Pub Date : 2023-10-10DOI: 10.17650/2313-805x-2023-10-3-98-102
V. Jawahar, S. Banerjee, J. Kini, S. Sreeram, M. S. Athiyamaan, J. Sunny, A. Krishna, C. Srinivas, D. Lobo, B. S. Mokkapatti
Introduction. Oropharyngeal squamous cell carcinomas are often found to be associated with human papilloma virus (HPV) infection. The prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients in India is comparatively lower to that of the same worldwide. Aim. To find out the prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients who presented in our hospital. Settings and design . Retrospective cross-sectional study. Materials and methods . Tissue block of 60 patients with biopsy-proven oropharyngeal squamous cell carcinomas were subjected to immunohistochemistry for evaluating p16 expression. The p16 expression pattern was correlated with the demographic details. Data was entered in Microsoft Excel and Statistical Analysis was done with the help of SPSS version 22 (IBM Corp. Released, 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). Results . Prevalence of HPV infection in our study was found to be 11.7 %. 85.8 % of all p16-positive patients had moderate-well differentiated disease. 6 out of 7 p16-positive patients had higher T stage (T3–4). All the patients who were p16+ were found to have a higher Nodal stage (N2–3). 100 % of all p16+ patients were found to have stage IV disease. Conclusion. Prevalence of HPV infection was found to be similar to that of previous studies conducted in India. These patients also presented with advanced nodal disease at presentation and thereby, an advanced overall stage.
介绍。口咽鳞状细胞癌常被发现与人乳头瘤病毒(HPV)感染有关。在印度,口咽鳞状细胞癌患者中HPV感染的患病率相对较低。的目标。目的了解我院口咽鳞状细胞癌患者HPV感染的流行情况。设置和设计。回顾性横断面研究。材料和方法。对60例经活检证实的口咽鳞状细胞癌患者进行组织阻滞免疫组织化学检测p16的表达。p16表达模式与人口统计学细节相关。数据在Microsoft Excel中输入,统计分析在SPSS version 22 (IBM Corp.发布,2013)的帮助下完成。IBM SPSS Statistics for Windows, Version 22.0。纽约州阿蒙克市:IBM Corp.)。结果。在我们的研究中发现HPV感染的患病率为11.7%。所有p16阳性患者中85.8%为中度分化良好的疾病。7例p16阳性患者中有6例T分期较高(T3-4)。所有p16+患者均有较高的淋巴结分期(N2-3)。100%的p16+患者被发现为IV期疾病。结论。发现HPV感染的流行程度与以前在印度进行的研究相似。这些患者在就诊时也表现为晚期淋巴结疾病,因此总体分期较晚。
{"title":"Prevalence of HPV/p16+ infection among oropharyngeal squamous cell carcinoma patients in a tertiary care centre in Southern India","authors":"V. Jawahar, S. Banerjee, J. Kini, S. Sreeram, M. S. Athiyamaan, J. Sunny, A. Krishna, C. Srinivas, D. Lobo, B. S. Mokkapatti","doi":"10.17650/2313-805x-2023-10-3-98-102","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-98-102","url":null,"abstract":"Introduction. Oropharyngeal squamous cell carcinomas are often found to be associated with human papilloma virus (HPV) infection. The prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients in India is comparatively lower to that of the same worldwide. Aim. To find out the prevalence of HPV infection among oropharyngeal squamous cell carcinomas patients who presented in our hospital. Settings and design . Retrospective cross-sectional study. Materials and methods . Tissue block of 60 patients with biopsy-proven oropharyngeal squamous cell carcinomas were subjected to immunohistochemistry for evaluating p16 expression. The p16 expression pattern was correlated with the demographic details. Data was entered in Microsoft Excel and Statistical Analysis was done with the help of SPSS version 22 (IBM Corp. Released, 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.). Results . Prevalence of HPV infection in our study was found to be 11.7 %. 85.8 % of all p16-positive patients had moderate-well differentiated disease. 6 out of 7 p16-positive patients had higher T stage (T3–4). All the patients who were p16+ were found to have a higher Nodal stage (N2–3). 100 % of all p16+ patients were found to have stage IV disease. Conclusion. Prevalence of HPV infection was found to be similar to that of previous studies conducted in India. These patients also presented with advanced nodal disease at presentation and thereby, an advanced overall stage.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136358121","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 : 2023-10-10DOI: 10.17650/2313-805x-2023-10-3-90-97
V. A. Yarovaya, I. A. Levashov, A. R. Zaretsky, L. V. Chudakova, V. V. Nazarova, A. D. Matyaeva, L. V. Demidov, A. A. Yarovoy
Introduction. Molecular genetic testing is actively used for prognostication in patients with uveal melanoma (UM). Tissue for genetic analysis may be obtained either by surgical excision or through fine-needle aspiration biopsy (FNAB). Performing genetic testing and FNAB in each institution can differ in surgical techniques and laboratory methodologies. Aim. To present our own experience of performing FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma. Materials and methods. Prognostic FNAB (n = 151) were combined with brachytherapy or stereotactic surgery. Genetic testing was performed by methods based on polymerase chain reaction ( GNAQ, GNA11, EIF1AX and SF3B1 mutations) and fluorescence in situ hybridization (copy numbers of PPARG and MYC genes); cytology of FNAB material was also assessed. Results. Fine-needle aspiration biopsy material was informative in 91 % of cases. At the median follow-up of 36 months, 12 cases of distant metastases were detected. Occurrence of the assessed mutations and copy numbers were related to other representative studies. PPARG deletion was shown to be a significant prognostic factor for metastasis-free survival (p <0,01), which was demonstrated for the first time; EIF1AX and SF3B1 mutations, MYC amplification and cytological class were not shown to be significantly associated with survival in our study. Conclusion. FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma was shown to be a reliable and highly informative approach. Some of the prognostic factors need to be evaluated further with longer follow-up.
{"title":"Prognostic fine needle aspiration biopsy of uveal melanoma: Molecular and genetic factors of metastasis risk","authors":"V. A. Yarovaya, I. A. Levashov, A. R. Zaretsky, L. V. Chudakova, V. V. Nazarova, A. D. Matyaeva, L. V. Demidov, A. A. Yarovoy","doi":"10.17650/2313-805x-2023-10-3-90-97","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-90-97","url":null,"abstract":"Introduction. Molecular genetic testing is actively used for prognostication in patients with uveal melanoma (UM). Tissue for genetic analysis may be obtained either by surgical excision or through fine-needle aspiration biopsy (FNAB). Performing genetic testing and FNAB in each institution can differ in surgical techniques and laboratory methodologies. Aim. To present our own experience of performing FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma. Materials and methods. Prognostic FNAB (n = 151) were combined with brachytherapy or stereotactic surgery. Genetic testing was performed by methods based on polymerase chain reaction ( GNAQ, GNA11, EIF1AX and SF3B1 mutations) and fluorescence in situ hybridization (copy numbers of PPARG and MYC genes); cytology of FNAB material was also assessed. Results. Fine-needle aspiration biopsy material was informative in 91 % of cases. At the median follow-up of 36 months, 12 cases of distant metastases were detected. Occurrence of the assessed mutations and copy numbers were related to other representative studies. PPARG deletion was shown to be a significant prognostic factor for metastasis-free survival (p <0,01), which was demonstrated for the first time; EIF1AX and SF3B1 mutations, MYC amplification and cytological class were not shown to be significantly associated with survival in our study. Conclusion. FNAB-based molecular genetic testing for prognostication in patients with uveal melanoma was shown to be a reliable and highly informative approach. Some of the prognostic factors need to be evaluated further with longer follow-up.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136358119","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-24-35
G. A. Belitsky, K. I. Kirsanov, E. A. Lesovaya, V. P. Maksimova, L. V. Krivosheeva, M. G. Yakubovskaya
The incidence and mortality of malignant neoplasms of non-reproductive organs both carcinomas and sarcomas in men is one and a half times higher than in women. This is based on genetic differences, which are superimposed by patterns of epigenetic regulation of the expression of sex chromosome genes that determine sex differences in the processes of tissue differentiation, which, in turn, mediates the formation of the hormonal status of the body. Compared to the Y chromosome, the mammalian X chromosome contains several dozen times more genes encoding major regulators of proliferation, metabolism, immunity, and tumor growth inhibitors, as well as X-linked microRNAs affecting transcription factors and cross-regulation by other non-coding RNAs. This results in a female or male gene expression profile that accounts for phenotypic differences. This peculiarity, along with the fact that in female cells on the second inactivatedX chromosome epigenetic repression of the most important genes is reversed and, accordingly, their expression level is doubled, may largely explain the sex disparity in carcinogenesis. The influence of sex hormones and disparity in the expression of antitumor immunity contribute significantly to this difference. A detailed study of the mechanisms underlying sex dimorphism in carcinogenesis will be an essential contribution to fundamental oncology and to the practice of diagnosis, prognosis and personalized treatment of malignances with regard to their gender-specific course. These studies are especially relevant in relation to insufficiently studied soft tissue sarcomas, the ratio of the frequencies of which in men and women varies greatly depending on the histological subtype of the tumor.
{"title":"Sexual dimorphism in cancer","authors":"G. A. Belitsky, K. I. Kirsanov, E. A. Lesovaya, V. P. Maksimova, L. V. Krivosheeva, M. G. Yakubovskaya","doi":"10.17650/2313-805x-2023-10-3-24-35","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-24-35","url":null,"abstract":"The incidence and mortality of malignant neoplasms of non-reproductive organs both carcinomas and sarcomas in men is one and a half times higher than in women. This is based on genetic differences, which are superimposed by patterns of epigenetic regulation of the expression of sex chromosome genes that determine sex differences in the processes of tissue differentiation, which, in turn, mediates the formation of the hormonal status of the body. Compared to the Y chromosome, the mammalian X chromosome contains several dozen times more genes encoding major regulators of proliferation, metabolism, immunity, and tumor growth inhibitors, as well as X-linked microRNAs affecting transcription factors and cross-regulation by other non-coding RNAs. This results in a female or male gene expression profile that accounts for phenotypic differences. This peculiarity, along with the fact that in female cells on the second inactivatedX chromosome epigenetic repression of the most important genes is reversed and, accordingly, their expression level is doubled, may largely explain the sex disparity in carcinogenesis. The influence of sex hormones and disparity in the expression of antitumor immunity contribute significantly to this difference. A detailed study of the mechanisms underlying sex dimorphism in carcinogenesis will be an essential contribution to fundamental oncology and to the practice of diagnosis, prognosis and personalized treatment of malignances with regard to their gender-specific course. These studies are especially relevant in relation to insufficiently studied soft tissue sarcomas, the ratio of the frequencies of which in men and women varies greatly depending on the histological subtype of the tumor.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146382","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-36-49
M. A. Galyamina, O. V. Pobeguts, A. Yu. Gorbachev
The review presents data on studies of the role of mycoplasmas as infectious agents in carcinogenesis, as well as their participation in cancer drug therapy and the impact on the outcome of treatment. Mycoplasmas are of particular interest because they have unique abilities to readily attach to and enter eukaryotic cells, modulate their functional state, and induce chronic inflammation while evading the host’s immune system. The review will highlight the data confirming the increased colonization of tumor tissue by mycoplasmas compared to healthy ones, describe the molecular mechanisms by which mycoplasmas activate the expression of oncogenes and growth factors, inactivate tumor suppressors, promote NF-κB-dependent migration of cancer cells and modulate apoptosis, which results in abnormal growth and transformation of host cells. The review also presents data on the effectiveness of anticancer drugs in mycoplasmal infections.
{"title":"The role of mycoplasmas as an infectious agent in carcinogenesis","authors":"M. A. Galyamina, O. V. Pobeguts, A. Yu. Gorbachev","doi":"10.17650/2313-805x-2023-10-3-36-49","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-36-49","url":null,"abstract":"The review presents data on studies of the role of mycoplasmas as infectious agents in carcinogenesis, as well as their participation in cancer drug therapy and the impact on the outcome of treatment. Mycoplasmas are of particular interest because they have unique abilities to readily attach to and enter eukaryotic cells, modulate their functional state, and induce chronic inflammation while evading the host’s immune system. The review will highlight the data confirming the increased colonization of tumor tissue by mycoplasmas compared to healthy ones, describe the molecular mechanisms by which mycoplasmas activate the expression of oncogenes and growth factors, inactivate tumor suppressors, promote NF-κB-dependent migration of cancer cells and modulate apoptosis, which results in abnormal growth and transformation of host cells. The review also presents data on the effectiveness of anticancer drugs in mycoplasmal infections.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146212","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-72-81
E. N. Voropaeva, T. I. Pospelova, M. I. Churkina, A. A. Gurazheva, O. V. Berezina, V. N. Maksimov
Introduction. A more in-depth description of molecular events that disrupt the functioning of the p53 signaling pathway is important for understanding the mechanisms of formation and progression of diffuse B-large cell lymphoma (DCCL), as well as its sensitivity to treatment. The p53 protein exhibits its oncosuppressive function and mediates the antitumor effects of drugs by regulating transcription and/or maturation of a wide range of target genes, including MIR-34A, MIR34B/C, MIR-129-2 and MIR-203 . In the tumor tissue of lymphomas, in comparison with normal lymphoid tissue, a decrease in the level of microRNAs encoded by these genes is shown. Aim. The aim of this study was to conduct a comprehensive analysis of the methylation of the genes of the p53-responsive microRNAs MIR-34A, MIR-34B/C, MIR-203 and MIR-129-2 , as well as mutations in the DNA-binding domain and destruction of the polyadenylation signal of the TP53 gene in DLBCL. Materials and methods. 136 DNA samples isolated from tumor tissue of patients with DLBCL and 11 DNA samples obtained from lymph nodes with reactive B-cell follicular hyperplasia were analyzed. The methylation status of MIR-203 and MIR-129-2 genes was determined by the method of methyl-specific polymerase chain reaction, MIR-34A and MIR-34B/C genes by the method of methyl-sensitive analysis of high-resolution melting curves. In tumor samples, rs78378222 genotyping was performed by polymerase chain reaction with restriction fragment length polymorphism, resulting in the destruction of the polyadenylation signal, and the nucleotide sequence of the region of the TP53 gene encoding the DNA-binding domain was determined by capillary direct sequencing by Sanger. Results. The methylation detected in lymphoma tissue was tumor-specific. The frequency of analyzed aberrations in the TP53 gene and methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 was 21, 23, 55, 65 and 66 %, respectively. At the same time, methylation of the analyzed genes of p53-responsive microRNAs and aberrations in the TP53 gene in the tumor tissue of patients with DLBCL were independent events with a tendency to mutual exclusion. At the same time, it was shown that in the vast majority of lymphoma samples, the methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes was combined. Conclusion. Along with aberrations in TP53 , methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes may be an important cause of decreased expression of miR-34a, miR-34b, miR-34c, miR-129 and miR-203 in DLBCL. The combined methylation of the MIR-203, MIR-129-2 and MIR-34B/C genes, as well as the MIR-34B/C and MIR-34A pairs, potentially has a more pronounced pro-tumor effect due to the presence of common targets in the microRNAs encoded by them.
{"title":"Mechanisms of impaired expression of p53-responsive microRNA genes in diffuse B-large cell lymphoma","authors":"E. N. Voropaeva, T. I. Pospelova, M. I. Churkina, A. A. Gurazheva, O. V. Berezina, V. N. Maksimov","doi":"10.17650/2313-805x-2023-10-3-72-81","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-72-81","url":null,"abstract":"Introduction. A more in-depth description of molecular events that disrupt the functioning of the p53 signaling pathway is important for understanding the mechanisms of formation and progression of diffuse B-large cell lymphoma (DCCL), as well as its sensitivity to treatment. The p53 protein exhibits its oncosuppressive function and mediates the antitumor effects of drugs by regulating transcription and/or maturation of a wide range of target genes, including MIR-34A, MIR34B/C, MIR-129-2 and MIR-203 . In the tumor tissue of lymphomas, in comparison with normal lymphoid tissue, a decrease in the level of microRNAs encoded by these genes is shown. Aim. The aim of this study was to conduct a comprehensive analysis of the methylation of the genes of the p53-responsive microRNAs MIR-34A, MIR-34B/C, MIR-203 and MIR-129-2 , as well as mutations in the DNA-binding domain and destruction of the polyadenylation signal of the TP53 gene in DLBCL. Materials and methods. 136 DNA samples isolated from tumor tissue of patients with DLBCL and 11 DNA samples obtained from lymph nodes with reactive B-cell follicular hyperplasia were analyzed. The methylation status of MIR-203 and MIR-129-2 genes was determined by the method of methyl-specific polymerase chain reaction, MIR-34A and MIR-34B/C genes by the method of methyl-sensitive analysis of high-resolution melting curves. In tumor samples, rs78378222 genotyping was performed by polymerase chain reaction with restriction fragment length polymorphism, resulting in the destruction of the polyadenylation signal, and the nucleotide sequence of the region of the TP53 gene encoding the DNA-binding domain was determined by capillary direct sequencing by Sanger. Results. The methylation detected in lymphoma tissue was tumor-specific. The frequency of analyzed aberrations in the TP53 gene and methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 was 21, 23, 55, 65 and 66 %, respectively. At the same time, methylation of the analyzed genes of p53-responsive microRNAs and aberrations in the TP53 gene in the tumor tissue of patients with DLBCL were independent events with a tendency to mutual exclusion. At the same time, it was shown that in the vast majority of lymphoma samples, the methylation of the MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes was combined. Conclusion. Along with aberrations in TP53 , methylation of MIR-34A, MIR-34B/C, MIR-129-2 and MIR-203 genes may be an important cause of decreased expression of miR-34a, miR-34b, miR-34c, miR-129 and miR-203 in DLBCL. The combined methylation of the MIR-203, MIR-129-2 and MIR-34B/C genes, as well as the MIR-34B/C and MIR-34A pairs, potentially has a more pronounced pro-tumor effect due to the presence of common targets in the microRNAs encoded by them.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146384","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-50-58
Yu. Yu. Shchegolev, M. A. Karpukhina, D. V. Sorokin, A. M. Scherbakov, O. E. Andreeva, V. E. Razuvaeva, T. A. Bogush, I. N. Mikhaylova, L. V. Demidov, M. V. Gudkova, M. A. Krasil’nikov
Introduction. Melanoma belongs to the group of the most malignant tumors characterized by aggressive growth and active metastasis. At the same time, the effectiveness of therapy, primarily targeted therapy, is largely limited by the rapid development of drug resistance. Aim. To study the effect of chronic ultraviolet (UV) irradiation on the formation of a population of radiation-resistant melanoma cells; to study the features of cell signaling and the sensitivity of UV-resistant melanoma cells to the antitumor drugs. Materials and methods. The experiments were carried out on in vitro cultured A375 melanoma cells. Cells were cultured in a standard DMEM + 10 % FBS medium; cell growth rate was analyzed using the MTT assay; cell survival after irradiation was analyzed using a colony-forming test. Determination of the transcriptional activity of the estrogen receptor (ER) was performed by reporter analysis upon transfection into cells of a plasmid containing the luciferase reporter gene controlled by estrogen responsive element. The immunoblotting method was used to analyze the expression of cellular proteins; comparative analysis of ERα and ERβ expression was performed by immunofluorescent method. Results. Long-term UV irradiation leads to the formation of a UV-resistant subpopulation of A375 melanoma cells, which is characterized by decreased sensitivity to targeted (vemurafenib) and hormonal (tamoxifen) drugs, increased expression of Snail, an activator of the epithelial-mesenchymal transition, and in the absence of noticeable changes in the expression of PI3K / mTOR signaling. Metformin reduces Snail expression in both parental and UV-resistant A375 cells and enhances the cytostatic effect in combination with vemurafenib or tamoxifen. Conclusion . The data obtained demonstrate a decrease in the sensitivity of melanoma cells to targeted drugs under the long-term exposure to UV. The ability of metformin to potentiate the action of targeted drugs and inhibit Snail allows us to consider metformin not only as an antitumor agent, but also as a potential inhibitor of the epithelial-mesenchymal transition.
{"title":"Continuous ultraviolet irradiation induces the development of irreversible resistance of melanoma cells to anticancer drugs","authors":"Yu. Yu. Shchegolev, M. A. Karpukhina, D. V. Sorokin, A. M. Scherbakov, O. E. Andreeva, V. E. Razuvaeva, T. A. Bogush, I. N. Mikhaylova, L. V. Demidov, M. V. Gudkova, M. A. Krasil’nikov","doi":"10.17650/2313-805x-2023-10-3-50-58","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-50-58","url":null,"abstract":"Introduction. Melanoma belongs to the group of the most malignant tumors characterized by aggressive growth and active metastasis. At the same time, the effectiveness of therapy, primarily targeted therapy, is largely limited by the rapid development of drug resistance. Aim. To study the effect of chronic ultraviolet (UV) irradiation on the formation of a population of radiation-resistant melanoma cells; to study the features of cell signaling and the sensitivity of UV-resistant melanoma cells to the antitumor drugs. Materials and methods. The experiments were carried out on in vitro cultured A375 melanoma cells. Cells were cultured in a standard DMEM + 10 % FBS medium; cell growth rate was analyzed using the MTT assay; cell survival after irradiation was analyzed using a colony-forming test. Determination of the transcriptional activity of the estrogen receptor (ER) was performed by reporter analysis upon transfection into cells of a plasmid containing the luciferase reporter gene controlled by estrogen responsive element. The immunoblotting method was used to analyze the expression of cellular proteins; comparative analysis of ERα and ERβ expression was performed by immunofluorescent method. Results. Long-term UV irradiation leads to the formation of a UV-resistant subpopulation of A375 melanoma cells, which is characterized by decreased sensitivity to targeted (vemurafenib) and hormonal (tamoxifen) drugs, increased expression of Snail, an activator of the epithelial-mesenchymal transition, and in the absence of noticeable changes in the expression of PI3K / mTOR signaling. Metformin reduces Snail expression in both parental and UV-resistant A375 cells and enhances the cytostatic effect in combination with vemurafenib or tamoxifen. Conclusion . The data obtained demonstrate a decrease in the sensitivity of melanoma cells to targeted drugs under the long-term exposure to UV. The ability of metformin to potentiate the action of targeted drugs and inhibit Snail allows us to consider metformin not only as an antitumor agent, but also as a potential inhibitor of the epithelial-mesenchymal transition.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135147279","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-82-89
T. A. Bogush, I. E. Mizaeva, A. A. Basharina, A. N. Grishanina, M. A. Baryshnikova, O. S. Burova, A. A. Rudakova, V. S. Kosorukov
Introduction. Despite advances in the treatment of melanoma, the results of therapy cannot be considered satisfactory, and the search for new drugs and effective combinations of medicine continues. The drugs are being developed aimed at reducing the metastatic tumor potential – migrastatics. The targets of the drugs can be cytoskeletal proteins of tumor cells – cytokeratin (CK) intermediate filaments and microtubule protein beta-III tubulin (TUBB3). Aim. To estimate of the CK and TUBB3 expression in melanoma cell lines to form an informative in vitro cell model for screening and studying migrastatics. Materials and methods. The molecular phenotype of 21 human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology, and 18 of which were isolated from tumor metastases in the lymph nodes, soft tissues or subcutaneously. The level of TUBB3 expression and de novo expression of CKs in vimentin-expressing cells (CK + Vim) were assessed by an immunofluorescent method and flow cytometry. Results. Beta-III tubulin expression was detected in all cultures studied, de novo expression of CKs was found in 20 / 21 lines. The exception was primary uveal melanoma 92-1, that did not express CK + Vim. Both parameters significantly differed between the cells of the studied panel: CK + Vim co-expression – from 0 to 91 %, TUBB3 – from 18 to 86 %. No correlation was found between the expression level of TUBB3 and CK + Vim (Pearson’s correlation coefficient r = 0.11; p = 0.65). Three groups of the cell lines with different ratio of TUBB3 expression and CK + Vim co-expression were identified: 1) similar level of expression of both markers; 2) the level of co-expression of CK + Vim more or less high than the index for TUBB3; 3) the level of TUBB3 expression more or less high than the index for CK + Vim co-expression. Conclusion. A panel of 21 human melanoma cell lines was formed with quantitatively estimated expression of cytoske-letal proteins responsible for the migration activity of tumor cells – CKs and TUBB3. Groups of the lines with different expression ratio of the markers can be used for screening and preclinical evaluation potential migrastatics that reduce the metastatic potential of melanoma and may reduce resistance to taxanes.
{"title":"Expression of the cytoskeletal proteins – cytokeratins and beta-III tubulin in human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology","authors":"T. A. Bogush, I. E. Mizaeva, A. A. Basharina, A. N. Grishanina, M. A. Baryshnikova, O. S. Burova, A. A. Rudakova, V. S. Kosorukov","doi":"10.17650/2313-805x-2023-10-3-82-89","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-82-89","url":null,"abstract":"Introduction. Despite advances in the treatment of melanoma, the results of therapy cannot be considered satisfactory, and the search for new drugs and effective combinations of medicine continues. The drugs are being developed aimed at reducing the metastatic tumor potential – migrastatics. The targets of the drugs can be cytoskeletal proteins of tumor cells – cytokeratin (CK) intermediate filaments and microtubule protein beta-III tubulin (TUBB3). Aim. To estimate of the CK and TUBB3 expression in melanoma cell lines to form an informative in vitro cell model for screening and studying migrastatics. Materials and methods. The molecular phenotype of 21 human melanoma cell lines from the collection of N. N. Blokhin National Medical Research Center of Oncology, and 18 of which were isolated from tumor metastases in the lymph nodes, soft tissues or subcutaneously. The level of TUBB3 expression and de novo expression of CKs in vimentin-expressing cells (CK + Vim) were assessed by an immunofluorescent method and flow cytometry. Results. Beta-III tubulin expression was detected in all cultures studied, de novo expression of CKs was found in 20 / 21 lines. The exception was primary uveal melanoma 92-1, that did not express CK + Vim. Both parameters significantly differed between the cells of the studied panel: CK + Vim co-expression – from 0 to 91 %, TUBB3 – from 18 to 86 %. No correlation was found between the expression level of TUBB3 and CK + Vim (Pearson’s correlation coefficient r = 0.11; p = 0.65). Three groups of the cell lines with different ratio of TUBB3 expression and CK + Vim co-expression were identified: 1) similar level of expression of both markers; 2) the level of co-expression of CK + Vim more or less high than the index for TUBB3; 3) the level of TUBB3 expression more or less high than the index for CK + Vim co-expression. Conclusion. A panel of 21 human melanoma cell lines was formed with quantitatively estimated expression of cytoske-letal proteins responsible for the migration activity of tumor cells – CKs and TUBB3. Groups of the lines with different expression ratio of the markers can be used for screening and preclinical evaluation potential migrastatics that reduce the metastatic potential of melanoma and may reduce resistance to taxanes.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146211","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 : 2023-10-09DOI: 10.17650/2313-805x-2023-10-3-59-71
A. R. Galembikova, P. D. Dunaev, F. F. Bikinieva, I. G. Mustafin, P. B. Kopnin, S. S. Zykova, F. I. Mukhutdinova, E. A. Sarbazyan, S. V. Boichuk
Introduction . Mitotic poisoning agents (MPAs) affecting the dynamic state of the microtubules, are the well-known and effective chemotherapeutic agents. Mitotic poisoning agents are binding to the microtubules, and thereby interfere with tubulin polymerization or depolymerization dynamic state, resulting in the cell cycle arrest in M-phase (mitotic catastrophe) and subsequent apoptotic cell death. We reported previously about potent cytotoxic activities against the pyrrole-carboxamides (PCs) (PC-61 and PC-84) against broad spectrum of cancer cell lines, including triple negative breast cancer, lung and prostate cancer. Aim. To examine the cytotoxic activities of PC-61 and PC-84 against multidrug-resistant cancer cell lines indicated above. Materials and methods. Studу was performed on the triple-negative paclitaxel-resistant breast cancer cell line HCC1806 Tx-R and doxorubicin-resistant osteosarcoma SaOS-2 Dox-R cell line. Results. The cytotoxic activity of PCs was due to the inhibition of tubulin polymerization. Immunofluorescence staining data revealed PC’s ability to interfere with tubulin’s assembly in multidrug-resistant cancer cell lines. As an outcome of inhibition of tubulin polymerization, PCs induced cell cycle arrest in M-phase, and further led to apoptotic cell death of cancer cells. Conclusion . Collectively, we demonstrated potent cytotoxic activity of PCs against cancer cell lines with multidrug-resistant phenotype, which arising the possibilities to develop novel and effective anti-tumor agents that belongs to mitotic poisoning agents
{"title":"Mechanisms of cytotoxic activity of pyrrole-carboxamides against multidrug-resistant tumor cell sublines","authors":"A. R. Galembikova, P. D. Dunaev, F. F. Bikinieva, I. G. Mustafin, P. B. Kopnin, S. S. Zykova, F. I. Mukhutdinova, E. A. Sarbazyan, S. V. Boichuk","doi":"10.17650/2313-805x-2023-10-3-59-71","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-59-71","url":null,"abstract":"Introduction . Mitotic poisoning agents (MPAs) affecting the dynamic state of the microtubules, are the well-known and effective chemotherapeutic agents. Mitotic poisoning agents are binding to the microtubules, and thereby interfere with tubulin polymerization or depolymerization dynamic state, resulting in the cell cycle arrest in M-phase (mitotic catastrophe) and subsequent apoptotic cell death. We reported previously about potent cytotoxic activities against the pyrrole-carboxamides (PCs) (PC-61 and PC-84) against broad spectrum of cancer cell lines, including triple negative breast cancer, lung and prostate cancer. Aim. To examine the cytotoxic activities of PC-61 and PC-84 against multidrug-resistant cancer cell lines indicated above. Materials and methods. Studу was performed on the triple-negative paclitaxel-resistant breast cancer cell line HCC1806 Tx-R and doxorubicin-resistant osteosarcoma SaOS-2 Dox-R cell line. Results. The cytotoxic activity of PCs was due to the inhibition of tubulin polymerization. Immunofluorescence staining data revealed PC’s ability to interfere with tubulin’s assembly in multidrug-resistant cancer cell lines. As an outcome of inhibition of tubulin polymerization, PCs induced cell cycle arrest in M-phase, and further led to apoptotic cell death of cancer cells. Conclusion . Collectively, we demonstrated potent cytotoxic activity of PCs against cancer cell lines with multidrug-resistant phenotype, which arising the possibilities to develop novel and effective anti-tumor agents that belongs to mitotic poisoning agents","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135146387","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 : 2023-10-08DOI: 10.17650/2313-805x-2023-10-3-15-23
N. P. Pavlova, S. S. Dyomin, M. I. Churnosov, I. V. Ponomarenko
The article presents current data on the etiopathogenesis and risk factors of breast cancer (BC). The search for the sources was carried out in the PubMed, Medline, Cochrane Library, eLIBRARY, NHGRI-EBI Catalog of GWAS systems, publications from January 2000 to December 2022 were included. The interaction of definite risk factors, endocrine stimuli and genetic disorders causes activation / inactivation of various signaling pathways that directly or indirectly affect carcinogenesis. According to modern genetic evaluations, the contribution of the hereditary component to the formation of BC reaches 40 %. Interactiones between various risk factors form several molecular subtypes of breast carcinomas, differing in receptor status and clinical course, as well as therapeutic approaches. The details of the interaction of etiopathogenetic factors of BC are not clear, and often have a multidirectional character. Matrix metalloproteinases (MMPs) regulate the mechanisms of proliferation and apoptosis, invasion and metastasis, formation of the tumor microenvironment, neoangiogenesis, as well as intergenic signaling interactions, being an important link in the pathogenesis of BC.
{"title":"Modern understanding of risk factors and mechanisms of breast cancer development","authors":"N. P. Pavlova, S. S. Dyomin, M. I. Churnosov, I. V. Ponomarenko","doi":"10.17650/2313-805x-2023-10-3-15-23","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-15-23","url":null,"abstract":"The article presents current data on the etiopathogenesis and risk factors of breast cancer (BC). The search for the sources was carried out in the PubMed, Medline, Cochrane Library, eLIBRARY, NHGRI-EBI Catalog of GWAS systems, publications from January 2000 to December 2022 were included. The interaction of definite risk factors, endocrine stimuli and genetic disorders causes activation / inactivation of various signaling pathways that directly or indirectly affect carcinogenesis. According to modern genetic evaluations, the contribution of the hereditary component to the formation of BC reaches 40 %. Interactiones between various risk factors form several molecular subtypes of breast carcinomas, differing in receptor status and clinical course, as well as therapeutic approaches. The details of the interaction of etiopathogenetic factors of BC are not clear, and often have a multidirectional character. Matrix metalloproteinases (MMPs) regulate the mechanisms of proliferation and apoptosis, invasion and metastasis, formation of the tumor microenvironment, neoangiogenesis, as well as intergenic signaling interactions, being an important link in the pathogenesis of BC.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135250748","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 : 2023-10-07DOI: 10.17650/2313-805x-2023-10-3-8-14
D. A. Enaldieva, P. V. Krivorotko, E. N. Imyanitov, E. K. Zhiltsova, R. V. Donskikh, L. F. Shaikhelislamova, L. P. Gigolaeva, V. F. Semiglazov
BRCA -associated triple-negative breast cancer (TNBC) is characterized by high sensitivity to DNA-damaging cytotoxic drugs. The use of well-known BRCA1/2 -specific antitumor agents – platinum derivatives and PARP inhibitors – has been discussed for a long time in the context of the treatment of metastatic BRCA -associated TNBC. Neoadjuvant regimens based on the use of anthracyclines and taxanes are the standard of drug therapy for primary BRCA -associated breast cancer. At present, there are few data regarding the addition of platinum drugs to anthracycline-taxane neoadjuvant chemotherapy in the treatment of primary BRCA -associated TNBC. This review details the various treatment options for both primary and metastatic BRCA -associated TNBC. It has been shown that the development of new strategies for the neoadjuvant chemotherapy of patients with primary BRCA -associated TNBC is an urgent clinical need to reduce the risks of recurrence and progression.
{"title":"Current approaches to systemic treatment of <i>BRCA</i>-associated triple-negative breast cancer","authors":"D. A. Enaldieva, P. V. Krivorotko, E. N. Imyanitov, E. K. Zhiltsova, R. V. Donskikh, L. F. Shaikhelislamova, L. P. Gigolaeva, V. F. Semiglazov","doi":"10.17650/2313-805x-2023-10-3-8-14","DOIUrl":"https://doi.org/10.17650/2313-805x-2023-10-3-8-14","url":null,"abstract":"BRCA -associated triple-negative breast cancer (TNBC) is characterized by high sensitivity to DNA-damaging cytotoxic drugs. The use of well-known BRCA1/2 -specific antitumor agents – platinum derivatives and PARP inhibitors – has been discussed for a long time in the context of the treatment of metastatic BRCA -associated TNBC. Neoadjuvant regimens based on the use of anthracyclines and taxanes are the standard of drug therapy for primary BRCA -associated breast cancer. At present, there are few data regarding the addition of platinum drugs to anthracycline-taxane neoadjuvant chemotherapy in the treatment of primary BRCA -associated TNBC. This review details the various treatment options for both primary and metastatic BRCA -associated TNBC. It has been shown that the development of new strategies for the neoadjuvant chemotherapy of patients with primary BRCA -associated TNBC is an urgent clinical need to reduce the risks of recurrence and progression.","PeriodicalId":36087,"journal":{"name":"Uspehi Molekularnoj Onkologii","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135302479","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}