA level. A decrease in the mTOR expression was accompanied by an increase in the AMPK expression in the GCs. The mTOR expression was reduced in patients with a cancer spreading; in contrast, AMPK grew with the tumor size. There was an increase in the LC3B expression, which can probably determine the response to therapy. An increase in LC3B mRNA before the start of treatment and the protein content in cancers after NACT with a decrease in therapy effectiveness was recorded. There was an increase in the protein level in patients with partial regression and stabilization by 3.65 and 5.78 times, respectively, when compared with patients with complete tumor regression was noted. Conclusions: The anticancer effectiveness in GCS is down to the LC3B, mTOR, and AMPK expression. These were found to be entire molecular targets affecting the cancer progression and metastasis as well as the NACT effectiveness.

The majority of colorectal cancer patients (CRCPs) develop tumors on the background of “metabolically healthy obesity” or metabolic syndrome. The aim of the work was to study the levels of matrix metalloproteinases (MMPs) and heat shock proteins (HSPs) on the surface of blood plasma CD9-positive and FABP4-positive small extracellular vesicles (sEVs) from CRCPs depending on metabolic status and tumor angiogenesis, as well as to evaluate the sEVs markers as predictors of the effectiveness of thermoradiotherapy. In CRCPs, compared with patients with colorectal polyps (CPPs), the proportion of triple positive EVs and EVs with the MMP9+MMP2-TIMP1+ phenotype increased significantly among FABP4-positive EVs (adipocyte-derived EVs), which in general may indicate the overexpression of MMP9 and TIMP1 by adipocytes or adipose tissue macrophages in CRCPs. The results obtained have prospects for use as markers to clarify cancer risk in CPPs. One can assume that for CRCPs with metabolic syndrome or metabolically healthy obesity, it is the FABP4+MMP9+MMP2-TIMP1- population of circulating sEVs that is the most optimal biomarker reflecting tumor angiogenesis. Determining this population in the blood will be useful in monitoring patients after treatment for the early detection of tumor progression. CD9+MMP9+MMP2-TIMP1- and MMP9+MMP2-TIMP1+ subpopulations of circulating sEVs are the most promising predictors of the efficacy of thermoradiation therapy because their levels at baseline differ significantly in CRCPs with different tumor responses.

Gastric cancer is the second most common cause of cancer-related deaths in the world. The surgical management of the tumor is the best therapeutic option for gastric cancer patients. A combination of a heterogeneous distribution of genetic and environmental factors appears to be required to explain patients' poor prognosis. A search for targeted and molecular-based approaches is affected by the optimal gastric cancer drug management. The modern multidisciplinary approach to treating the pathology used worldwide prolongs the overall patient survival and decreases the rate of recurrence. An understanding of the mechanisms that underlie therapies will provide new insights into gastric cancer treatment. The improvement in medicine will probably be associated with a study of tumor biology, followed by a personalized and molecular-based approach development in anticancer drugs administration. The modern perspective in gastric cancer detection and treatment is the application of nanoparticles. Nanoparticles affecting the intensity of biological processes in cancer cells can be used to treat cancers to increase the effectiveness of anti-tumor therapy. Their cytotoxicity involves a wide range of pathological events. Their targets are the extracellular matrix degradation, epithelial-mesenchymal transition, tumor angiogenesis, tumor microenvironment modulation. These are accompanied by lipid peroxidation, apoptosis, and autophagic flux. Preliminary studies on the efficacy of the use of nanoparticles in cultured gastric cancers open new opportunities for anti-tumor treatment to overcome the toxicity of therapeutic agents and decrease the rate of resistance to anticancer drugs and therapies.

Objective The aim of the study was to develop a model for predicting cancer risk in colorectal polyps' patients (CPPs), as well as to reveal additional prognosis factors for Stage III colorectal cancer based on differences in subpopulations of tetraspanins, tetraspanin-associated and tetraspanin-non-associated proteases in blood plasma exosomes of CPPs and colorectal cancer patients (CRCPs). Methods The subpopulations of CD151- and Tspan8-positive exosomes, the subpopulations of metalloproteinase at the surface of СD9-positive exosomes and the level of 20S proteasomes in plasma exosomes in 15 CPPs (tubulovillous adenomas) and 60 CRCPs were evaluated using flow cytometry and Western blotting. Logistic regression analysis was performed to predict cancer risk of CPPs. Results The levels of 20S proteasomes in exosomes, MMP9+, MMP9+/MMP2+/EMMPRIN+ in CD9-positive blood plasma exosomes are associated with the risk of malignant transformation of colorectal tubulovillous adenomas. In patients with Stage III CRC, the levels of 20S proteasomes (less than 2 units) and MMP9+ subpopulations (more than 61%) in plasma exosomes are unfavorable prognostic factors for overall survival. The levels of 20S proteasomes and ADAM10+/ADAM17- subpopulations in CD9-positive blood plasma exosomes are the most significant values for predicting relapse-free survival. Conclusion Protease cargo in CD9-positive blood plasma exosomes is prognostic biomarker for colorectal polyps and colorectal cancer.

Gastric cancer (GC) is biologically and genetically heterogeneous with complex carcinogenesis at the molecular level. Despite the application of multiple approaches in the GC treatment, its 5-year survival is poor. A major limitation of anti-cancer drugs application is intrinsic or acquired resistance, especially to chemotherapeutical agents. It is known that the effectiveness of chemotherapy remains debatable and varies according to the molecular type of GC. Chemotherapy has an established role in the management of GC. Perioperative chemotherapy or postoperative chemotherapy is applied for localized ones. Most of the advanced GC patients have a poor response to treatment and unfavorable outcomes with standard therapies. : Resistance substantially limits the depth and duration of clinical responses to targeted anticancer therapies. Through the use of complementary experimental approaches, investigators have revealed that cancer cells can achieve resistance through adaptation or selection driven by specific genetic, epigenetic, or microenvironmental alterations. Ultimately, these diverse alterations often lead to the activation of MAPK, AKT/mTOR, and Wnt/β-catenin signaling pathways that, when co-opted, enable cancer cells to survive drug treatments. We have summarized the mechanisms of resistance development to cisplatin, 5-fluorouracil, and multidrug resistance in the GC management. The complexity of molecular targets and components of signaling cascades altered in the resistance development results in the absence of significant benefits in GC treatment, and its efficacy remains low. The universal process responsible for the failure in the multimodal approach in GC treatment is autophagy. Its dual role in oncogenesis is the most unexplored issue. We have discussed the possible mechanism of autophagy regulation upon the action of endogenous factors and drugs. The experimental data obtained in the cultured GC cells need further verification. To overcome the cancer resistance and to prevent autophagy as the main reason of ineffective treatment, it is suggested the concept of the direct influence of autophagy molecular markers followed by the standard chemotherapy. Dozen of studies have focused on finding the rationale for the benefits of such complex therapy. The perspectives in the molecular-based management of GC are associated with the development of molecular markers predicting the protective autophagy initiation and search for novel targets of effective anticancer therapy.

The purpose of the study: to analyze the efficacy of combined modality treatment including preoperative chemotherapy with gemcitabine/cisplatin in patients with stage II-III esophageal cancer (EC). Materials and methods: The study included 70 patients with stage II-III EC, who were treated at the Cancer Research Institute (Tomsk, Russia) from 2012 to 2019. The patients were divided into 2 groups. Group I comprised 35 patients, who received 2 cycles of preoperative chemotherapy with gem-citabine (1250 mg/m2 on days 1 and 8) and cisplatin (80 mg/ m2 on day 1) followed by radical surgery. Group II included 35 patients who underwent surgery alone. All patients underwent subtotal resection of the esophagus with simultaneous esophageal reconstruction using gastric tube (68.6%) or colon tissue (31.4%). Results: The overall tumor response to preoperative chemotherapy according to RECIST 1.1 criteria was 57.1%, including complete response (5.7%) and partial response (51.4%). No severe complications were observed. R0 resection was achieved in all patients (100%). No difference in the rate of postoperative complications between Group I and Group II was found (34.3% and 40%, respectively). There was no statistically significant difference in the mortality rate between treatment groups (8.6% versus 57%) (p>0.05). Pathological complete tumor response was 5.7%. In Group I patients, the 2-year disease-free and overall survival rates were 71.8% and 81.3%, respectively. The corresponding values in Group II patients were 39.4% and 51.5%, respectively (p=0.01). Conclusion: Preoperative chemotherapy for patients with stage II-III EC demonstrated high response rates, having no adverse effect on the perioperative period and mortality. The 2-year survival rates were significantly higher in patients, who received combined modality treatment with preoperative chemotherapy than in patients, who underwent surgery alone.

The objective is to study the treatment results of patients with low rectal cancer with complete tumor regression after neoadjuvant chemoradiation (CRT) and consolidating chemotherapy. Materials and methods. The investigation involved 70 patients with adenocarcinoma of the low rectal cancer with the stage mrT2-3N0-1M0 who were treated from 2013 till 2018. All of these patients were given chemoradiation in the standard long-course fractionated radiation 2.0 Gy per day, total dose of 45 Gy and with Capecitabine in the daily dose of 825 mg / m2 in the days of radiation. If complete clinical and morphological regression of tumor was registered in 6 weeks after completion of CRT the patients were held 2 courses of consolidating chemotherapy with capecitabine in the daily dose of 3,500 mg / m2 for 14 days (the interval between chemotherapy courses was 7 days). Results. Complete tumor regression was recorded in 22 (31.4 ± 5.5%) of 70 patients. The median follow-up was 26 months: any signs of progression weren’t detected in 20 (90.9 ± 6.1%) patients with detailed survey which was held every 3 months, and local recurrence was detected (R0) in 2 (9.1 ± 6.1%) patients in the first year of follow-up. Conclusions. Neoadjuvant CLT and consolidating chemotherapy provide reliable local monitoring and prevention of hematogenous metastasis in patients with low rectal cancer. The preliminary results which were obtained in our research confirm the adequacy of the surviving approach after Complete tumor regression using the condition of active monitoring using a complex of clinical and instrumental methods. Final conclusions require further research.

The objective is to study the incidence of metabolic syndrome (MS) and overweight in patients with colorectal cancer as well as to evaluate the relationship with clinical and morphological features and to analyze the incidence of 3-, 4- and 5- components МS in patients with colorectal cancer. Materials and methods. The investigation involved 99 people with the prevalence of the tumor process T2-3N1-2M1. Depending on the presence of MS or overweight patients were divided into 3 groups. The recommendations of the International Diabetes Federation (2005) were used for inclusion in the group with MS. Statistical processing of the results was made with the Statistica 10.0 software package. Results. About 78% of patients with colorectal cancer had metabolic disorders: 67% had MS, 11% had overweight. The patients with colorectal cancer had mainly the 3- and 4-components variants of MS (46% and 47%, respectively), the 5 components MS occurred in 7% of cases. No significant relationship was found between the presence/absence of the MS, and MS variant and age, sex, stage, and localization of the tumor process. A significant correlation was revealed between the presence of MS/ MS variants and tumor Grade. In particular, G3 adenocarcinomas meet more often in the presence of MS5. An association of MS and its individual components was identified with recurrence- free / overall survival, in particular, the presence of MS, an increase in body mass index, waist size, and the presence of diabetes mellitus type II is associated with a decrease in recurrence-free survival. Increased blood triglyceride levels are associated with a decrease in overall survival.

Purpose: Exosomal proteases are important in regulation of molecular signaling from growth factor receptors and adhesion molecules and also the regulation of cell motility and protein folding. The aim of this study was to evaluate the level of ADAM10, ADAM17 and 20S proteasomes in exosomes isolated from colorectal cancer patients (CRCPs) in relation with clinical and histopathological parameters. Methods: Blood plasma exosomes of 60 CRCPs at stage T2-4N0-2M0-1 and 10 control subjects (CSs) with colorectal polyps were isolated using ultrafiltration in combination with ultracentrifugation. The level of tetraspanin-associated (ADAM20 and ADAM17) and tetraspanin-non-associated (20S proteasome) proteases were evaluated by flow cytometry and western blot analysis. Results: The ADAM10-/ ADAM17- population predominated in plasma exosomes of CRCPs and the level of ADAM10+ exosomes was significantly higher in exosomes of CSs compared with CRCPs. No difference was found between subpopulations of ADAM10/ADAM17 exosomes and level of exosomal 20S proteasomes in terms of sex, age and tumor grade. Simultaneous decrease of ADAM10+/ADAM17-subpopulation of exosomes and level of exosomal 20S proteasomes in patients with metastatic CRC was observed compared with patients with non-metastatic CRC. The level of ADAM17+ exosomes significantly reduced in exosomes of CRCPs with metabolic syndrome compared to CRCPs without metabolic syndrome( 3.97±0.71 (%) vs. 13.04±1.34 (%), respectively (p

The article describes the experience of using ther-mochioradiotherapy in the combined treatment of distal locally advanced colorectal cancer, as well as comparing the effectiveness of treatment with chemoradiation therapy. The use of the proposed method as a component of the combined treatment of patients with rectal cancer allowed to increase the percentage of organ-preserving operations. As a result of thermochemotherapy, the prevalence of the primary tumor was significantly reduced, as a result of which the number of sphincter-bearing operations was reduced by almost 2 times (p

Background. Autophagy plays a dual role in oncogenesis processes. On the one hand, increasing the cell's resistance to oncogenic factors, and on the other hand, participating in the processes of tumor progression and the formation of resistance to antitumor treatment. It has been shown that autophagy correlates with the aggressive course of the disease and its poor prognosis. The molecular cascades that regulate autophagy are numerous and varied and play a role in tumorigenesis that has not yet been studied.The study aimed to study the expression of LC3B, mTOR, AMPK, the content of the LC3B protein in gastric cancer tissue, and its relationship with disease progression, and the response to anti-cancer therapy.Material and methods. The study included 34 patients with morphologically verified gastric cancer. All patients were hospitalized in the Department of Abdominal Oncology of the TNIMTs Research Institute of Oncology. All patients had FLOT neoadjunvant chemotherapy (NACT) (fluorouracil, leucovorin, oxaliplatin, and docetaxel) followed the gastrectomy. The response to the combined treatment of patients was evaluated according to the RECIST 1.1 criteria.The study's material was the non-transformed and tumor tissues obtained during diagnostic video gastroscopy in patients before the start of combined treatment and after surgical treatment, frozen after collection and stored at t -800C. The expression of LC3B, mTOR, AMPK was determined by real-time PCR, the LC3B protein level - using the Western Blotting method.Results and their discussion. The mRNA level and the content of the LC3B protein are associated with the size of the tumor, damage to regional lymph nodes (spread of the disease), and the presence of cricoid cells. The AMPK mRNA level increased in patients with the T4N0-2M0 stage in 37.7 and 7.33 times, respectively, compared with patients with the T2N0M0 and T3N0-1M0 stages. The opposite character in mTOR, AMPK changes in the GCs before anti-cancer therapy is noted. At the same time, the local prevalence of the tumor and the lesion of regional lymph nodes were associated with a decrease in mTOR mRNA level.A decrease in mTOR expression is accompanied by an increase in AMPK expression in a gastric tumor. It is associated, first of all, with the clinical and morphological parameters of the primary process. mTOR expression is reduced in patients with a higher local prevalence of the process; in contrast, AMPK grows with tumor size.There is an increase in the LC3B expression, which, probably, can determine the response to therapy. As a result of the study, an increase in LC3B mRNA before the start of treatment and the concentration of autophagy protein after NACT with a decrease in therapy effectiveness was recorded. An increase in the protein level in patients with partial regression and stabilization of the tumor process by 3.65 and 5.78 times compared with patients with complete tumor regression was noted. Conclusion. The development of the disease and the prediction of anticancer therapy's effectiveness is directly related to the expression level of LC3B, mTOR, and AMPK. The following relationship was revealed: a decrease in mTOR expression and an increase in the level of mRNA and protein LC3B, AMPK expression combined with the progression of the disease in the form of the development of distant metastases, as well as the predicted future low effectiveness of NACT.

Metabolic syndrome (MS) is one of the leading risk factors for the development of cardiovascular diseases, type II diabetes mellitus and reproductive system diseases. Currently, not only cardiovascular disease and reproductive history risks related with MS are frequently discussed, but it has been also shown that MS is associated with increased risk of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer, biliary tract cancers and liver cancer for men). Further studies are required to understand the mechanisms of the involvement of MS components in the pathogenesis of malignant neoplasms. Changes in the expression of transcription and growth factors in the peripheral tissues as well as in cancer tissues of patients with MS were revealed. Transcription factors (AMP-activated protein kinase-1, STAT3, sterol regulatory element-binding protein-1 and peroxisome proliferator-activated receptor-γ), leptin and adiponectin receptors seem to be the most promising molecular targets for the therapy of cancers associated with MS.

Pre-selection of tumor exosomes from a total pool of circulating microvesicles is an important stage required to increase sensitivity and specificity of the developing methods for diagnostics of oncological diseases. In this study, universal proteins characterized by increased expression in plasma exosomes have been identified in patients with colorectal cancer, head and neck squamous cell carcinomas, and lung cancer. The use of antibodies against major exosomal proteins will help to develop a simple and high-performance method of affinity isolation of tumor exosomes.

Aim of the study To compare the functional activity of natural killer cells depending on the presence of a malignant process and its dissemination. Material and methods The study included 20 patients with Stage IIIB, C (FIGO, 2009) ovarian cancer, 10 patients with benign ovarian tumours (BOT), and 20 patients with colorectal cancer (T2-4N0-2M0). The control group consisted of 9 healthy donors. To evaluate the number and functional activity of NK cells, multicolour flow cytometry was performed. Results In cancer patients, the relative number of activated NK cells secreting granzyme B (GB) (CD56+CD107a+GB+PF-) was significantly decreased, and the proportion of degranulated NK cells (CD56+CD107a+GB-PF-) was significantly increased, compared to those observed in healthy donors. The total number of NK cells in peripheral blood was low in ovarian cancer patients (p < 0.05). The proportion of activated peripheral blood NK cells containing cytolytic granules GB and perforin (PF) in colorectal cancer patients increased with tumour growth. However, lymph node metastasis did not affect the content and activation of NK cells. Comparative analysis of NK-cell populations in patients with benign and malignant ovarian tumours revealed that the level of CD56+ cells was significantly higher in ascites than in peripheral blood. However, CD56+CD107a+ activated cells and CD56+CD107a+GB+PF+ cells were found more frequently in ascites of BOT patients than in ovarian cancer patients. The degranulated population of NK cells (CD56+CD107a+GB-PF-) was mainly observed in the peripheral blood of ovarian cancer patients.

The study of the pathogenetic features of malignant tumors associated with metabolic syndrome (MS) is relevant because of high incidence of these tumors. Investigations of the mechanisms of involvement of MS in the pathogenesis of cancer reasonably supplemented by the study of transcription and growth factors associated with energy imbalance of the cell and involved in proliferation, apoptosis, angiogenesis, cell motility and inflammation. More research is needed to identify the most promising molecular targets for therapy of malignant tumors associated with MS with a view to increasing the survival and quality of life of these patients.

Metabolic syndrome (MS) is one of the leading risk factors for the development of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer). Currently, a drug-induced metabolic syndrome related with androgen deprivation therapy in patients with prostate cancer represents a serious medical problem. Not only MS, or its individual components, but MS variants with different levels of leptin, adiponectin, visfatin, resistin are associated with tumor invasion, metastasis and survival rates in patients with MS-associated malignancies.

Exosomes are extracellular membrane structures involved in many physiological and pathological processes including cancerogenesis and metastasis. The purpose of the study was to isolate, identify and analyze the total content of exosomes in biological fluids. The exosomes from the plasma and ascites samples of the patients with ovarian cancer, from the blood plasma of the patients with colorectal and head and neck squamous cell cancer as well as from the blood plasma of healthy donors were characterized using transmission electron microscopy and flow cytometry. The subpopulations of the exosomes in the biological fluids of the patients with different types of cancer were similar, but the protein concentrations of exosomes were different. In this paper we present the methodological approaches allowing us to obtain high quality exosome preparations from biological fluids.

To assess IGFBP-6 expression in relation with the presence of the metabolic syndrome, adiponectin receptors (AdipoR1 and AdipoR2) and IGF-IR levels in colorectal adenocarcinoma cases.IGFBP-6 mRNA and protein levels were analyzed using real-time quantitative PCR and Western blotting in 46 patients. ELISA and ow cytometry were used for evaluation of AdipoR1, AdipoR2 and IGF-IR.The results showed that IGFBP-6 mRNA expression and the IGFBP-6 content were higher in tumor tissue samples of colorectal cancer patients with and without the metabolic syndrome. In addition, IGFBP-6 mRNA expression was associated with tumor invasion (tumor size) and the IGFBP-6 protein level was associated with nodal status. Positive correlations and positive nonlinear relations were found between the IGFBP-6 level and the AdipoR1 and AdipoR2 contents in colorectal cancer patients.The IGFBP-6 mRNA level and protein level were found to be associated with presence of the metabolic syndrome. Positive correlations indicated probable cross-talk between the IGF-IR-mediated and adiponectin-mediated signaling pathways in colorectal carcinomas. IGFBP-6 may be considered as a potential biomarker associated with lymphogenous metastasis and the metabolic syndrome in colorectal cancer.

Exosomes are extracellular membrane structures involved in many physiological and pathological processes including cancerogenesis and metastasis. The clarification of the criteria for exosome isolating and identifying is the purpose of this study. Exosome samples from the plasma of patients with colorectal cancer and healthy donors were examined using transmission electron microscopy and flow cytometry in accordance with the minimum requirements of “International Society for Extracellular Vesicles”. The choice of the method for isolation of exosomes from the blood plasma by ultrafiltration and ultracentrifugation allowed obtaining highly purified samples of exosomes, in which all the structural components were clearly seen. The results obtained with flow cytometry suggest that exosomes of blood plasma from patients with colorectal cancer can be produced by epithelial cells. Moreover, cells produce different types of exosomes, which correspond to different mechanisms in sorting macromolecules in the membrane of multivesicular bodies. Determination of significant differences in the expression of specific exosomal proteins from colorectal cancer patients compared to healthy donors suggests a high diagnostic potential significance of circulating exosomes.

Results of experimental and theoretical investigations of free-localized and directed microwave discharges (MWD) are presented. The control over plasma parameters is achieved by changing of MW power level, pulse duration and by application of transverse magnetic field (0 200mT) and gas flows (V ~ 0.7 1M). The flexible scheme for MW energy supply (F=13GHz, W~10-50 kW/cm, τ~5-40μs) of plasma region and for changing the interaction conditions (MWD magnetic field, MWD gas flow) is used in this study. Such general features of discharges as its structure, velocity and size, the temperature and conductivity in plasma channels and their evolution in external magnetic field and airflow are explored. The obvious changing of separate discharge channels behavior and MWD structure modifying, the formation of circular plasma meshes and vortexes and plasma swirls are registered in our experiments. Comparative study of MW and RF ball discharges is performed. The similarity of ball RF and MW discharges is shown.