Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-22-30
V. A. Bogdanova, L. V. Spirina, S. U. Chizhevskaya, I. V. Kovaleva, K. V. Nikulnikov
Melanoma of the skin and mucous membranes remains a global medical problem, which is associated with the increasing prevalence of this disease and the lack of adequate molecular genetic markers for its diagnosis and prognosis. The development of molecular approaches in the treatment of this type of tumor is associated with the identification of mutations, and with the development of immunotherapeutic and targeted drugs that can improve the effectiveness of treatment of patients with this pathology. However, the heterogeneity of the mechanisms of tumor development and the formation of resistance are a problem. It is worth noting the presence of many epigenetic mechanisms that are promising markers of the development, diagnosis and prognosis of the effectiveness of treatment of melanoma of the skin and mucous membranes. This review contains up-to-date information on the molecular mechanisms of the disease associated with the genetic characteristics of the tumor and biological factors of resistance to therapy. Of particular interest is the intersection of signaling pathways associated with melanocyte-inducing transcription factor (MITF), which is associated with transcription and growth factors, and is a target of epigenetic regulation using microRNAs and long non-coding RNAs.
{"title":"Contemporary views on the clinical, epidemiological and molecular genetic characteristics of melanoma of the skin and mucous membranes","authors":"V. A. Bogdanova, L. V. Spirina, S. U. Chizhevskaya, I. V. Kovaleva, K. V. Nikulnikov","doi":"10.17650/2313-805x-2024-11-1-22-30","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-22-30","url":null,"abstract":"Melanoma of the skin and mucous membranes remains a global medical problem, which is associated with the increasing prevalence of this disease and the lack of adequate molecular genetic markers for its diagnosis and prognosis. The development of molecular approaches in the treatment of this type of tumor is associated with the identification of mutations, and with the development of immunotherapeutic and targeted drugs that can improve the effectiveness of treatment of patients with this pathology. However, the heterogeneity of the mechanisms of tumor development and the formation of resistance are a problem. It is worth noting the presence of many epigenetic mechanisms that are promising markers of the development, diagnosis and prognosis of the effectiveness of treatment of melanoma of the skin and mucous membranes. This review contains up-to-date information on the molecular mechanisms of the disease associated with the genetic characteristics of the tumor and biological factors of resistance to therapy. Of particular interest is the intersection of signaling pathways associated with melanocyte-inducing transcription factor (MITF), which is associated with transcription and growth factors, and is a target of epigenetic regulation using microRNAs and long non-coding RNAs.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"3 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-90-98
N. Persiyantseva, S. Y. Vikhrova, M. S. Korotkova, D. B. Kazansky, V. V. Tatarsky, M. Zamkova
Contacts: Maria Anatolievna Zamkova zamkovam@gmail.com Introduction. Due to the toxicity of high doses of chemotherapy, low concentrations used in cancer treatment leads to the development of senescence phenotype in tumor cells, characterized by a block in the cell cycle progression and the absence of division; changes in the transcriptional and metabolic profile of cells. A negative consequence of this stage is acquisition of individual cells the ability to escape from senescence and return to re-proliferation.Aim. To estimate the effect of the duration of drug treatment of HCT116 tumor cells on their ability to escape from therapy induced senescence.Materials and methods. The senescence phenotype was confirmed by the analysis of β-galactosidase activity; cell cycle analysis; estimation of protein levels by western blotting. Colonies were stained with crystal violet dye.Results. In our study, we showed that the duration of HCT116 cells incubation with low-dose doxorubicin affects their ability to return to re-proliferation – increasing the treatment time using same drug dose reduces the process of colony formation. The duration of doxorubicin treatment does not affect the formation of the senescence phenotype, which was confirmed by analyzing different markers of this stage (changes in β-galactosidase activity, cell cycle analysis, assessment of p21 and γH2AX protein levels). However, there is a delay in the development of cellular response to DNA damage caused by doxorubicin in cells exposed to prolong treatment protocol (increase in β-galactosidase activity, formation of polyploid cells).Conclusion. The duration of doxorubicin treatment of HCT116 cancer cells affects long-term consequences, reducing the ability of senescent cells to escape this stage when the incubation time with the drug is extended.
联系人： Maria Anatolievna ZamkovaMaria Anatolievna Zamkova zamkovam@gmail.com 简介。由于高剂量化疗的毒性，低浓度化疗在癌症治疗中的使用导致肿瘤细胞衰老表型的形成，其特征是细胞周期进展受阻和不分裂；细胞的转录和代谢谱发生变化。这一阶段的一个消极后果是，单个细胞获得了摆脱衰老和重新增殖的能力。估计药物治疗 HCT116 肿瘤细胞的持续时间对其摆脱治疗诱导的衰老能力的影响。通过β-半乳糖苷酶活性分析、细胞周期分析、Western 印迹法评估蛋白质水平来确认衰老表型。用结晶紫染料对菌落进行染色。我们的研究表明，HCT116 细胞与低剂量多柔比星共培养的时间长短会影响其恢复再增殖的能力--在使用相同剂量药物的情况下，延长治疗时间会减少菌落形成的过程。多柔比星处理时间的长短不会影响衰老表型的形成，这一点已通过分析这一阶段的不同标记物（β-半乳糖苷酶活性变化、细胞周期分析、p21 和 γH2AX 蛋白水平评估）得到证实。然而，细胞对多柔比星造成的 DNA 损伤的反应（β-半乳糖苷酶活性增加、多倍体细胞的形成）的发展会出现延迟。对 HCT116 癌细胞进行多柔比星治疗的时间长短会影响长期后果，延长药物孵育时间会降低衰老细胞摆脱这一阶段的能力。
{"title":"Decreasing the ability of HCT116 cells to escape from therapy induced senescence by increasing the duration of doxorubicin treatment","authors":"N. Persiyantseva, S. Y. Vikhrova, M. S. Korotkova, D. B. Kazansky, V. V. Tatarsky, M. Zamkova","doi":"10.17650/2313-805x-2024-11-1-90-98","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-90-98","url":null,"abstract":"Contacts: Maria Anatolievna Zamkova zamkovam@gmail.com Introduction. Due to the toxicity of high doses of chemotherapy, low concentrations used in cancer treatment leads to the development of senescence phenotype in tumor cells, characterized by a block in the cell cycle progression and the absence of division; changes in the transcriptional and metabolic profile of cells. A negative consequence of this stage is acquisition of individual cells the ability to escape from senescence and return to re-proliferation.Aim. To estimate the effect of the duration of drug treatment of HCT116 tumor cells on their ability to escape from therapy induced senescence.Materials and methods. The senescence phenotype was confirmed by the analysis of β-galactosidase activity; cell cycle analysis; estimation of protein levels by western blotting. Colonies were stained with crystal violet dye.Results. In our study, we showed that the duration of HCT116 cells incubation with low-dose doxorubicin affects their ability to return to re-proliferation – increasing the treatment time using same drug dose reduces the process of colony formation. The duration of doxorubicin treatment does not affect the formation of the senescence phenotype, which was confirmed by analyzing different markers of this stage (changes in β-galactosidase activity, cell cycle analysis, assessment of p21 and γH2AX protein levels). However, there is a delay in the development of cellular response to DNA damage caused by doxorubicin in cells exposed to prolong treatment protocol (increase in β-galactosidase activity, formation of polyploid cells).Conclusion. The duration of doxorubicin treatment of HCT116 cancer cells affects long-term consequences, reducing the ability of senescent cells to escape this stage when the incubation time with the drug is extended.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"1 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140737102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-46-54
K. V. Nikulnikov, V. A. Bogdanova, L. V. Spirina, S. U. Chizhevskaya, I. V. Kondakova, E. Choynzonov, V. I. Chernov
Introduction. Melanoma is the most dangerous neoplasm of the skin, characterized by a malignant and aggressive course. Transcriptional and growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death are involved in significant processes of oncogenesis.Aim. To study the expression of components of the AKT/mTOR (mTOR – mammalian target of rapamycin) signaling pathway, transcription and growth factors, expression of AMPK, LC3B, programmed cell death 1 (PD-1), programmed death-ligand 1 PD-L1 and programmed death-ligand 2 (PD-L2) in skin and mucosal tumor tissues.Materials and methods. The study included 21 patients with a verified diagnosis of melanoma of the skin of various localizations and mucous membranes of the nasal cavity T1a–4bN0M0 (I–IV stages) and 18 patients with basal cell carcinoma of the skin of various localizations T1–4N0M0 (I–VIA stages), aged 45 to 72 years old, who were treated in the department of head and neck tumors of the Cancer Research Institute, Tomsk National Research Medical Center. The presence of tumor ulceration was determined by microscopy and registration of the true absence of the epidermis over the tumor or due to traumatization of the epidermis. Expression of components of the AKT/mTOR signaling pathway, transcription and growth factors, expression of AMPK, LC3B, PD-1, PD-L1 and PD-L2 in the tumor tissue was determined by real-time polymerase chain reaction.Results. An increase in the expression of 70 S6 kinase and VHL was found in melanoma tissues compared to basal cell carcinoma. At the same time, the presence of signs of ulceration was associated with a low level of c-RAF, nuclear factor kappa B (NF-kB) p50 and hypoxia-inducible factor 1 (HIF-1) matrix RNA (mRNA) against the background of an increase in the expression of the hypoxia-inducible factor 2 (HIF-2) transcription factor. The study of the molecular features of neoplasms in relation to the tumor thickness according to Breslow revealed the contribution of transcription and growth factors, the intensity of intracellular signaling processes, modification of the microenvironment, autophagy and neoangiogenesis.Conclusion. The molecular and biological features of melanomas associated with invasive tumor growth have been identified. An increase in the expression of 70 S6 kinase and VHL are characteristic of a malignant skin tumor. The presence of signs of ulceration and tumor invasion were associated with a change in the transcriptional characteristics of factors with the induction of key markers, oncogenesis, which contributes to the formation of the invasive potential of the tumor.
{"title":"Transcriptional, growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death expression in melanoma","authors":"K. V. Nikulnikov, V. A. Bogdanova, L. V. Spirina, S. U. Chizhevskaya, I. V. Kondakova, E. Choynzonov, V. I. Chernov","doi":"10.17650/2313-805x-2024-11-1-46-54","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-46-54","url":null,"abstract":"Introduction. Melanoma is the most dangerous neoplasm of the skin, characterized by a malignant and aggressive course. Transcriptional and growth factors, components of the AKT/mTOR signaling pathway, receptors and ligands of programmed cell death are involved in significant processes of oncogenesis.Aim. To study the expression of components of the AKT/mTOR (mTOR – mammalian target of rapamycin) signaling pathway, transcription and growth factors, expression of AMPK, LC3B, programmed cell death 1 (PD-1), programmed death-ligand 1 PD-L1 and programmed death-ligand 2 (PD-L2) in skin and mucosal tumor tissues.Materials and methods. The study included 21 patients with a verified diagnosis of melanoma of the skin of various localizations and mucous membranes of the nasal cavity T1a–4bN0M0 (I–IV stages) and 18 patients with basal cell carcinoma of the skin of various localizations T1–4N0M0 (I–VIA stages), aged 45 to 72 years old, who were treated in the department of head and neck tumors of the Cancer Research Institute, Tomsk National Research Medical Center. The presence of tumor ulceration was determined by microscopy and registration of the true absence of the epidermis over the tumor or due to traumatization of the epidermis. Expression of components of the AKT/mTOR signaling pathway, transcription and growth factors, expression of AMPK, LC3B, PD-1, PD-L1 and PD-L2 in the tumor tissue was determined by real-time polymerase chain reaction.Results. An increase in the expression of 70 S6 kinase and VHL was found in melanoma tissues compared to basal cell carcinoma. At the same time, the presence of signs of ulceration was associated with a low level of c-RAF, nuclear factor kappa B (NF-kB) p50 and hypoxia-inducible factor 1 (HIF-1) matrix RNA (mRNA) against the background of an increase in the expression of the hypoxia-inducible factor 2 (HIF-2) transcription factor. The study of the molecular features of neoplasms in relation to the tumor thickness according to Breslow revealed the contribution of transcription and growth factors, the intensity of intracellular signaling processes, modification of the microenvironment, autophagy and neoangiogenesis.Conclusion. The molecular and biological features of melanomas associated with invasive tumor growth have been identified. An increase in the expression of 70 S6 kinase and VHL are characteristic of a malignant skin tumor. The presence of signs of ulceration and tumor invasion were associated with a change in the transcriptional characteristics of factors with the induction of key markers, oncogenesis, which contributes to the formation of the invasive potential of the tumor.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"102 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140740911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-105-112
A. A. Korolyova, S. Gerasimov, L. N. Lyubchenko
Introduction. Malignant tumor is one of the leading factors of venous and arterial thrombosis. But there is no data on the need for a genetic testing protocol of cancer patients for genetic predisposition thrombotic conditions, despite the fact that a number of polymorphisms of hemostasis genes are considered to be unconditionally proven factors of high cumulative thrombogenic risk, and proteins encoded by these genes are direct links in the cascades of pathological hypercoagulation in neoplastic processes.Aim. To identify groups of high genetic risk of thrombotic complications among patients with malignant thoracoabdominal tumors.Materials and methods. The study included 223 patients with malignant tumors of the lung, stomach, esophagus, operated in the Department of Thoracic Oncology of the N.N. Blokhin National Research Center of Oncology in 2018–2019. The study groups consisted of patients with myocardial infarction (n = 62), ischemic stroke (n = 24), venous thrombosis/ venous thromboembolic complications (n = 40), patients without cardiovascular diseases, but with a family history burdened by cardiovascular diseases (n = 33). The control group included 81 patients.Results. Among patients with malignant tumors of thoracoabdominal localization, a statistically significant difference was determined in the frequency of carriage of the heterozygous genotype FV 1691GA (Arg506Gln) in patients who had a myocardial infarction (χ2 = 4.0; p = 0.046), who had venous thrombosis (χ2 = 4.118; p = 0.043), in the group of patients with burdened with a family history (χ2 = 4.997; p = 0.026) in comparison with the control group. Statistically significant difference in the frequency of carriage of the heterozygous variant of the mutation in the FII G20210A gene relative to the control group, it was determined in the group of patients who had an acute cerebrovascular accident (χ2 = 6.881; p = 0.009) and among patients with a burdened history (χ2 = 7.563; p = 0.006).Conclusion. In order to assess the risk of development and prevention of thrombotic complications in the perioperative period in patients with malignant thoracoabdominal tumors, who have suffered myocardial infarction, ischemic stroke, venous thrombosis/venous thromboembolic complications, as well as patients without cardiovascular pathology, but with thrombotic conditions in relatives of the first degree, it is advisable to perform DNA diagnostics at the prehospital stage to identify of gene polymorphisms FII G20210A and FV G1691A (Arg506Gln).
{"title":"Genetic factors of thrombosis FII G20210A, FV G1691A (Arg506Gln) in patients with thoracoabdominal malignant tumors","authors":"A. A. Korolyova, S. Gerasimov, L. N. Lyubchenko","doi":"10.17650/2313-805x-2024-11-1-105-112","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-105-112","url":null,"abstract":"Introduction. Malignant tumor is one of the leading factors of venous and arterial thrombosis. But there is no data on the need for a genetic testing protocol of cancer patients for genetic predisposition thrombotic conditions, despite the fact that a number of polymorphisms of hemostasis genes are considered to be unconditionally proven factors of high cumulative thrombogenic risk, and proteins encoded by these genes are direct links in the cascades of pathological hypercoagulation in neoplastic processes.Aim. To identify groups of high genetic risk of thrombotic complications among patients with malignant thoracoabdominal tumors.Materials and methods. The study included 223 patients with malignant tumors of the lung, stomach, esophagus, operated in the Department of Thoracic Oncology of the N.N. Blokhin National Research Center of Oncology in 2018–2019. The study groups consisted of patients with myocardial infarction (n = 62), ischemic stroke (n = 24), venous thrombosis/ venous thromboembolic complications (n = 40), patients without cardiovascular diseases, but with a family history burdened by cardiovascular diseases (n = 33). The control group included 81 patients.Results. Among patients with malignant tumors of thoracoabdominal localization, a statistically significant difference was determined in the frequency of carriage of the heterozygous genotype FV 1691GA (Arg506Gln) in patients who had a myocardial infarction (χ2 = 4.0; p = 0.046), who had venous thrombosis (χ2 = 4.118; p = 0.043), in the group of patients with burdened with a family history (χ2 = 4.997; p = 0.026) in comparison with the control group. Statistically significant difference in the frequency of carriage of the heterozygous variant of the mutation in the FII G20210A gene relative to the control group, it was determined in the group of patients who had an acute cerebrovascular accident (χ2 = 6.881; p = 0.009) and among patients with a burdened history (χ2 = 7.563; p = 0.006).Conclusion. In order to assess the risk of development and prevention of thrombotic complications in the perioperative period in patients with malignant thoracoabdominal tumors, who have suffered myocardial infarction, ischemic stroke, venous thrombosis/venous thromboembolic complications, as well as patients without cardiovascular pathology, but with thrombotic conditions in relatives of the first degree, it is advisable to perform DNA diagnostics at the prehospital stage to identify of gene polymorphisms FII G20210A and FV G1691A (Arg506Gln).","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"50 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140736773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-113-123
G. Skryabin, A. A. Beliaeva, A. D. Enikeev, D. Bagrov, A. M. Keremet, А. V. Komelkov, D. S. Elkin, D. M. Sylantieva, E. Tchevkina
Introduction. The identification of markers for liquid diagnostics of ovarian cancer is one of the most urgent tasks of gynecologic oncology. Currently, extracellular vesicles (EVs) are of great interest as a source of oncomarkers, including miRNA markers. We have previously shown that the levels of miR-125a-5p, -27a-5p, -193a-5p and 135b-5p are significantly elevated and miR-451a, -495-3p and -136-5p are significantly decreased in the EVs from uterine aspirates of ovarian cancer patients.Aim. Analysis of miR-125a-5p, -27a-5p, -193a-5p, 135b-5p, 451a, 495-3p and -136-5p levels in ovarian cancer cell cultures and secreted EVs.Material and methods. Cultivation of ovarian cancer cell lines: OVCAR-3, OVCAR-4, OVCAR-8 and SKOV3; EVs isolation from conditioned medium by ultracentrifugation; EVs validation by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), western blot analysis of exosomal markers; isolation of miRNAs from cells and EVs; analysis of miRNAs by Stem-Loop – reverse transcription-quantitative polymerase chain reaction.Results. In all cell lines studied, the expression of miR-125a-5p, -27a-5p, -193a-5p and -135b-5p significantly exceeds the expression of -451a, -495-3p and -136-5p. All ovarian cancer cell lines are featured by a “cells >EVs” ratio for highly expressed miRNAs and “EVs >cells” ratio for poorly expressed miRNAs.Conclusion. The results of the study support the relation between the differential expression of studied miRNAs and the pathogenesis of ovarian cancer and confirm the high diagnostic potential of these molecules.
{"title":"Analysis of miRNAs miR-125a-5p, -27a-5p, -193a-5p, -135b-5p, -451a, -495-3p and -136-5p in parental ovarian cancer cells and secreted extracellular vesicles","authors":"G. Skryabin, A. A. Beliaeva, A. D. Enikeev, D. Bagrov, A. M. Keremet, А. V. Komelkov, D. S. Elkin, D. M. Sylantieva, E. Tchevkina","doi":"10.17650/2313-805x-2024-11-1-113-123","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-113-123","url":null,"abstract":"Introduction. The identification of markers for liquid diagnostics of ovarian cancer is one of the most urgent tasks of gynecologic oncology. Currently, extracellular vesicles (EVs) are of great interest as a source of oncomarkers, including miRNA markers. We have previously shown that the levels of miR-125a-5p, -27a-5p, -193a-5p and 135b-5p are significantly elevated and miR-451a, -495-3p and -136-5p are significantly decreased in the EVs from uterine aspirates of ovarian cancer patients.Aim. Analysis of miR-125a-5p, -27a-5p, -193a-5p, 135b-5p, 451a, 495-3p and -136-5p levels in ovarian cancer cell cultures and secreted EVs.Material and methods. Cultivation of ovarian cancer cell lines: OVCAR-3, OVCAR-4, OVCAR-8 and SKOV3; EVs isolation from conditioned medium by ultracentrifugation; EVs validation by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), western blot analysis of exosomal markers; isolation of miRNAs from cells and EVs; analysis of miRNAs by Stem-Loop – reverse transcription-quantitative polymerase chain reaction.Results. In all cell lines studied, the expression of miR-125a-5p, -27a-5p, -193a-5p and -135b-5p significantly exceeds the expression of -451a, -495-3p and -136-5p. All ovarian cancer cell lines are featured by a “cells >EVs” ratio for highly expressed miRNAs and “EVs >cells” ratio for poorly expressed miRNAs.Conclusion. The results of the study support the relation between the differential expression of studied miRNAs and the pathogenesis of ovarian cancer and confirm the high diagnostic potential of these molecules.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"14 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140736608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-79-89
M. Patysheva, M. Stakheyeva, E. S. Grigoryeva, P. Iamshchikov, I. V. Larionova, А. A. Budnickya, N. Tarabanovskaya, N. Cherdyntseva, J. Kzhyshkowska
Introduction. Chemotherapy is a common treatment for breast cancer. Chemotherapeutic drugs effect blood monocytes, which are major contributors to cancer pathogenesis. However, to date, pro-tumor or anti-tumor programming by chemotherapy of monocytes is controversial.Aim. To characterize changes in phenotypic and transcriptomic profiles of monocytes of breast cancer patients before and after chemotherapeutic treatment.Materials and methods. In a cohort of 50 breast cancer patients, monocyte populations were identified based on their expression of CD14, CD16, CD163, and HLA-DR evaluated by flow cytometry before and after neoadjuvant chemotherapy. Bulk RNA sequencing was adopted to explore the transcriptomic profile of CD14+ monocytes before and after treatment. After treatment, we observed an increase in the activity of signaling pathways related to lipid metabolism and intracellular transport of vesicles from the endoplasmic reticulum, against the background of a decreased response to exposure to interferon γ and interferon α, and foreign molecules (exogenous nucleic acids, viruses and bacteria).Results. In breast cancer patients, neoadjuvant chemotherapy decreased in CD14+16+HLA-DR+ monocytes. Under cytostatic treatment, increased gene expression of MGLL, NR4A2, UCK1, YOD1, ABCA2, PAPSS2, ATP10 (log2FoldChange ≥0.8; false discovery rate (FDR) ≤0.01) and decreased gene expression of KPNA2, ERCC4, JAGN1, RUBCNL, SMYD4, B3GALT4 (log2FoldChange ≥0.8; FDR ≤0.01) were observed in monocytes of patients. Using discriminant analysis, the relative numbers of CD14+16–, CD14+16+, CD14-16+, CD14+16-HLA-DR+, CD14+16+HLA-DR+ and CD14–16+HLA-DR+ monocytes in the blood were found to be valuable in predicting response to neoadjuvant chemotherapy.Conclusion. Thus, association of blood monocytes with chemotherapeutic treatment in breast cancer was revealed.
{"title":"Immune-phenotyping and transcriptomic profiling of blood monocytes from patients with breast cancer under neoadjuvant chemotherapy","authors":"M. Patysheva, M. Stakheyeva, E. S. Grigoryeva, P. Iamshchikov, I. V. Larionova, А. A. Budnickya, N. Tarabanovskaya, N. Cherdyntseva, J. Kzhyshkowska","doi":"10.17650/2313-805x-2024-11-1-79-89","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-79-89","url":null,"abstract":"Introduction. Chemotherapy is a common treatment for breast cancer. Chemotherapeutic drugs effect blood monocytes, which are major contributors to cancer pathogenesis. However, to date, pro-tumor or anti-tumor programming by chemotherapy of monocytes is controversial.Aim. To characterize changes in phenotypic and transcriptomic profiles of monocytes of breast cancer patients before and after chemotherapeutic treatment.Materials and methods. In a cohort of 50 breast cancer patients, monocyte populations were identified based on their expression of CD14, CD16, CD163, and HLA-DR evaluated by flow cytometry before and after neoadjuvant chemotherapy. Bulk RNA sequencing was adopted to explore the transcriptomic profile of CD14+ monocytes before and after treatment. After treatment, we observed an increase in the activity of signaling pathways related to lipid metabolism and intracellular transport of vesicles from the endoplasmic reticulum, against the background of a decreased response to exposure to interferon γ and interferon α, and foreign molecules (exogenous nucleic acids, viruses and bacteria).Results. In breast cancer patients, neoadjuvant chemotherapy decreased in CD14+16+HLA-DR+ monocytes. Under cytostatic treatment, increased gene expression of MGLL, NR4A2, UCK1, YOD1, ABCA2, PAPSS2, ATP10 (log2FoldChange ≥0.8; false discovery rate (FDR) ≤0.01) and decreased gene expression of KPNA2, ERCC4, JAGN1, RUBCNL, SMYD4, B3GALT4 (log2FoldChange ≥0.8; FDR ≤0.01) were observed in monocytes of patients. Using discriminant analysis, the relative numbers of CD14+16–, CD14+16+, CD14-16+, CD14+16-HLA-DR+, CD14+16+HLA-DR+ and CD14–16+HLA-DR+ monocytes in the blood were found to be valuable in predicting response to neoadjuvant chemotherapy.Conclusion. Thus, association of blood monocytes with chemotherapeutic treatment in breast cancer was revealed.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"27 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140738791","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-8-21
S. Boichuk, T. V. Ivoilova
ABC transporters (ATP Binding Cassette (ABC) transporters) are proteins, which play a dual role in the substances transport across the membrane. On the one hand, they transport nutrients and other molecules inside the cell to supply the necessary nutrients, on the other hand, these proteins excrete some endogenous and exogenous substrates from the cell to maintain their homeostasis in the body and prevent from effects of aggressive environment. ABC transporters play a role in the pathogenesis of various metabolic disorders. In addition, a large amount of evidence has been accumulated about the participation of these proteins in oncogenesis because of their involvement into initiation, progression, invasion and metastasis of tumors, as well as development of multidrug resistance phenotype. Currently, these proteins are attractive therapeutic targets, influence on which can significantly increase the effectiveness of anticancer therapy and improve the prognosis of patients with oncological diseases, including recurrent, metastatic and inoperable forms.The review provides information on drugs that affect the functional activity of ABC transporters and the mechanisms of their action, and also presents the results of clinical trials of these inhibitors.
{"title":"The role of ABC-transporters in homeostasis, cancer pathogenesis and therapy","authors":"S. Boichuk, T. V. Ivoilova","doi":"10.17650/2313-805x-2024-11-1-8-21","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-8-21","url":null,"abstract":"ABC transporters (ATP Binding Cassette (ABC) transporters) are proteins, which play a dual role in the substances transport across the membrane. On the one hand, they transport nutrients and other molecules inside the cell to supply the necessary nutrients, on the other hand, these proteins excrete some endogenous and exogenous substrates from the cell to maintain their homeostasis in the body and prevent from effects of aggressive environment. ABC transporters play a role in the pathogenesis of various metabolic disorders. In addition, a large amount of evidence has been accumulated about the participation of these proteins in oncogenesis because of their involvement into initiation, progression, invasion and metastasis of tumors, as well as development of multidrug resistance phenotype. Currently, these proteins are attractive therapeutic targets, influence on which can significantly increase the effectiveness of anticancer therapy and improve the prognosis of patients with oncological diseases, including recurrent, metastatic and inoperable forms.The review provides information on drugs that affect the functional activity of ABC transporters and the mechanisms of their action, and also presents the results of clinical trials of these inhibitors.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"37 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140740025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-99-104
I. R. Magdieva, T. Abakumova, D. Dolgova, O. Y. Gorshkov, T. P. Gening
Introduction. Currently, the question of the role of neutrophils in the progression of kidney cancer remains relevant. Neutrophils are capable of exhibiting protumor properties through the secretion of cytokines, chemokines, and growth factors, which is determined by the expression of genes for these molecules. And the functional heterogeneity of neutrophils is characterized by differences in gene expression patterns.Aim. To assess the role of circulating neutrophils in the progression of kidney cancer.Materials and methods. In circulating neutrophils of patients with verified clear cell kidney cancer at stages I–III according to Tumor, Nodus and Metastasis (TNM) (n = 88) before surgical treatment and conditionally healthy donors (control group) (n = 20), the expression of NGAL genes was determined using quantitative reverse transcription polymerase chain reaction, MMP-13 and VEGF-A.Results. There was an increase in NGAL gene expression in circulating neutrophils (p = 0.05) at the initial stage and a decrease in it at advanced stages of kidney cancer (p = 0.03). High expression of the MMP-13 gene by circulating neutrophils was detected at all stages of kidney cancer relative to control values (at stage I p = 0.005; at stage II p = 0.003; at stage III p = 0.0008). A significant direct correlation was observed between the expression of the NGAL and MMP-13 genes in neutrophils at stage I kidney cancer (r = 0.696; p = 0.003). In the group of patients with kidney cancer, a direct correlation was found between the expression of the NGAL and VEGF-A genes (r = 0.322; p = 0.049). A multivariable Cox regression model for disease-free survival revealed the predictive value of VEGF-A and NGAL genes expression in circulating neutrophils. With an increase in the expression of the VEGF-A and NGAL genes in neutrophils by 1 unit, the risk of metastases increases by 0.80 (0.65–0.99; p = 0.043) and 1.42 (1.01–2.00; p = 0.046) times, respectively. The Kaplan–Meier analysis of disease-free survival in patients with kidney cancer showed the influence of NGAL expression in circulating neutrophils on progression-free time. In the group of patients with high NGAL expression, the median follow-up was 31.7 months, and in the group with low NGAL expression – more than 36 months (log-rank-test; p = 0.017).Conclusion. Thus, the data obtained suggest that circulating neutrophils play a leading role in the progression of kidney cancer. The level of expression of NGAL in circulating neutrophils can be used to predict the relapse-free period in patients with kidney cancer.
{"title":"The role of circulating neutrophils in the progression of kidney cancer","authors":"I. R. Magdieva, T. Abakumova, D. Dolgova, O. Y. Gorshkov, T. P. Gening","doi":"10.17650/2313-805x-2024-11-1-99-104","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-99-104","url":null,"abstract":"Introduction. Currently, the question of the role of neutrophils in the progression of kidney cancer remains relevant. Neutrophils are capable of exhibiting protumor properties through the secretion of cytokines, chemokines, and growth factors, which is determined by the expression of genes for these molecules. And the functional heterogeneity of neutrophils is characterized by differences in gene expression patterns.Aim. To assess the role of circulating neutrophils in the progression of kidney cancer.Materials and methods. In circulating neutrophils of patients with verified clear cell kidney cancer at stages I–III according to Tumor, Nodus and Metastasis (TNM) (n = 88) before surgical treatment and conditionally healthy donors (control group) (n = 20), the expression of NGAL genes was determined using quantitative reverse transcription polymerase chain reaction, MMP-13 and VEGF-A.Results. There was an increase in NGAL gene expression in circulating neutrophils (p = 0.05) at the initial stage and a decrease in it at advanced stages of kidney cancer (p = 0.03). High expression of the MMP-13 gene by circulating neutrophils was detected at all stages of kidney cancer relative to control values (at stage I p = 0.005; at stage II p = 0.003; at stage III p = 0.0008). A significant direct correlation was observed between the expression of the NGAL and MMP-13 genes in neutrophils at stage I kidney cancer (r = 0.696; p = 0.003). In the group of patients with kidney cancer, a direct correlation was found between the expression of the NGAL and VEGF-A genes (r = 0.322; p = 0.049). A multivariable Cox regression model for disease-free survival revealed the predictive value of VEGF-A and NGAL genes expression in circulating neutrophils. With an increase in the expression of the VEGF-A and NGAL genes in neutrophils by 1 unit, the risk of metastases increases by 0.80 (0.65–0.99; p = 0.043) and 1.42 (1.01–2.00; p = 0.046) times, respectively. The Kaplan–Meier analysis of disease-free survival in patients with kidney cancer showed the influence of NGAL expression in circulating neutrophils on progression-free time. In the group of patients with high NGAL expression, the median follow-up was 31.7 months, and in the group with low NGAL expression – more than 36 months (log-rank-test; p = 0.017).Conclusion. Thus, the data obtained suggest that circulating neutrophils play a leading role in the progression of kidney cancer. The level of expression of NGAL in circulating neutrophils can be used to predict the relapse-free period in patients with kidney cancer.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"23 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-31-45
M. Khaliulin, R. Safin, M. A. Kunst, E. Bulatov
The introduction of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological diseases, particularly in combating blood cancer. The success of this cell therapy approach has led to the development of approximately seven commercial CAR-T based drugs. However, the application of CAR-T therapy for solid tumors has proven to be less effective due to challenges such as the varied antigens in solid tumors, an immunosuppressive tumor environment, limited immune cell infiltration, reduced CAR-T cell activity and toxicity issues. To solve these problems, scientists are making efforts to improve and improve the methods of treatment of solid tumors. Chemotherapy is the standard treatment for a large number of malignant neoplasms. It is also used before starting cell therapy for lymphodepletion and better engraftment of injected CAR-T cells. It has been shown that chemotherapy can reduce the immunosuppressive effect of the tumor microenvironment, destroy the stroma, and promote better infiltration of the tumor by CAR-T cells, improving their survival, persistence, cytotoxicity, and influencing the metabolism of immune cells inside the tumor. The effectiveness of combining chemotherapy and CAR-T cell therapy relies on various factors such as tumor type, dosage, treatment schedule, CAR-T cell composition, and individual biological traits. Similarly, radiation therapy can enhance tumor cell vulnerability to specific treatments while also supporting tumor cell survival.In this review, we discuss the use of CAR-T therapy to combat solid tumors, regarding the challenges of treating solid tumors, ways to overcome them, and also touch upon the possibility of using combination treatments to improve the effectiveness of cell therapy.
{"title":"The use of T-cells with chimeric antigen receptor (CAR-T) in combination with chemotherapy and radiotherapy for the treatment of solid tumors","authors":"M. Khaliulin, R. Safin, M. A. Kunst, E. Bulatov","doi":"10.17650/2313-805x-2024-11-1-31-45","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-31-45","url":null,"abstract":"The introduction of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological diseases, particularly in combating blood cancer. The success of this cell therapy approach has led to the development of approximately seven commercial CAR-T based drugs. However, the application of CAR-T therapy for solid tumors has proven to be less effective due to challenges such as the varied antigens in solid tumors, an immunosuppressive tumor environment, limited immune cell infiltration, reduced CAR-T cell activity and toxicity issues. To solve these problems, scientists are making efforts to improve and improve the methods of treatment of solid tumors. Chemotherapy is the standard treatment for a large number of malignant neoplasms. It is also used before starting cell therapy for lymphodepletion and better engraftment of injected CAR-T cells. It has been shown that chemotherapy can reduce the immunosuppressive effect of the tumor microenvironment, destroy the stroma, and promote better infiltration of the tumor by CAR-T cells, improving their survival, persistence, cytotoxicity, and influencing the metabolism of immune cells inside the tumor. The effectiveness of combining chemotherapy and CAR-T cell therapy relies on various factors such as tumor type, dosage, treatment schedule, CAR-T cell composition, and individual biological traits. Similarly, radiation therapy can enhance tumor cell vulnerability to specific treatments while also supporting tumor cell survival.In this review, we discuss the use of CAR-T therapy to combat solid tumors, regarding the challenges of treating solid tumors, ways to overcome them, and also touch upon the possibility of using combination treatments to improve the effectiveness of cell therapy.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"19 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140740359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.17650/2313-805x-2024-11-1-55-78
E. V. Shutko, O. Bryzgunova, I. A. Ostal’cev, S. V. Pak, S. E. Krasi’nikov, P. P. Laktionov, M. Konoshenko
Introduction. It is known that the treatment of oncological diseases including prostate cancer (PCa) causes changes in the expression of oncogenic and oncosuppressive miRNAs. The analysis of miRNA expression dynamics can be used to predict the course of the disease and its response to therapy. However, the effect of PCa therapy on the expression of extracellular miRNAs is just beginning to be investigated.Aim. To study the expression dynamics of 14 miRNAs (miR-19b, -22-3p, -30e, -31, -92a, -125b, -144, -200b, -205, -222, -375, -378a, -425, -660) in urine extracellular vesicles of PCa patients after radical prostatectomy and to reveal prognostic miRNA ratios.Materials and methods. Urine samples of 18 donors and 18 PCa patients, obtained before radical prostatectomy, 1 week and 3 months after surgery, were examined. Extracellular vesicles were isolated by aggregation-precipitation protocol; extracellular vesicles miRNAs were isolated using fiberglass sorbents and octane acid. Data on threshold detection cycles of 14 miRNAs were obtained using reverse transcription – loop polymerase chain reaction (TaqMan).Results. It was found that prostatectomy causes a significant change in the relative expression of 44 miRNA ratios in the urine of PCa patients. Four groups of miRNA ratios can be distinguished: 1) miRNA ratios, which expression level significantly differed between donors and PCa patients before surgery and significantly changed in PCa patients 3 months after prostatectomy in the direction of the level of donors (6 pairs); 2) miRNA ratios, which expression did not significantly differ between donors and PCa patients before surgery, but significantly differed from the baseline in PCa patients and donors 3 months after prostatectomy (5 pairs); 3) miRNA ratios, based on expression ratios of which PCa patients can be divided into two or three significantly different subgroups 3 months after prostatectomy (19 pairs); 4) miRNA ratios that did not significantly change their expression after prostatectomy (30 pairs).Conclusion. Prostatectomy causes a significant change in the level of expression of miRNA in urine. 6 pairs of miRNAs, the relative expression of which after surgery significantly changed towards that of healthy donors and 19 pairs of miRNAs, according to the level of relative expression of which patients with prostate cancer were divided into two significantly different subgroups 3 months after prostatectomy, were identified based on the analysis of the dynamics of miRNA expression after prostatectomy.
{"title":"Dynamics of miRNA expression in urine extracellular vesicles of prostate cancer patients after radical prostatectomy","authors":"E. V. Shutko, O. Bryzgunova, I. A. Ostal’cev, S. V. Pak, S. E. Krasi’nikov, P. P. Laktionov, M. Konoshenko","doi":"10.17650/2313-805x-2024-11-1-55-78","DOIUrl":"https://doi.org/10.17650/2313-805x-2024-11-1-55-78","url":null,"abstract":"Introduction. It is known that the treatment of oncological diseases including prostate cancer (PCa) causes changes in the expression of oncogenic and oncosuppressive miRNAs. The analysis of miRNA expression dynamics can be used to predict the course of the disease and its response to therapy. However, the effect of PCa therapy on the expression of extracellular miRNAs is just beginning to be investigated.Aim. To study the expression dynamics of 14 miRNAs (miR-19b, -22-3p, -30e, -31, -92a, -125b, -144, -200b, -205, -222, -375, -378a, -425, -660) in urine extracellular vesicles of PCa patients after radical prostatectomy and to reveal prognostic miRNA ratios.Materials and methods. Urine samples of 18 donors and 18 PCa patients, obtained before radical prostatectomy, 1 week and 3 months after surgery, were examined. Extracellular vesicles were isolated by aggregation-precipitation protocol; extracellular vesicles miRNAs were isolated using fiberglass sorbents and octane acid. Data on threshold detection cycles of 14 miRNAs were obtained using reverse transcription – loop polymerase chain reaction (TaqMan).Results. It was found that prostatectomy causes a significant change in the relative expression of 44 miRNA ratios in the urine of PCa patients. Four groups of miRNA ratios can be distinguished: 1) miRNA ratios, which expression level significantly differed between donors and PCa patients before surgery and significantly changed in PCa patients 3 months after prostatectomy in the direction of the level of donors (6 pairs); 2) miRNA ratios, which expression did not significantly differ between donors and PCa patients before surgery, but significantly differed from the baseline in PCa patients and donors 3 months after prostatectomy (5 pairs); 3) miRNA ratios, based on expression ratios of which PCa patients can be divided into two or three significantly different subgroups 3 months after prostatectomy (19 pairs); 4) miRNA ratios that did not significantly change their expression after prostatectomy (30 pairs).Conclusion. Prostatectomy causes a significant change in the level of expression of miRNA in urine. 6 pairs of miRNAs, the relative expression of which after surgery significantly changed towards that of healthy donors and 19 pairs of miRNAs, according to the level of relative expression of which patients with prostate cancer were divided into two significantly different subgroups 3 months after prostatectomy, were identified based on the analysis of the dynamics of miRNA expression after prostatectomy.","PeriodicalId":505368,"journal":{"name":"Advances in Molecular Oncology","volume":"60 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140739413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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