Publications by authors named "Marina V Zavyalova"

18 Publications

  • Page 1 of 1

Heterogeneous Manifestations of Epithelial-Mesenchymal Plasticity of Circulating Tumor Cells in Breast Cancer Patients.

Int J Mol Sci 2021 Mar 2;22(5). Epub 2021 Mar 2.

Cancer Research Institute, Tomsk National Research Medical Center, 634050 Tomsk, Russia.

To date, there is indisputable evidence of significant CTC heterogeneity in carcinomas, in particular breast cancer. The heterogeneity of CTCs is manifested in the key characteristics of tumor cells related to metastatic progression - stemness and epithelial-mesenchymal (EMT) plasticity. It is still not clear what markers can characterize the phenomenon of EMT plasticity in the range from epithelial to mesenchymal phenotypes. In this article we examine the manifestations of EMT plasticity in the CTCs in breast cancer. The prospective study included 39 patients with invasive carcinoma of no special type. CTC phenotypes were determined by flow cytometry before any type of treatment. EMT features of CTC were assessed using antibodies against CD45, CD326 (EpCam), CD325 (N-cadherin), CK7, Snail, and Vimentin. Circulating tumor cells in breast cancer are characterized by pronounced heterogeneity of EMT manifestations. The results of the study indicate that the majority of heterogeneous CTC phenotypes (22 out of 24 detectable) exhibit epithelial-mesenchymal plasticity. The variability of EMT manifestations does not prevent intravasation. Co-expression of EpCAM and CK7, regardless of the variant of co-expression of Snail, N-cadherin, and Vimentin, are associated with a low number of CTCs. Intrapersonal heterogeneity is manifested by the detection of several CTC phenotypes in each patient. Interpersonal heterogeneity is manifested by various combinations of CTC phenotypes in patients (from 1 to 17 phenotypes).
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http://dx.doi.org/10.3390/ijms22052504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958863PMC
March 2021

Prognosis of Different Types of Non-Small Cell Lung Cancer Progression: Current State and Perspectives.

Cell Physiol Biochem 2021 Mar;55(S2):29-48

Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia,

Despite advances in diagnostics and therapy of non-small cell lung cancer (NSCLC), the problem of prognosis and prevention of tumor progression is still highly important. Even if NSCLC is diagnosed in the early stages, almost a quarter of patients develop relapse; most of them die from recurrent disease. A large number of different markers have been proposed to predict the risk of NSCLC progression; however, none of them are used in clinical practice. It is obvious that this situation is related to the economic and methodological complexity of the proposed markers and/or their insufficient efficiency due to a lack of effective study models and tumor heterogeneity. Another reason may be that potential markers are developed for NSCLC progression in general, which is represented by at least four pathogenetically-distinct processes: synchronous lymph node metastasis, local, regional, and distant recurrence. In this review, we summarize data from published literature on clinicopathological, genetic, and molecular factors associated with different types of NSCLC progression and emphasize challenges and approaches to developing prognostic factors. In conclusion, we highlight the importance of further studies to reveal molecular mechanisms of NSCLC progression and the need for differential analysis of markers of local, regional, and distant recurrences for disease prognosis.
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http://dx.doi.org/10.33594/000000340DOI Listing
March 2021

The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer.

Cancers (Basel) 2020 Jul 15;12(7). Epub 2020 Jul 15.

Laboratory of Cancer Progression Biology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634009 Tomsk, Russia.

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.
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http://dx.doi.org/10.3390/cancers12071909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409151PMC
July 2020

Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer.

Int J Mol Sci 2020 Apr 16;21(8). Epub 2020 Apr 16.

Cancer Research Institute, Tomsk National Research Medical Center, 634050 Tomsk, Russia.

The presence of stem and epithelial-mesenchymal-transition (EMT) features in circulating tumor cells (CTCs) determines their invasiveness, adaptability to the microenvironment, and resistance to proapoptotic signals and chemotherapy. It also allows them to fulfil the role of metastatic "seeds". We evaluated the heterogeneity of stem CTCs by their CD44, ALDH1, and CD133 expression depending on N-cadherin expression in breast-cancer patients. A total of 38 female patients were selected for this study. CTC phenotypes were determined by flow cytometry before any type of treatment. Multiplex immunofluorescence was used for the evaluation of tumor-cell heterogeneity in primary lesions. In patients who had CD44-CD24- CTCs, a subset of cells with the expression of other stem-cell markers (CD133 and ALDH1) were detected. Expression of CD133 and/or ALDH1 may be associated with expression of N-cadherin: all populations of N-cadherin+ CTCs demonstrate stem features; in the absence of N-cadherin expression, true nonstem (CD44-CD24-CD133-ALDH1-) cells are found. The heterogeneity of stem marker expression in CTCs was observed regardless of N-cadherin expression. In our study, stromal cell-derived factor-1 (SDF-1) receptor expression in CTCs did not depend on stemlike traits, but was instead associated with N-cadherin expression. Subpopulations of tumor cells, detected both in tumors and blood, were identified. Breast cancer was characterized by pronounced interpersonal and intrapersonal heterogeneity of CTCs by the presence and combination of various stem features and N-cadherin expression. To complete the characterization of stemlike features of CTCs, we suggest the simultaneous use of the three stem markers.
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http://dx.doi.org/10.3390/ijms21082780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216207PMC
April 2020

Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis.

Front Oncol 2020 19;10:50. Epub 2020 Feb 19.

Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Tomsk, Russia.

The identification of tumor cells that can be potential metastatic seeds would reach two key aims-prognosis of metastasis risk and appointment of the optimal adjuvant therapy to prevent metastatic disease. Single tumor cells (STCs) located out of multicellular structures can most likely demonstrate features that are needed to initiate metastasis. One-hundred-and-thirty-five patients with invasive breast carcinoma of no special type have been enrolled. Molecular subtypes of breast cancer were categorized according to St. Gallen recommendations. Hematoxylin and eosin staining was used to identify STCs with epithelial-like morphology (eSTCs) in breast tumors. Immunofluorescence staining was applied to evaluate stemness and epithelial-mesenchymal transition (EMT) in STCs. The correlation between STCs and recurrence and metastasis-free survival (MFS) was performed using the Kaplan-Meier method and the log-rank test. Distant metastasis was more frequent in eSTC-positive than eSTC-negative patients (28.0% vs. 9.4%, = 0.007). When tumor types were analyzed separately, distant metastasis tended to be more frequent in eSTC-positive than eSTC-negative patients for HER2-positive cancer [75.0% (3/4) vs. 12.5% (1/8), = 0.066]. In luminal A [22.7% (5/22) vs. 10.0% (3/30), = 0.259], luminal B [21.1% (4/19) vs. 6.7% (2/30), = 0.189], and triple-negative [40.0% (2/5) vs. 11.8% (2/17), = 0.209] cancers, distance metastasis was not associated with eSTCs. Median MFS was not reached in eSTC-positive and eSTC-negative patients. eSTC-positive patients had a higher risk of breast cancer metastasis [hazard ratio (HR) 3.57, 95% confidence interval (CI): 1.46-8.71; = 0.001]. When tumor types were analyzed separately, a higher risk of breast cancer metastasis occurred only in HER2-positive patients (HR 8.49, 95% CI: 1.29-55.59; = 0.016). Immunofluorescence analysis revealed mesenchymal-like STCs (mSTCs) and inter- and intra-tumor heterogeneity in STCs. There were breast tumors with either eSTCs or mSTCs and tumors with both types of STCs. Both eSTCs and mSTCs were represented by cells with different stem and/or EMT phenotypes. STCs with epithelial-like morphology contribute to breast cancer metastasis and represent an attractive model for studying mechanisms of metastatic seeding. The assessment of STCs in histological sections of breast tumors can be a simple and effective method for the prediction of metastasis risk.
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http://dx.doi.org/10.3389/fonc.2020.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050653PMC
February 2020

Markers of Cancer Cell Invasion: Are They Good Enough?

J Clin Med 2019 Jul 24;8(8). Epub 2019 Jul 24.

Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, 634009 Tomsk, Russia.

Invasion, or directed migration of tumor cells into adjacent tissues, is one of the hallmarks of cancer and the first step towards metastasis. Penetrating to adjacent tissues, tumor cells form the so-called invasive front/edge. The cellular plasticity afforded by different kinds of phenotypic transitions (epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and ) significantly contributes to the diversity of cancer cell invasion patterns and mechanisms. Nevertheless, despite the advances in the understanding of invasion, it is problematic to identify tumor cells with the motile phenotype in cancer tissue specimens due to the absence of reliable and acceptable molecular markers. In this review, we summarize the current information about molecules such as extracellular matrix components, factors of epithelial-mesenchymal transition, proteases, cell adhesion, and actin cytoskeleton proteins involved in cell migration and invasion that could be used as invasive markers and discuss their advantages and limitations. Based on the reviewed data, we conclude that future studies focused on the identification of specific invasive markers should use new models one of which may be the intratumor morphological heterogeneity in breast cancer reflecting different patterns of cancer cell invasion.
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http://dx.doi.org/10.3390/jcm8081092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723901PMC
July 2019

Mechanisms behind prometastatic changes induced by neoadjuvant chemotherapy in the breast cancer microenvironment.

Breast Cancer (Dove Med Press) 2019 5;11:209-219. Epub 2019 Jul 5.

Cancer Research Institute, Tomsk National Research Medical Center, Tomsk 634050, Russia.

Chemotherapy, along with surgery and radiotherapy, is a key treatment option for malignant tumors. Neoadjuvant chemotherapy (NACT) reduces the tumor size and enables total tumor resection. In addition, NACT is believed to be more effective in destroying micrometastases than the same chemotherapy performed after surgery. To date, various NACT regimens have been tested and implemented, which provide a favorable outcome in primary tumors and reduce the risk of progression. However, there is increasing evidence of the NACT ability to increase the risk of cancer progression. This review discusses potential mechanisms by which NACT promotes distant metastasis of breast cancer through changes in the microenvironment of tumor cells. We describe prometastatic NACT-mediated changes in angiogenesis, immuno-inflammatory reactions in the stroma, intravasation, and amount of circulating tumor cells. The role of NACT-related cellular stress in cancer metastasis is also discussed.
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http://dx.doi.org/10.2147/BCTT.S175161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616300PMC
July 2019

Clinically relevant morphological structures in breast cancer represent transcriptionally distinct tumor cell populations with varied degrees of epithelial-mesenchymal transition and CD44CD24 stemness.

Oncotarget 2017 Sep 19;8(37):61163-61180. Epub 2017 May 19.

Department of General and Molecular Pathology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, 634050, Tomsk, Russian Federation.

Intratumor morphological heterogeneity in breast cancer is represented by different morphological structures (tubular, alveolar, solid, trabecular, and discrete) and contributes to poor prognosis; however, the mechanisms involved remain unclear. In this study, we performed 3D imaging, laser microdissection-assisted array comparative genomic hybridization and gene expression microarray analysis of different morphological structures and examined their association with the standard immunohistochemistry scorings and CD44CD24 cancer stem cells. We found that the intratumor morphological heterogeneity is not associated with chromosomal aberrations. By contrast, morphological structures were characterized by specific gene expression profiles and signaling pathways and significantly differed in progesterone receptor and Ki-67 expression. Most importantly, we observed significant differences between structures in the number of expressed genes of the epithelial and mesenchymal phenotypes and the association with cancer invasion pathways. Tubular (tube-shaped) and alveolar (spheroid-shaped) structures were transcriptionally similar and demonstrated co-expression of epithelial and mesenchymal markers. Solid (large shapeless) structures retained epithelial features but demonstrated an increase in mesenchymal traits and collective cell migration hallmarks. Mesenchymal genes and cancer invasion pathways, as well as Ki-67 expression, were enriched in trabecular (one/two rows of tumor cells) and discrete groups (single cells and/or arrangements of 2-5 cells). Surprisingly, the number of CD44CD24 cells was found to be the lowest in discrete groups and the highest in alveolar and solid structures. Overall, our findings indicate the association of intratumor morphological heterogeneity in breast cancer with the epithelial-mesenchymal transition and CD44CD24 stemness and the appeal of this heterogeneity as a model for the study of cancer invasion.
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http://dx.doi.org/10.18632/oncotarget.18022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617414PMC
September 2017

Development of Novel Monoclonal Antibodies for Evaluation of Transmembrane Prostate Androgen-Induced Protein 1 (TMEPAI) Expression Patterns in Gastric Cancer.

Pathol Oncol Res 2018 Apr 5;24(2):427-438. Epub 2017 Jun 5.

Department of Molecular Oncology and Immunology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, Tomsk, Russian Federation, 634050.

Transmembrane prostate androgen-induced protein 1 (TMEPAI) is a single-span membrane protein, functionally involved in transforming growth factor beta signaling pathway. The particular protein presented in cells in three isoforms, which differs in the length of the soluble N-terminal extracellular domain, making it challenging for the immunochemical recognition. By using quantitative real-time polymerase chain reaction, we identified significant upregulation of PMEPA1 gene expression in malignant tissues of patients with gastric adenocarcinoma. The main part of commercially available anti-TMEPAI antibodies are having polyclonal nature or not suitable for immunocytochemical localization of target protein in tissue specimens. Hence, we decide to generate a set of novel rat monoclonal antibodies (mAb) directed against conservative C-terminal cytoplasmic epitope. Immunoblotting analysis showed that monoclonal antibodies, 2E1, 6C6, and 10A7 were able to recognize specifically target protein in transiently transfected HEK293T and CHO-K1 cells. Especially established mAb, named 10A7, showed the excellent binding ability to target protein in immunohistochemistry. By using developed antibodies, we observed pronounced expression of TMEPAI in normal gastric epithelial cells while tumor cells from gastric adenomas, and adenocarcinoma samples were mostly negative for target protein expression. Also, we found that gastric epithelium cells lose the TMEPAI expression concurrently with severe dysplasia progression, which probably caused by a mechanism involving specific microRNA.
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http://dx.doi.org/10.1007/s12253-017-0247-xDOI Listing
April 2018

Intratumoral heterogeneity of macrophages and fibroblasts in breast cancer is associated with the morphological diversity of tumor cells and contributes to lymph node metastasis.

Immunobiology 2017 04 27;222(4):631-640. Epub 2016 Nov 27.

Department of Pathological Anatomy and Cytology, Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Kooperativny Str. 5, 634050 Tomsk, Russian Federation.

Recent studies have highlighted the heterogeneity of the tumor microenvironment (ME) and the importance of its analysis to the understanding of its impact on clinical outcomes. In this study, we aimed to analyze the intratumoral distribution of macrophages and fibroblasts in breast cancer (BC) based on the morphological diversity of tumor cells (tubular, alveolar, solid, trabecular and discrete structures) and the clinicopathological parameters of the disease. Thirty-six patients with invasive breast carcinoma of no special type were included in the study. The distribution of macrophages and fibroblasts in the MEs of different morphological structures was assessed using laser microdissection-assisted quantitative RT-PCR analysis of marker genes and double immunofluorescence staining for the CD68, RS1, aSMA, and FAP proteins. Gene expression microarrays were used to determine the expression of genes involved in the regulation of macrophage and fibroblast phenotypes in different morphological structures. We found that different macrophage and fibroblast subpopulations were simultaneously observed in the MEs of morphologically distinct structures but that the frequency of their detection and number of cells detected varied significantly among these structures. In particular, macrophages and fibroblasts were more frequently detected in the ME of solid structures and were rarely observed in tubular structures. A high number of CD68RS1 macrophages in the ME of solid structures was found to be associated with an increased frequency of lymph node metastasis in luminal B HER2 BC. In contrast, in luminal B HER2 BC, lymph node involvement was related to the high representation of aSMAFAP fibroblasts around trabecular structures. Morphologically distinct structures differed in the mechanisms regulating the macrophage and fibroblast phenotypes. The highest number of overexpressed genes controlling macrophage and fibroblast functions was observed in discrete groups of tumor cells, and the lowest number was observed in alveolar and solid structures. Taken together, our findings indicate the heterogeneous distribution of macrophages and fibroblasts in breast tumors and its close relation to the intratumoral morphological diversity of BC and contribution to lymph node metastasis.
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http://dx.doi.org/10.1016/j.imbio.2016.11.012DOI Listing
April 2017

Functional state of the Hsp27 chaperone as a molecular marker of an unfavorable course of larynx cancer.

Cancer Biomark 2016 Jun;17(2):145-53

Tomsk Cancer Research Institute, Tomsk, Russian Federation.

Background: The small heat shock protein 27 kDA (Hsp27) acts as an ATP-independent chaperone in protein folding, but is also implicated in architecture of the cytoskeleton, cell migration, metabolism, cell survival, growth/differentiation, mRNA stabilization, and tumor progression.

Objective: To study the intracellular localization of phosphorylated and non-phosphorylated forms of Hsp27 in squamous cell carcinoma of the larynx (SCCL) and to evaluate their relationship with regional lymphatic metastasis and overall five-year survival.

Methods: Tumor biopsies of larynx tissue were collected from 50 patients who were between the ages of 30 to 80 years and had a confirmed diagnosis of squamous cell carcinoma of the larynx. Immunohistochemistry was used to determine the intracellular localization of the phosphorylated and non-phosphorylated forms of Hsp27.

Results: The study revealed that the Hsp27 chaperone was expressed in both the cytoplasm and the nucleus of tumor cells in SCCL. The biopsies of patients with lymph node metastases showed significantly higher expression of the phosphorylated and unphosphorylated forms of Hsp27 in the nucleus compared to those of patients without lymph node metastases. At the same time, the cytoplasmic expression of Hsp27 in these patients did not differ statistically. Analysis of the overall five-year survival rates showed that negative Hsp27 expression in the nucleus of tumor cells is associated with the survival rate of patients with SCCL.

Conclusion: The nuclear expression of phosphorylated and unphosphorylated forms of Hsp27 is a molecular marker of unfavorable squamous cell carcinoma of the larynx associated with lymphogenous metastasis and decreased total five-year survival.
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http://dx.doi.org/10.3233/CBM-160625DOI Listing
June 2016

Relationship between morphological and cytogenetic heterogeneity in invasive micropapillary carcinoma of the breast: a report of one case.

J Clin Pathol 2015 Sep 15;68(9):758-62. Epub 2015 Jun 15.

Department of Pathological Anatomy and Cytology, Tomsk Cancer Research Institute, Tomsk, Russian Federation Department of Pathological Anatomy, Siberian State Medical University, Tomsk, Russian Federation.

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http://dx.doi.org/10.1136/jclinpath-2015-203009DOI Listing
September 2015

Relationship between the expression of phosphorylated heat shock protein beta-1 with lymph node metastases of breast cancer.

Cancer Biomark 2015 ;15(2):143-50

Tomsk Cancer Research Institute, Tomsk, Russian Federation Siberian State Medical University, Tomsk, Russian Federation.

Background: Heat shock protein beta-1 (HspB1) is a chaperone of the sHsp (small heat shock protein). The common functions of sHsps are chaperone activity, inhibition of apoptosis, regulation of cell development, and cell differentiation, take part in signal transduction.

Objective: To study the intracellular localization of phosphorylated features and non-phosphorylated forms of HspB1 in primary breast cancer cells and to evaluate their relationship with regional lymphatic metastasis.

Material And Methods: Tumor biopsies of breast tissue were collected from 100 patients with a confirmed diagnosis of invasive carcinoma, nonspecific type, between the ages of 31-80 years. Immunohistochemistry was used to determine the intracellular localization of phosphorylated and non-phosphorylated forms of HspB1.

Results: The result of this study showed that biopsies from patients with lymph node metastasis exhibited significantly higher levels of phosphorylated forms of HspB1 in the nucleus and cytoplasm compared with the group without lymph node metastasis. Analysis showed that the expression of phosphorylated forms of the chaperone HspB1 correlates with the amount and percentage of lymph node metastases affected.

Conclusion: The nuclear expression of phosphorylated and non-phosphorylated forms of the chaperone HspB1 is a marker of tumor cells associated with lymphatic metastasis of breast cancer.
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http://dx.doi.org/10.3233/CBM-140446DOI Listing
February 2016

Intratumoral morphological heterogeneity of breast cancer: neoadjuvant chemotherapy efficiency and multidrug resistance gene expression.

Sci Rep 2014 Apr 16;4:4709. Epub 2014 Apr 16.

1] Department of Experimental Oncology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russian Federation [2] Laboratory of Translational Cell and Molecular Biomedicine, Tomsk State University, Tomsk, Russian Federation [3] Department of Oncology, Siberian State Medical University, Tomsk, Russian Federation.

In this study, the influence of intratumoral morphological heterogeneity of breast cancer on neoadjuvant chemotherapy (NAC) efficiency was investigated. In particular, we analysed the association of NAC response and pre- and post-NAC expression of the main multidrug resistance (MDR) genes--ABCB1, ABCC1, ABCC5, ABCG1, and ABCG2, with the presence of different morphological structures in breast tumors. In addition, the expression of MDR genes was investigated in different morphological structures and in their microenvironment by comparing probes obtained using laser microdissection. The results of this study showed that tumors with alveolar structures were more frequently NAC-nonresponsive than cases without this structural type (p = 0.0028, Bonferroni-corrected p = 0.014). The presence of trabecular structures in breast tumors was also associated with chemoresistance (p = 0.0272, Bonferroni-corrected p = 0.136). High expression of MDR genes was not found in alveolar structures (including their microenvironment) and in tumors containing this structural type. In contrast, more active MDR genes and expression of the ABCB1 gene were found only in trabecular structures. Taken together, our data indicate that breast tumors with alveolar structures possess resistance to NAC, which is not related to high expression of MDR genes, whereas chemoresistance of tumors with trabecular structures can depend on the expression level of ABCB1.
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http://dx.doi.org/10.1038/srep04709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3988480PMC
April 2014

Expression of cyclophilin A in gastric adenocarcinoma patients and its inverse association with local relapses and distant metastasis.

Pathol Oncol Res 2014 Apr 24;20(2):467-73. Epub 2013 Nov 24.

Cancer Research Institute of Siberian Branch of RAMS, Tomsk, Russian Federation,

The aim of this study was to identify new protein markers of the intestinal and diffuse type gastric adenocarcinoma and to determine their relation to local relapses and distant metastasis. Using two-dimensional gel electrophoresis, we searched for proteins that are overexpressed in the intestinal and/or diffuse type gastric adenocarcinoma, as compared to matched normal mucosa samples with further change confirmation by Western blot. Expression of the selected proteins was further assessed by immunohistocemistry in a large panel of gastric adenocarcinoma with various clinicopathological features. Expression level of cyclophilin A measured with western blot appeared to be increased on average ten times in 63 % of gastric adenocarcinoma vs. paired samples of normal mucosa. The frequency of immunihistochemistry detected cyclophilin A protein expression was found to be equal in tumor of both histotypes, but staining intensity was higher in intestinal versus diffuse types of gastric adenocarcinoma. cyclophilin A protein expression appeared to be lower in deeply invading glandular and cribriform structures of intestinal tumors, as well as in discretely placed groups of the intestinal tumor cells. Local relapses as well as distant metastases registered within 3 year follow up were observed to occur much less frequently in patients with positive cyclophilin A immunostaining in gastric tumors. Analysis of cyclophilin A expression has a potential value for prognosis of gastric adenocarcinoma recurrence and distant metastasis.
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http://dx.doi.org/10.1007/s12253-013-9718-xDOI Listing
April 2014

Phenotypic drift as a cause for intratumoral morphological heterogeneity of invasive ductal breast carcinoma not otherwise specified.

Biores Open Access 2013 Apr;2(2):148-54

Department of Pathological Anatomy and Cytology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences , Tomsk, Russian Federation. ; Department of Pathological Anatomy, Siberian State Medical University , Tomsk, Russian Federation.

Invasive ductal carcinoma (IDC) not otherwise specified (NOS), the most common type of breast cancer, demonstrates great intratumoral morphological heterogeneity, which encompasses the presence of different types of morphological structures-tubular, trabecular, solid, and alveolar structures and discrete groups of tumor cells, the origins of which remain unclear at present. In this study of 162 IDC NOS patients, we investigated whether the distribution of different types of morphological structures is related to the basic clinicopathological parameters of IDC NOS. Our results showed that in patients with only one type of tumor structure, the presence of any one of the five types was equally probable; however, cases with two types of structures were more likely to contain trabecular structures than the other four types. The development of intratumoral morphological heterogeneity was not associated with menopausal status, tumor size, histological grade, hematogenic metastasis, or recurrence. However, the number of different types of morphological structures was significantly higher in luminal tumors than in triple-negative tumors. An increase in the frequency of lymph node metastasis correlated with the increased number of different types of structures in breast tumors; however, in contrast to premenopausal patients, this association was explained by the presence of alveolar structures in postmenopausal women. In addition, we showed a significant decrease in the numbers of positive lymph nodes in tumors with high numbers of morphological variants. The frequency of lymph node metastases and the number of positive nodes were generally independent features and formed by different mechanisms. Based on the evidence, the term "phenotypic drift" has been designated as the basis for the development of intratumoral morphological heterogeneity of IDC NOS.
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http://dx.doi.org/10.1089/biores.2012.0278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620470PMC
April 2013

Changing the expression vector of multidrug resistance genes is related to neoadjuvant chemotherapy response.

Cancer Chemother Pharmacol 2013 Jan 2;71(1):153-63. Epub 2012 Oct 2.

Department of Experimental Oncology, Cancer Research Institute, Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russian Federation.

Purpose: We aimed to examine the association between alterations in multidrug resistance (MDR) gene expression, measured before and after neoadjuvant chemotherapy (NAC), and short-term response in a cohort of stage IIA-IIIC breast cancer patients (n = 84).

Methods: All patients were treated with two to four preoperative cycles of FAC (5-fluorouracil-adriamycin-cyclophosphamide), CAX (cyclophosphamide-adriamycin-xeloda) or taxane regimes. The expression levels of key MDR genes (ABCB1, ABCC1, ABCC2, ABCC3, ABCC5, ABCG1, ABCG2, GSTP1, and MVP) were evaluated in both tumor tissues obtained pre-therapy and in specimens removed by final surgery, using TaqMan-based quantitative reverse transcriptase PCR.

Results: No significant difference in the average level of MDR gene expression in paired breast tumors before and after NAC was found when analyzed in both responsive and non-responsive patients. There was no correlation between the expression levels of MDR genes in pre-NAC tumors and immediate NAC response. In the group with tumor responses, we found a statistically significant downregulation of expression of ABCB1, ABCC1, ABCC2, ABCC5, ABCG1, ABCG2, GSTP1, and MVP genes following NAC in FAC and CAX-treated patients (67-93% of cases). In contrast, we found that expression of these genes was upregulated after NAC, mostly in non-responsive patients (55-96% of cases). Responsiveness to taxotere was related to reduced levels of ABCB1, ABCC2, ABCG1, ABCG2, and MVP mRNA in tumor samples collected after chemotherapy.

Conclusion: Our results suggest that reductions in MDR gene expression in post-NAC samples in comparison with pre-NAC are associated with tumor response to FAC and CAX as well as taxotere-based NAC, while patients displaying MDR gene upregulation had resistance to therapy.
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http://dx.doi.org/10.1007/s00280-012-1992-xDOI Listing
January 2013