Pub Date : 2015-11-01DOI: 10.1016/J.EJCSUP.2015.08.109
L. Tashireva, E. Denisov, O. Savelieva, M. Zavyalova, E. Kaigorodova, E. Slonimskaya, V. Perelmuter
{"title":"A14: Heterogeneity in breast tumor microenvironment: A report from one case","authors":"L. Tashireva, E. Denisov, O. Savelieva, M. Zavyalova, E. Kaigorodova, E. Slonimskaya, V. Perelmuter","doi":"10.1016/J.EJCSUP.2015.08.109","DOIUrl":"https://doi.org/10.1016/J.EJCSUP.2015.08.109","url":null,"abstract":"","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"61"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/J.EJCSUP.2015.08.109","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310888","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 : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.114
T. Tyrinova, O. Leplina, M. Tikhonova, S. Mishinov, S. Chernov, Sakhno Lv, V. Stupak, E. Chernykh
{"title":"P52: Glioma-derived soluble factors pose strong chemoattractants and partially change the cytotoxic activity of IFN-alpha-induced dendritic cells","authors":"T. Tyrinova, O. Leplina, M. Tikhonova, S. Mishinov, S. Chernov, Sakhno Lv, V. Stupak, E. Chernykh","doi":"10.1016/j.ejcsup.2015.08.114","DOIUrl":"https://doi.org/10.1016/j.ejcsup.2015.08.114","url":null,"abstract":"","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"64-65"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54310957","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 : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.003
A. Alexandrova, A. Chikina
During cancer development, tumor cells gain the ability to invade and metastasize. Individual cells use alternative migration modes based on different cellular mechanisms. One of them is mesenchymal motility mode which is driven by leading edge protrusion in the form of filopodia or/and lamellipodia based on Arp2/3 dependent actin polymerization. Mesenchymal motility depends on formation of cell-substrate adhesions, activity of matrix metalloproteases (MMPs) and on activity of small GTPaseRac. Another mode is amoeboid motility, which involves formation of blebs – hollow membrane protrusions extruded from the cell surface by actin-myosin contraction. Amoeboid motility does not need both pronounced cell-substrate adhesions and MMPs activity and required increase of activity of small GTPase Rho. Fibroblasts and scattered epithelial cells migrate by mesenchymal mode, while blood cells – lymphocytes or macrophages mainly use amoeboid mode for migration. It was shown that some treatments cause transition from one motility mode to another. Switches from mesenchymal to amoeboid motility and opposite are called mesenchymal-amoeboid transition (MAT) and amoeboid -mesenchymal transition (AMT) respectively. The ability of cells for such transitions was named as plasticity of migration. We compared the plasticity of migration of normal and tumor cells. To study plasticity of mesenchymally migrated cells (MAT) we choose fibrosarcoma cells HT1080 as tumor and non-transformed subcutaneous fibroblasts 1036 as normal counterpart. To study AMT we choose a few lines of myeloid leukemia THP1, K562, KG1 in contrast to normal leukocytes obtained from healthy donors. We showed that fibrosarcoma cells in opposite to non-transformed fibroblasts could undergo MAT under treatments, which limited mesenchymal migration. Two approaches to limit mesenchymal motility of cells were used. One was decrease of substrate adhesiveness by treatment of coverslips with PolyHema solutions, which simulated the alteration of environmental conditions during cell migration. The other approach was influence on cellular pathways regulated cell motility. We used CK666, the inhibitor of Arp2/3 activity, which stopped actin polymerization and thus lamellipodia formation through Arp2/3 dependent mechanism. We showed that under both treatments the fraction of tumor cells switched from lamellipodia formation to blebbing and thus underwent MAT, while in non-transformed fibroblasts these treatments led to retraction of lamellipodia and significant failure of motility. Both leukemia cells and leucocytes of healthy donors showed blebs formation (amoeboid motility). We induced transition to mesenchymal motility by alteration of culture conditions. The first approach was the increase of substrate adhesiveness by treatment with fibronectin. Another way was to inhibit of small GTPase Rho activity. In result of both treatments, leukemia cells switched from amoeboid to mesenchymal motility (underwent A
{"title":"T117","authors":"A. Alexandrova, A. Chikina","doi":"10.1016/j.ejcsup.2015.08.003","DOIUrl":"10.1016/j.ejcsup.2015.08.003","url":null,"abstract":"<div><p>During cancer development, tumor cells gain the ability to invade and metastasize. Individual cells use alternative migration modes based on different cellular mechanisms. One of them is mesenchymal motility mode which is driven by leading edge protrusion in the form of filopodia or/and lamellipodia based on Arp2/3 dependent actin polymerization. Mesenchymal motility depends on formation of cell-substrate adhesions, activity of matrix metalloproteases (MMPs) and on activity of small GTPaseRac. Another mode is amoeboid motility, which involves formation of blebs – hollow membrane protrusions extruded from the cell surface by actin-myosin contraction. Amoeboid motility does not need both pronounced cell-substrate adhesions and MMPs activity and required increase of activity of small GTPase Rho. Fibroblasts and scattered epithelial cells migrate by mesenchymal mode, while blood cells – lymphocytes or macrophages mainly use amoeboid mode for migration. It was shown that some treatments cause transition from one motility mode to another. Switches from mesenchymal to amoeboid motility and opposite are called mesenchymal-amoeboid transition (MAT) and amoeboid -mesenchymal transition (AMT) respectively. The ability of cells for such transitions was named as plasticity of migration. We compared the plasticity of migration of normal and tumor cells. To study plasticity of mesenchymally migrated cells (MAT) we choose fibrosarcoma cells HT1080 as tumor and non-transformed subcutaneous fibroblasts 1036 as normal counterpart. To study AMT we choose a few lines of myeloid leukemia THP1, K562, KG1 in contrast to normal leukocytes obtained from healthy donors. We showed that fibrosarcoma cells in opposite to non-transformed fibroblasts could undergo MAT under treatments, which limited mesenchymal migration. Two approaches to limit mesenchymal motility of cells were used. One was decrease of substrate adhesiveness by treatment of coverslips with PolyHema solutions, which simulated the alteration of environmental conditions during cell migration. The other approach was influence on cellular pathways regulated cell motility. We used CK666, the inhibitor of Arp2/3 activity, which stopped actin polymerization and thus lamellipodia formation through Arp2/3 dependent mechanism. We showed that under both treatments the fraction of tumor cells switched from lamellipodia formation to blebbing and thus underwent MAT, while in non-transformed fibroblasts these treatments led to retraction of lamellipodia and significant failure of motility. Both leukemia cells and leucocytes of healthy donors showed blebs formation (amoeboid motility). We induced transition to mesenchymal motility by alteration of culture conditions. The first approach was the increase of substrate adhesiveness by treatment with fibronectin. Another way was to inhibit of small GTPase Rho activity. In result of both treatments, leukemia cells switched from amoeboid to mesenchymal motility (underwent A","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 1-2"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.003","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.006
N. Barlev , O. Fedorova , L. Lezina , S. Piletsky
Discovery of new pharmacologically active small molecules is an important and rapidly expanding area of modern molecular pharmacology. Given a limited number of proteins that are druggable, it is important to identify as many chemical effectors as possible to define the best regimen of anti-cancer therapy in each particular case. An E3 ubiquitin ligase, Mdm2, which mediates ubiquitin-dependent degradation of the critical tumor suppressor p53, is a promising target for small molecule inhibitors. Using a hybrid approach which combines the rational design of small molecules selected from the virtual library and the high-content screening using cancer cell lines we discovered several new inhibitors of the p53-Mdm2 interaction. These compounds were able to activate and stabilize the p53 protein causing massive apoptosis preferably in p53-positive cells at rates higher than the well-known inhibitor of Mdm2, Nutlin-3. The molecular mechanisms of their action will be discussed.
As another example of rational design of potential anti-cancer drugs, we will talk about artificial nano-Matrix-Imprinted -Polymers (MIPs) that recognize the structure of peptides and other biological molecules and thus dubbed as “plastic antibodies”. We have generated such nanoparticles against the surface region of the oncogenic receptor, EGFR, which is overexpressed in many forms of solid tumors. Selection of the linear epitope for creating “plastic antibodies” against the receptor was performed by analysis of a three-dimensional structure of the protein. The obtained “plastic antibodies” were specific against the epitope of EGFR. These plastic antibodies when loaded with a genotoxic drug, doxorubicin, were able to specifically induce cell death of breast cancer cell lines that overexpress the EGFR receptor. Experiments in vivo using xenografts of breast cancer cell lines pre-incubated with these plastic antibodies in nude mice showed that they have a pronounced therapeutic effect. Furthermore, since the commercial drug, Cetuximab, recognizes an epitope of EGFR, different from the one recognized by our plastic antibodies, it is likely that the latter may increase the efficacy of the commercial monoclonal antibody. Collectively, we demonstrate that the rationally designed small molecules can be potent and specific drugs for anti-cancer therapy.
{"title":"T86","authors":"N. Barlev , O. Fedorova , L. Lezina , S. Piletsky","doi":"10.1016/j.ejcsup.2015.08.006","DOIUrl":"10.1016/j.ejcsup.2015.08.006","url":null,"abstract":"<div><p>Discovery of new pharmacologically active small molecules is an important and rapidly expanding area of modern molecular pharmacology. Given a limited number of proteins that are druggable, it is important to identify as many chemical effectors as possible to define the best regimen of anti-cancer therapy in each particular case. An E3 ubiquitin ligase, Mdm2, which mediates ubiquitin-dependent degradation of the critical tumor suppressor p53, is a promising target for small molecule inhibitors. Using a hybrid approach which combines the rational design of small molecules selected from the virtual library and the high-content screening using cancer cell lines we discovered several new inhibitors of the p53-Mdm2 interaction. These compounds were able to activate and stabilize the p53 protein causing massive apoptosis preferably in p53-positive cells at rates higher than the well-known inhibitor of Mdm2, Nutlin-3. The molecular mechanisms of their action will be discussed.</p><p>As another example of rational design of potential anti-cancer drugs, we will talk about artificial nano-Matrix-Imprinted -Polymers (MIPs) that recognize the structure of peptides and other biological molecules and thus dubbed as “plastic antibodies”. We have generated such nanoparticles against the surface region of the oncogenic receptor, EGFR, which is overexpressed in many forms of solid tumors. Selection of the linear epitope for creating “plastic antibodies” against the receptor was performed by analysis of a three-dimensional structure of the protein. The obtained “plastic antibodies” were specific against the epitope of EGFR. These plastic antibodies when loaded with a genotoxic drug, doxorubicin, were able to specifically induce cell death of breast cancer cell lines that overexpress the EGFR receptor. Experiments in vivo using xenografts of breast cancer cell lines pre-incubated with these plastic antibodies in nude mice showed that they have a pronounced therapeutic effect. Furthermore, since the commercial drug, Cetuximab, recognizes an epitope of EGFR, different from the one recognized by our plastic antibodies, it is likely that the latter may increase the efficacy of the commercial monoclonal antibody. Collectively, we demonstrate that the rationally designed small molecules can be potent and specific drugs for anti-cancer therapy.</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 3-4"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.006","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.015
L. Buchynska, N. Iurchenko, N. Verko, N. Glushchenko
Background
According to the “immune-editing” theory, immunocompetent cells being important component of the tumor microenvironment can both show antitumor activity and contribute to the tumor progression. Tumor pathophysiological features affect the structural and functional changes of certain components of tumor microenvironment, in particular, increase the number of T-lymphocytes with regulatory activity (Treg). FOXP3, transcription factor, acts as master regulator for suppressive function of Treg. Recent studies have shown FOXP3 is expressed both in immunocompetent cells and tumor cells; however, the function of this gene in malignant tumors of different genesis is ambiguous (GirdhariLal, et al., 2014). The aim of the study was quantitative assessment of subpopulations CD4+, CD8+, FOXP3+-lymphocytes associated with the tumor, FOXP3+-tumor cells and comparison of these parameters with the clinical and morphological characteristics of endometrial cancer (EC).
Materials and methods
A total of 40 EC patients who did not receive special treatment before surgery with the mean age 56.9 ± 2.8 years were included in the study. Morphological and immunohistochemical methods were used in the study (primary monoclonal antibodies: CD4 – clone 4B12, “Millipore”, USA, CD8 – clone RIV – 11, “Millipore”, USA, FOXP3 – clone 5H5L12, “Invitrogen”, USA, Ki-67 - clone MIB1, “DakoCytomation”, Denmark) and Real-Time PCR was also used to determine the DNA methylation status of FOXP3 gene mathematical statistics.
Results
The dependence of the number of intratumoral CD4+-, CD8+- lymphocytes and FOXP3-lymphocytes on such biological characteristics as the degree of differentiation, growth rate and depth of invasion into the myometrium was established. In endometrial adenocarcinomas, low grade content of FOXP3+ lymphocytes increased (27.8 ± 2.6%), number of intratumoral CD4+ (15,3 ± 0,2%), CD8+-lymphocytes (29.6 ± 0.3%) and FOXP3+-tumor cells (15,5 ± 3,3%) decreased in contrast to the same parameters in high grade tumors: FOXP3+-lymphocytes (17.4 ± 3.0%), CD4+ (52.0 ± 2.7%), CD8+ (46.4 ± 5.6%), FOXP3+-tumor cells (27.8 ± 2.6%), p < 0.05. DNA analysis of endometrial tumor showed that FOXP3 gene promoter was methylated in 71% of cases. The number of cases with positive methylation status was increasing with lower differentiation grade, that was associated with the low number of FOXP3+-tumor cells. Statistically significant correlation (p < 0.05) (Spearman rank correlation) was observed between the deep invasion of tumor in myometrium and the number of FOXP3+-tumor cells (R = −0.63), number of FOXP3+- and CD4+-lymphocytes (R =
{"title":"A111","authors":"L. Buchynska, N. Iurchenko, N. Verko, N. Glushchenko","doi":"10.1016/j.ejcsup.2015.08.015","DOIUrl":"10.1016/j.ejcsup.2015.08.015","url":null,"abstract":"<div><h3>Background</h3><p>According to the “immune-editing” theory, immunocompetent cells being important component of the tumor microenvironment can both show antitumor activity and contribute to the tumor progression. Tumor pathophysiological features affect the structural and functional changes of certain components of tumor microenvironment, in particular, increase the number of T-lymphocytes with regulatory activity (Treg). FOXP3, transcription factor, acts as master regulator for suppressive function of Treg. Recent studies have shown FOXP3 is expressed both in immunocompetent cells and tumor cells; however, the function of this gene in malignant tumors of different genesis is ambiguous (GirdhariLal, et al., 2014). The aim of the study was quantitative assessment of subpopulations CD4+, CD8+, FOXP3+-lymphocytes associated with the tumor, FOXP3+-tumor cells and comparison of these parameters with the clinical and morphological characteristics of endometrial cancer (EC).</p></div><div><h3>Materials and methods</h3><p>A total of 40 EC patients who did not receive special treatment before surgery with the mean age 56.9<!--> <!-->±<!--> <!-->2.8<!--> <!-->years were included in the study. Morphological and immunohistochemical methods were used in the study (primary monoclonal antibodies: CD4 – clone 4B12, “Millipore”, USA, CD8 – clone RIV – 11, “Millipore”, USA, FOXP3 – clone 5H5L12, “Invitrogen”, USA, Ki-67 - clone MIB1, “DakoCytomation”, Denmark) and Real-Time PCR was also used to determine the DNA methylation status of FOXP3 gene mathematical statistics.</p></div><div><h3>Results</h3><p>The dependence of the number of intratumoral CD4+-, CD8+- lymphocytes and FOXP3-lymphocytes on such biological characteristics as the degree of differentiation, growth rate and depth of invasion into the myometrium was established. In endometrial adenocarcinomas, low grade content of FOXP3+ lymphocytes increased (27.8<!--> <!-->±<!--> <!-->2.6%), number of intratumoral CD4+ (15,3<!--> <!-->±<!--> <!-->0,2%), CD8+-lymphocytes (29.6<!--> <!-->±<!--> <!-->0.3%) and FOXP3+-tumor cells (15,5<!--> <!-->±<!--> <!-->3,3%) decreased in contrast to the same parameters in high grade tumors: FOXP3+-lymphocytes (17.4<!--> <!-->±<!--> <!-->3.0%), CD4+ (52.0<!--> <!-->±<!--> <!-->2.7%), CD8+ (46.4<!--> <!-->±<!--> <!-->5.6%), FOXP3+-tumor cells (27.8<!--> <!-->±<!--> <!-->2.6%), <em>p</em> <!--><<!--> <!-->0.05. DNA analysis of endometrial tumor showed that FOXP3 gene promoter was methylated in 71% of cases. The number of cases with positive methylation status was increasing with lower differentiation grade, that was associated with the low number of FOXP3+-tumor cells. Statistically significant correlation (<em>p</em> <!--><<!--> <!-->0.05) (Spearman rank correlation) was observed between the deep invasion of tumor in myometrium and the number of FOXP3+-tumor cells (<em>R</em> <!-->=<!--> <!-->−0.63), number of FOXP3+- and CD4+-lymphocytes (<em>R</em> <!-->=<!--> <!-","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Pages 8-9"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.023
E. Denisov , T. Gerashchenko , D. Pautova , N. Krakhmal , M. Zavyalova , N. Litviakov , E. Slonimskaya , N. Cherdyntseva , V. Perelmuter
Background
Breast cancer, particularly invasive carcinoma of no special type (IC NST), demonstrates considerable intratumor morphological heterogeneity. Five types of morphological structures representing different architectural arrangements of tumor cells – tubular, alveolar, trabecular, solid structures, and discrete groups have been described in IC NST. Previous studies reported the contribution of intratumor morphological heterogeneity of IC NST to chemotherapy efficiency and lymph node metastasis (Zavyalova et al., 2013; Denisov et al., 2014); however, its role in distant metastasis remains unidentified. Aim: to study the contribution of intratumor morphological heterogeneity of IC NST to distant metastasis and to identify gene expression features of metastatic behavior of different morphological structures.
Materials and methods
358 IC NST patients (age range 29–90, mean age 49.8 9.5, T1-4N0-3M0-1) treated with neoadjuvant chemotherapy (NAC) have been enrolled in this study. Chi-square test and Kaplan–Meier analysis were used to estimate the association between the presence of certain morphological structures in breast tumors and the frequency of distant metastasis and metastasis-free survival. qRT-PCR was applied for measurement of the expression levels of genes involved in cell motility (CDH1, CDH2, CDH3, CTNNA1, CTNNB1, ITGA6, ITGAV, ITGB1, ITGB3, ITGB4, SNAIL, MMP14, ROCK2, L1CAM, MMP2, MMP9, PDPN) and pre-metastatic niche formation (TNFa, TGFb, VEGFa, LOX, M-CSF, GM-CSF, HIF1A, SDF2) in different morphological structures isolated from breast tumors (n = 4) by laser microdissection.
Results
Patients with alveolar structures in breast tumors more frequently displayed distant metastasis than cases without this morphological variant (71.9% vs. 56.5%; p = 0.004). The association between alveolar structures and high frequency of hematogenous metastasis was found only in patients with poor response to NAC (p = 0.003), but not in cases with good chemotherapy efficiency (p = 0.377). Increased distant metastasis was also shown in patients with trabecular structures as compared to cases without this morphological type (88.3% vs. 70.0%; p = 0.0001). Kaplan–Meier analysis demonstrated a significantly higher probability of developing metastasis in patients with alveolar or trabecular structures in breast tumors (p = 0.011). No significant association between other morphological structures and distant metastasis was found. Expression analysis showed the presence of cell motility phenotype in all morphological structures. In particular, we found changes in cell adhesion gene expression, which declined in the row: solid–alveolar–trabecular structures–discrete groups of tumor cells (p
{"title":"P78","authors":"E. Denisov , T. Gerashchenko , D. Pautova , N. Krakhmal , M. Zavyalova , N. Litviakov , E. Slonimskaya , N. Cherdyntseva , V. Perelmuter","doi":"10.1016/j.ejcsup.2015.08.023","DOIUrl":"10.1016/j.ejcsup.2015.08.023","url":null,"abstract":"<div><h3>Background</h3><p>Breast cancer, particularly invasive carcinoma of no special type (IC NST), demonstrates considerable intratumor morphological heterogeneity. Five types of morphological structures representing different architectural arrangements of tumor cells – tubular, alveolar, trabecular, solid structures, and discrete groups have been described in IC NST. Previous studies reported the contribution of intratumor morphological heterogeneity of IC NST to chemotherapy efficiency and lymph node metastasis (Zavyalova et al., 2013; Denisov et al., 2014); however, its role in distant metastasis remains unidentified. Aim: to study the contribution of intratumor morphological heterogeneity of IC NST to distant metastasis and to identify gene expression features of metastatic behavior of different morphological structures.</p></div><div><h3>Materials and methods</h3><p>358 IC NST patients (age range 29–90, mean age 49.8<!--> <span><math><mrow><mo>±</mo></mrow></math></span> <!-->9.5, T1-4N0-3M0-1) treated with neoadjuvant chemotherapy (NAC) have been enrolled in this study. Chi-square test and Kaplan–Meier analysis were used to estimate the association between the presence of certain morphological structures in breast tumors and the frequency of distant metastasis and metastasis-free survival. qRT-PCR was applied for measurement of the expression levels of genes involved in cell motility (CDH1, CDH2, CDH3, CTNNA1, CTNNB1, ITGA6, ITGAV, ITGB1, ITGB3, ITGB4, SNAIL, MMP14, ROCK2, L1CAM, MMP2, MMP9, PDPN) and pre-metastatic niche formation (TNFa, TGFb, VEGFa, LOX, M-CSF, GM-CSF, HIF1A, SDF2) in different morphological structures isolated from breast tumors (<em>n</em> <!-->=<!--> <!-->4) by laser microdissection.</p></div><div><h3>Results</h3><p>Patients with alveolar structures in breast tumors more frequently displayed distant metastasis than cases without this morphological variant (71.9% vs. 56.5%; <em>p</em> <!-->=<!--> <!-->0.004). The association between alveolar structures and high frequency of hematogenous metastasis was found only in patients with poor response to NAC (<em>p</em> <!-->=<!--> <!-->0.003), but not in cases with good chemotherapy efficiency (<em>p</em> <!-->=<!--> <!-->0.377). Increased distant metastasis was also shown in patients with trabecular structures as compared to cases without this morphological type (88.3% vs. 70.0%; <em>p</em> <!-->=<!--> <!-->0.0001). Kaplan–Meier analysis demonstrated a significantly higher probability of developing metastasis in patients with alveolar or trabecular structures in breast tumors (<em>p</em> <!-->=<!--> <!-->0.011). No significant association between other morphological structures and distant metastasis was found. Expression analysis showed the presence of cell motility phenotype in all morphological structures. In particular, we found changes in cell adhesion gene expression, which declined in the row: solid–alveolar–trabecular structures–discrete groups of tumor cells (<em>p","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Page 13"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54308924","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.051
V. Kristensen
Combined analyses of molecular data, such as DNA copy-number alteration, mRNA and protein expression, point to biological functions and molecular pathways being deregulated in multiple cancers. Genomic, metabolomic and clinical data from a variety of solid cancers and model systems are emerging and can be used to identify novel patient subgroups for tailored therapy and monitoring. The first solid tumor to be profiled by expression arrays was carcinoma of the breast. The most reproducible classification by mRNA expression is based on the biological entities referred to as the intrinsic subtypes; Luminal A, Luminal B, Basal-like, HER2 enriched, and the Normal-like groups. In the past decade a number of molecular studies to classify breast cancer have added one or two additional molecular levels, most frequently DNA copy number, and gene sequencing. However, few of the studies have integrated more than two levels of information from the same patients. We have in our lab collected several layers of high throughput molecular data, TP53 mutation status and high throughput paired end sequencing on a dataset of 110 patients. This dataset was clustered according to each molecular level studied using an unbiased, unsupervised clustering, and survival KM plots for each patient subgroup was created. While some samples always cluster together at any molecular level, others cluster in different groups according to each particular molecular endpoint. Therefore, we used an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We show that massive interleukin signaling profiles are observed in invasive cancers and are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. A good correlation was observed between methylation and mRNA expression based classification (p = 2.29 × 10−6). Using PARADIGM based on mRNA and miRNA expression, CNAs, and methylation five new clusters with survival differences were revealed. Given the increasing importance of immune constitution for the success of chemotherapy and targeted treatment, this additional information may prove useful in the clinic in the future.
{"title":"T143","authors":"V. Kristensen","doi":"10.1016/j.ejcsup.2015.08.051","DOIUrl":"10.1016/j.ejcsup.2015.08.051","url":null,"abstract":"<div><p>Combined analyses of molecular data, such as DNA copy-number alteration, mRNA and protein expression, point to biological functions and molecular pathways being deregulated in multiple cancers. Genomic, metabolomic and clinical data from a variety of solid cancers and model systems are emerging and can be used to identify novel patient subgroups for tailored therapy and monitoring. The first solid tumor to be profiled by expression arrays was carcinoma of the breast. The most reproducible classification by mRNA expression is based on the biological entities referred to as the intrinsic subtypes; Luminal A, Luminal B, Basal-like, HER2 enriched, and the Normal-like groups. In the past decade a number of molecular studies to classify breast cancer have added one or two additional molecular levels, most frequently DNA copy number, and gene sequencing. However, few of the studies have integrated more than two levels of information from the same patients. We have in our lab collected several layers of high throughput molecular data, TP53 mutation status and high throughput paired end sequencing on a dataset of 110 patients. This dataset was clustered according to each molecular level studied using an unbiased, unsupervised clustering, and survival KM plots for each patient subgroup was created. While some samples always cluster together at any molecular level, others cluster in different groups according to each particular molecular endpoint. Therefore, we used an integrated approach to understand breast cancer heterogeneity by modeling mRNA, copy number alterations, microRNAs, and methylation in a pathway context utilizing the pathway recognition algorithm using data integration on genomic models (PARADIGM). We show that massive interleukin signaling profiles are observed in invasive cancers and are absent or weakly expressed in healthy tissue but already prominent in ductal carcinoma in situ, together with ECM and cell-cell adhesion regulating pathways. A good correlation was observed between methylation and mRNA expression based classification (<em>p</em> <!-->=<!--> <!-->2.29<!--> <!-->×<!--> <!-->10<sup>−6</sup>). Using PARADIGM based on mRNA and miRNA expression, CNAs, and methylation five new clusters with survival differences were revealed. Given the increasing importance of immune constitution for the success of chemotherapy and targeted treatment, this additional information may prove useful in the clinic in the future.</p></div>","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Page 29"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54309539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.062
A. Makashov , A. Kozlov
Background
Earlier we showed that at least some of nucleotide sequences with tumor-specific expression are evolutionary novel (reviewed in [A.P. Kozlov, 2014]). In this paper we performed the study of the relative evolutionary novelty of human oncogenes, all protein-coding genes, genes encoding tumor antigens, tumor suppressors and tumor-associated genes using homology searches in genomes of different taxa in human lineage.
Materials and methods
The following databases were used as a source of human genes: oncogenes – COSMIC (574 genes), tumor suppressors – TSGene (636 genes), all tumor-associated genes – allOnco (2116 genes) and NCG (2001 genes), cancer-testis (CT) antigen genes – CTDatabase (276 genes) and all annotated human protein coding genes – Genome assembly GRCh38 (21694 genes). The list of cancer vaccine antigen genes was retrieved from paper of Cheever et al., 2007, where 75 cancer antigens were ranked according to their potential suitability for anticancer vaccines. Some of cancer antigens are non-protein molecules, mutant or fusion-proteins. Thus, we examined the evolutionary novelty of only 58 protein-coding cancer vaccine antigen genes. To analyze the evolutionary novelty of the explored genes the HomoloGene release 68 tool and ProteinHistorian tool were used. The HomoloGene tool searches the orthologs in 11 taxa of the human lineage (Eukaryota, Opisthokonta, Bilateria, Euteleostomi, Tetrapoda, Amniota, Boreoeutheria, Euarchontoglires Catarrhini, Homininae, H.sapiens) and the ProteinHistorian tool searches the orthologs in 16 taxa of the human ligeage (Cellular Organisms, Eukaryota, Opisthokonta, Bilateria, Deuterostomia, Chordata, Euteleostomi, Tetrapoda, Amniota, Mammalia, Theria, Eutheria, Euarchontoglires, Catarrhini, Homininae, H.sapiens). To analyze the statistical significance of data Fisher’s exact test was used.
Results
Several curves of taxonomic distribution of orthologs of different classes of human genes have been generated. A set of curves forms a peculiar picture where different curves are organized in a definite order. The curves never intersect after Bilateria. The uppermost position occupies the curve which describes the oncogene orthologs distribution. Right below the oncogene curve, the distribution curve of tumor suppressor genes orthologs taxonomic is located, and the difference between these curves is significant. The distribution curves of other tumor-associated genes orthologs overlap with tumor suppressor curve. The medium position in the whole picture is occupied by the distribution curve of orthologs of all human protein-coding genes. Below this curve the distribution curves of orthologs of different tumor antigens are located. The first below the medium curve is tumor vaccine antigen curve, then CT and CT-X antigen genes orthologs distribution curves are located. Thus at any given timepoint the relative proportion of oncogene orthologs de
{"title":"P126","authors":"A. Makashov , A. Kozlov","doi":"10.1016/j.ejcsup.2015.08.062","DOIUrl":"10.1016/j.ejcsup.2015.08.062","url":null,"abstract":"<div><h3>Background</h3><p>Earlier we showed that at least some of nucleotide sequences with tumor-specific expression are evolutionary novel (reviewed in [A.P. Kozlov, 2014]). In this paper we performed the study of the relative evolutionary novelty of human oncogenes, all protein-coding genes, genes encoding tumor antigens, tumor suppressors and tumor-associated genes using homology searches in genomes of different taxa in human lineage.</p></div><div><h3>Materials and methods</h3><p>The following databases were used as a source of human genes: oncogenes – COSMIC (574 genes), tumor suppressors – TSGene (636 genes), all tumor-associated genes – allOnco (2116 genes) and NCG (2001 genes), cancer-testis (CT) antigen genes – CTDatabase (276 genes) and all annotated human protein coding genes – Genome assembly GRCh38 (21694 genes). The list of cancer vaccine antigen genes was retrieved from paper of Cheever et al., 2007, where 75 cancer antigens were ranked according to their potential suitability for anticancer vaccines. Some of cancer antigens are non-protein molecules, mutant or fusion-proteins. Thus, we examined the evolutionary novelty of only 58 protein-coding cancer vaccine antigen genes. To analyze the evolutionary novelty of the explored genes the HomoloGene release 68 tool and ProteinHistorian tool were used. The HomoloGene tool searches the orthologs in 11 taxa of the human lineage (Eukaryota, Opisthokonta, Bilateria, Euteleostomi, Tetrapoda, Amniota, Boreoeutheria, Euarchontoglires Catarrhini, Homininae, H.sapiens) and the ProteinHistorian tool searches the orthologs in 16 taxa of the human ligeage (Cellular Organisms, Eukaryota, Opisthokonta, Bilateria, Deuterostomia, Chordata, Euteleostomi, Tetrapoda, Amniota, Mammalia, Theria, Eutheria, Euarchontoglires, Catarrhini, Homininae, H.sapiens). To analyze the statistical significance of data Fisher’s exact test was used.</p></div><div><h3>Results</h3><p>Several curves of taxonomic distribution of orthologs of different classes of human genes have been generated. A set of curves forms a peculiar picture where different curves are organized in a definite order. The curves never intersect after Bilateria. The uppermost position occupies the curve which describes the oncogene orthologs distribution. Right below the oncogene curve, the distribution curve of tumor suppressor genes orthologs taxonomic is located, and the difference between these curves is significant. The distribution curves of other tumor-associated genes orthologs overlap with tumor suppressor curve. The medium position in the whole picture is occupied by the distribution curve of orthologs of all human protein-coding genes. Below this curve the distribution curves of orthologs of different tumor antigens are located. The first below the medium curve is tumor vaccine antigen curve, then CT and CT-X antigen genes orthologs distribution curves are located. Thus at any given timepoint the relative proportion of oncogene orthologs de","PeriodicalId":11675,"journal":{"name":"Ejc Supplements","volume":"13 1","pages":"Page 35"},"PeriodicalIF":0.0,"publicationDate":"2015-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.ejcsup.2015.08.062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54309675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.068
M. Mukhacheva, B. Beyn
This work is devoted to the actual problem of studying modern ideas about the systemic treatment of brain tumors, in particular on the implementation and effectiveness of modern methods of immunomodulation in neuro-oncology. The aim is to clarify the existence of patients with brain tumors immunosuppression, resulting in testimony to the development and application of methods of immunotherapy. Method of research consistent with the goal and objectives of the study, which included a dynamic examination of 32 operated patients with hemispheric brain gliomas. Cycloferon interferonogens from the group, which has antiviral and antitumor action potential was used as an immunomodulator us. It is of interest to determine the effectiveness of immunomodulatory action of cycloferon in patients with brain tumors in different phases of development of cancer. This work represents a scientific novelty and practical significance for solving urgent problems of neurology and neurosurgery – the study of the cycloferon drug, has proved its effectiveness in the reinforcement of clinical remission and increased the life expectancy of patients with brain tumors after surgery.
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Pub Date : 2015-11-01DOI: 10.1016/j.ejcsup.2015.08.072
I. Novikova, E. Zlatnik, E. Ulyanova, Yu. Shatova
The purpose of the study was to assess parameters of local cellular immunity, expression of apoptosis-controlling proteins and some other receptors in various molecular subtypes of breast cancer (BC) with different clinical course and prognosis.
Materials and methods
100 BC patients aged 30–76 years (59 ± 3.4) were recruited. Tissues of tumor and peritumoral area were homogenized by MediMachine, subset contents of T, B, NK-lymphocytes were estimated by flow cytometer FACS CantoII. Percentage of lymphocytes expressing CD3, CD4, CD8, CD19, CD16/56, were counted from total amount of CD45+ lymphocytes. Sections of paraffin-embedded blocks were studied by immunohistochemical method with polyvalent HRP-DAB detection system. Staining was performed using Thermo Scientific autostainer. Tumor was considered p53-positive when >25% of tumor cell nuclei were positively stained, and bcl-2-positive when >25% of cells showed specific cytoplasmic staining. Expression of E-cadherin was assessed by the number of cells with positive membrane expression of this marker, taking into account intensity of the reaction. Expression of topoisomerase 2α and androgen receptors was assessed by the number of tumor cells with positive nuclear expression of these markers; number of stained nuclei per 100 nuclei in 3 fields of view was counted.
Results
Some differences characterizing tumor cells of molecular breast cancer subtypes were found. Tumor tissue contained higher amount of T-lymphocytes than blood (85.9 ± 2.36% vs 60.1 ± 4.5%, P < 0.05) predominantly CD3+CD8+ cells (34.0 ± 1.9% vs 20.3 ± 5.36%, P < 0.05) but lower percentage of B- and NK-cells. In tissue of peritumoral area amounts of CD3+ and CD3+CD8+ cells were also higher, while CD19+ level was lower than in blood. In the same samples content of CD3+CD4+ was lower and amount of NK-cells was higher than in tumor tissue. Triple- negative subtype was characterized by maximal content of CD3+ lymphocytes (92.2 ± 1.4%), luminal A contained the highest amount of CD3+CD16/56+ cells (10.6 ± 1.73%) vs luminal B (4.34 ± 1.27%) and triple-negative (4.13 ± 1.63%). Her2+ neu BC demonstrated high amount of NK-cells in peritumoral area but not in tumor.
p53 overexpression was equally often recorded in luminal B and Her2+ subtypes of BC and slightly less frequently in triple-negative subtype. Accumulation of p53 was 2 times less frequently detected in luminal A subtype in comparison with triple -negative cancer and 2.5 and 2.7 times less frequently in comparison with luminal B and Her2+ BC, respectively. Study of bcl-2 expression showed reducing the frequency of positive tumor cell staining in dependence on the recepto
本研究的目的是评估不同临床病程和预后的不同分子亚型乳腺癌(BC)的局部细胞免疫参数、凋亡控制蛋白和其他受体的表达。材料与方法入选BC患者100例，年龄30 ~ 76岁(59±3.4)。采用MediMachine对肿瘤组织及肿瘤周围进行匀浆，流式细胞仪FACS CantoII检测T、B、nk淋巴细胞亚群含量。从CD45+淋巴细胞总数中计数表达CD3、CD4、CD8、CD19、CD16/56的淋巴细胞百分比。采用免疫组织化学方法，采用多价HRP-DAB检测系统对石蜡包埋块切片进行研究。使用Thermo Scientific自动染色机进行染色。当25%的肿瘤细胞核呈阳性染色时，认为肿瘤为p53阳性;当25%的细胞呈特异性细胞质染色时，认为肿瘤为bcl-2阳性。考虑到反应的强度，通过膜上表达E-cadherin阳性的细胞数量来评估E-cadherin的表达。通过核表达阳性的肿瘤细胞数评估拓扑异构酶2α和雄激素受体的表达;计算3个视场内每100个染色细胞核的数目。结果发现不同分子乳腺癌亚型的肿瘤细胞具有一定的差异。肿瘤组织t淋巴细胞含量高于血液(85.9±2.36% vs 60.1±4.5%，P <0.05)主要CD3 + CD8 +细胞(34.0±1.9%和20.3±5.36%,P & lt;0.05)，但B细胞和nk细胞比例较低。肿瘤周围组织中CD3+和CD3+CD8+细胞含量均高于血中，CD19+水平低于血中。同一标本中CD3+CD4+含量低于肿瘤组织，nk细胞数量高于肿瘤组织。三阴性亚型CD3+淋巴细胞含量最高(92.2±1.4%)，其中A型CD3+CD16/56+细胞含量最高(10.6±1.73%)，B型为4.34±1.27%，三阴性为4.13±1.63%。Her2+ new BC在肿瘤周围可见大量的nk细胞，而在肿瘤中没有。在BC的luminal B和Her2+亚型中，p53过表达同样常见，而在三阴性亚型中，p53过表达的频率略低。与三阴性肿瘤相比，在luminal A亚型中检测到p53积累的频率低2倍，与luminal B和Her2+ BC相比，p53积累的频率分别低2.5倍和2.7倍。对bcl-2表达的研究表明，肿瘤细胞阳性染色频率的降低依赖于肿瘤的受体状态:三阴性和Her2+亚型的阳性病例数倍于luminal A和B亚型。Luminal A亚型的特点是p53、拓扑异构酶2α和雄激素受体的表达最少，bcl-2和E-cadherin的表达最多。Luminal B亚型高表达p53、bcl-2和雄激素受体，中等表达拓扑异构酶2α和E-cadherin。三阴性BC中拓扑异构酶2α高表达，雄激素受体低表达，E-钙粘蛋白中等表达。在Her2+亚型中，拓扑异构酶2α和p53的表达量最大，bcl-2和E-cadherin的表达量较低。结论scd8 + t淋巴细胞在BC肿瘤组织中占主导地位。此外，腔内A型BC的肿瘤组织中含有较多的nk细胞。在乳腺癌的不同分子亚型中，凋亡控制蛋白的表达存在许多差异。Luminal A BC中p53表达最低，bcl-2表达最高。Luminal B亚型高p53和bcl- 2表达。在Her2+ BC中，p53表达最多，bcl-2表达较低。所描述的差异允许评估乳腺癌的分子亚型，并从以前未探索的角度预测疾病病程。
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