Jekaterina Erenpreisa - Academia.edu (original) (raw)

Papers by Jekaterina Erenpreisa

Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withs... more Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withstand cell death. TP53, the pivotal tumor suppressor plays an important role in this process by inducing a prolonged dual state with senescence and self-renewal as potential outcomes. Molecularly, this is achieved by activating both OCT4A (POU5F1) and p21CIP1. OCT4A suppresses the excessive activity of p21 preventing the immediate precipitation of apoptosis or terminal senescence. It persists as long as sufficient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the bottleneck of these TP53-dependent senescence reversal processes, as well terminal senescence will follow if DNA damage is not ultimately repaired. In TP53 mutants the CSC-like state is boosted by stressed cells overcoming the tetraploidy barrier. These cells acquire additional DNA repair capacity through mitotic slippage and entrance to a sequence of ploidy cycles, allowing repair and sorting DNA damage, ultimately facilitating the genesis of mitotically competent daughter cells following final depolyploidisa-tion. Again, autophagy is required to fuel this process. More detailed knowledge of these arcane processes anticipates the provision of anti-cancer drug targets, such as AURORA B kinase and Survivin, which ensure mitotic slippage and the continuity of ploidy cycles.

Mechanisms of Ageing and Development, 1999

Growth plate chondrocytes of embryonic chick femurs were examined by electron microscopy, cytopho... more Growth plate chondrocytes of embryonic chick femurs were examined by electron microscopy, cytophotometry and autoradiography. Apart from the well-described`light' chondrocyte, a different`dark' type of chondrocyte was present, comprising 10 ± 35% of the cell population. They were found at all stages of chondrocyte differentiation and in all ages of the femurs studied. Well developed rough endoplasmatic reticulum and Golgi complex, many secretory vesicles, energetically active mitochondria and a lot of glycogen, indicating high activity of the cytoplasm, were combined with low RNA synthesis, gentle margination and scattered compaction of the chromatin. DNA cytometry revealed that most of dark cells were diploid, but 15 ± 30% were tetraploid, with the absence of an S-phase. Substantial loss of DNA was found in about 10% of dark chondrocytes. The TUNEL reaction demonstrated a limited number of DNA strand breaks. Advanced dark cells possessed the nuclear features of both apoptosis and necrosis. Besides chromomeric-chromonemic compaction, a chromatin arrangement similar to that of prometaphase and metaphase, as well as amitotic nuclear segregation, all of them degenerative, were found. Our interpretation is that the dark chondrocytes undergo an aberrant type of cell death which may be combined with aberrant cell cycle. Cell death of dark chondrocytes is preceded by a pre-mortal burst of secretion.

Acta Histochemica, 1981

Rat liver and hepatoma cells fixed with formaldehyd e, e mbedded into Epon and treated on section... more Rat liver and hepatoma cells fixed with formaldehyd e, e mbedded into Epon and treated on sections with 5 n HCl and then with aqueous uranylacetate show preferential DNase-sensitive reaction. The reaction is highly d e pendent upon proper fixation, hydrolysis improves its specificity. The binding of the contl'astant with DNA is of ionic nature. B ecause of its simplicity, sufficient contrast and resolution the suggest ed technique is r eco mmended [or ultrastructural sturlies of D NA-containing substrates.

PloS one, 2015

The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue ... more The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue in bioscience. We addressed it in terms of phase transition by a systemic approach based on both density analysis and characteristics of temporal fluctuation for the time-course mRNA expression in differentiating MCF-7 breast cancer cells. In a recent work, we suggested criticality as an essential aspect of dynamic control of genome-wide gene expression. Criticality was evident by a unimodal-bimodal transition through flattened unimodal expression profile. The flatness on the transition suggests the existence of a critical transition at which up- and down-regulated expression is balanced. Mean field (averaging) behavior of mRNAs based on the temporal expression changes reveals a sandpile type of transition in the flattened profile. Furthermore, around the transition, a self-similar unimodal-bimodal transition of the whole expression occurs in the density profile of an ensemble of mRNA ex...

Indian journal of experimental biology

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences

European journal of histochemistry: EJH

Currently we experience crisis of the concept on the origin of cancer. The reductionistic theory ... more Currently we experience crisis of the concept on the origin of cancer. The reductionistic theory of cancer origin from stochastic somatic mutations is stagnating and the best witness of its failure are the patients, which continue to die from advanced cancer. The concept of cancer stem cell (CSC), which appeared relatively recently as a complementation to somatic mutation theory needs to be put into the evolutionary biological context. This commentary is an attempt to return through CSC bridge to the most old embryological theory of cancer origin proposed in the 19th century. This theory postulates that immortality of cancer cells is achieved through the ontogenetic cycle of reproduction. It may represent the evolutionary primitive life-cycle which remained preserved in the genome memory of higher organisms and is recapitulated in their early embryogenesis and cancer.

Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a ... more Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for amechanism for genomere duction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the subcellular localisation of REC8 in the resulting ETCs.We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to...

Acta Crystallographica Section A Foundations of Crystallography, 2008

Cell Cycle, 2015

Tumour cellular senescence induced by genotoxic treatments has recently been found to be paradoxi... more Tumour cellular senescence induced by genotoxic treatments has recently been found to be paradoxically linked to the induction of "stemness". This observation is critical as it directly impinges upon the response of tumours to current chemoradio-therapy treatment regimens. Previously, we showed that following etoposide (ETO) treatment embryonal carcinoma PA-1 cells undergo a p53-dependent upregulation of OCT4A and p21Cip1 (governing self-renewal and regulating cell cycle inhibition and senescence, respectively). Here we report further detail on the relationship between these and other critical cell-fate regulators. PA-1 cells treated with ETO display highly heterogeneous increases in OCT4A and p21Cip1

Experimental oncology, 2014

Worldwide, breast cancer in women remains to be the most common malignancy that in a considerable... more Worldwide, breast cancer in women remains to be the most common malignancy that in a considerable proportion shows the resistance to genotoxic treatments and poor outcome. Chromosomal instability manifested as aneuploidy represents an integral cha-racteristics of the malignant genotype not only because of the selection of mutated aneuploid sub-clones that stipulate the tumor progression, but also because of the reversible endopolyploidy of tumor cells that serves for the endless maintenance of therapy-resistant tumor stem cells. Therefore, cytometric determination of DNA content in tissue samples for detecting malignancy, monitoring responses to therapy, and prognosing disease outcome needs to be revived. Both flow and image cytometry are most frequently used for generation of DNA content profiles (histograms), interpretation of which, however, may have some caveats. This review presents the major characterization criteria and analysis tools for breast cancer DNA histograms.

Cancer cell international, Jan 16, 2005

Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes - CTA)... more Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes - CTA) have become the most extensively studied antigen group in the field of tumour immunology. Despite this, many fundamentally important questions remain unanswered: what is the connection between germ-cell specific genes and tumours? Is the expression of these genes yet another proof for the importance of genome destabilisation in the process of tumorigenesis?, or maybe activation of these genes is not quite random but instead related to some programme giving tumours a survival advantage?This review collates most of the recent information available about CTAs expression, function, and regulation. The data suggests a programme related to ontogenesis, mostly to gametogenesis. In the "brain-storming" part, facts in conflict with the hypothesis of random CTA gene activation are discussed. We propose a programme borrowed from organisms phylogenetically much older than humans, which ex...

Journal of andrology

Controversy exists over levels of DNA integrity in the sperm of fertile and infertile men. In add... more Controversy exists over levels of DNA integrity in the sperm of fertile and infertile men. In addition, the effect of leukocytospermia on sperm DNA in these 2 groups is unclear. We decided to address these questions by collecting semen samples from men known or presumed to be fertile and men from infertile couples. Samples were analyzed and assessed for sperm concentration, motility, and morphology. Samples failing to meet World Health Organization (WHO) standards in one or more of these parameters were judged abnormal. Samples were then arbitrarily assigned normalized scores in each of the above parameters, and scores were summed to give a normalized value for overall sperm quality. DNA abnormality was determined by an in situ DNA denaturation test with acridine orange and expressed as a percentage of cells with abnormal DNA integrity (ADI). Assessment of 187 samples revealed a moderate inverse correlation between ADI and sperm quality (r =.58), although a large degree of ADI dispe...

Journal of andrology

Tests were carried out on sperm from 40 fertile and infertile men to evaluate 2 DNA in situ denat... more Tests were carried out on sperm from 40 fertile and infertile men to evaluate 2 DNA in situ denaturation methods using acridine orange (AO; the modified Rigler-Roschlau method and the Tejada method), alongside routine aniline blue (AB) and toluidine blue (TB) tests in our modification, and in order to estimate and compare the practical value of different in situ cytochemical tests for sperm chromatin structure. In addition, the methods were applied to rat and boar spermiogenesis models. The sperm heads with abnormal versus normal chromatin structure were specified as orange-red versus green by the AO method, blue versus uncolored by the AB method, and purple-violet versus light blue by the TB method. A good correlation for the proportion of sperm heads with abnormal chromatin structure was found among all the methods (r = .63-.70; P < .01), which characterized all 4 techniques as sensitive enough to estimate in situ sperm DNA integrity. In our study, the average value of abnormal...

Journal of Aging Research, 2011

Endopolyploidy and genomic instability are shared features of both stress-induced cellular senesc... more Endopolyploidy and genomic instability are shared features of both stress-induced cellular senescence and malignant growth. Here, we examined these facets in the widely used normal human fibroblast model of senescence, IMR90. At the presenescence stage, a small (2-7%) proportion of cells overcome the 4n-G1 checkpoint, simultaneously inducing self-renewal (NANOG-positivity), the DNA damage response (DDR; γ-H2AX-positive foci), and senescence (p16inka4a-and p21CIP1-positivity) signalling, some cells reach octoploid DNA content and divide. All of these markers initially appear and partially colocalise in the perinucleolar compartment. Further, with development of senescence and accumulation of p16inka4a and p21CIP1, NANOG is downregulated in most cells. The cells increasingly arrest in the 4n-G1 fraction, completely halt divisions and ultimately degenerate. A positive link between DDR, self-renewal, and senescence signalling is initiated in the cells overcoming the tetraploidy barrier, indicating that cellular and molecular context of induced tetraploidy during this period of presenescence is favourable for carcinogenesis.

Evolutionary Biology from Concept to Application, 2008

Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withs... more Accelerated senescence of cancer stem cells (CSCs) represents an adaptive response allowing withstand cell death. TP53, the pivotal tumor suppressor plays an important role in this process by inducing a prolonged dual state with senescence and self-renewal as potential outcomes. Molecularly, this is achieved by activating both OCT4A (POU5F1) and p21CIP1. OCT4A suppresses the excessive activity of p21 preventing the immediate precipitation of apoptosis or terminal senescence. It persists as long as sufficient cellular energy remains; generated through autophagy, itself sequestrating p16INK4A in the cytoplasm. As such, autophagic capacity is the bottleneck of these TP53-dependent senescence reversal processes, as well terminal senescence will follow if DNA damage is not ultimately repaired. In TP53 mutants the CSC-like state is boosted by stressed cells overcoming the tetraploidy barrier. These cells acquire additional DNA repair capacity through mitotic slippage and entrance to a sequence of ploidy cycles, allowing repair and sorting DNA damage, ultimately facilitating the genesis of mitotically competent daughter cells following final depolyploidisa-tion. Again, autophagy is required to fuel this process. More detailed knowledge of these arcane processes anticipates the provision of anti-cancer drug targets, such as AURORA B kinase and Survivin, which ensure mitotic slippage and the continuity of ploidy cycles.

Mechanisms of Ageing and Development, 1999

Growth plate chondrocytes of embryonic chick femurs were examined by electron microscopy, cytopho... more Growth plate chondrocytes of embryonic chick femurs were examined by electron microscopy, cytophotometry and autoradiography. Apart from the well-described`light' chondrocyte, a different`dark' type of chondrocyte was present, comprising 10 ± 35% of the cell population. They were found at all stages of chondrocyte differentiation and in all ages of the femurs studied. Well developed rough endoplasmatic reticulum and Golgi complex, many secretory vesicles, energetically active mitochondria and a lot of glycogen, indicating high activity of the cytoplasm, were combined with low RNA synthesis, gentle margination and scattered compaction of the chromatin. DNA cytometry revealed that most of dark cells were diploid, but 15 ± 30% were tetraploid, with the absence of an S-phase. Substantial loss of DNA was found in about 10% of dark chondrocytes. The TUNEL reaction demonstrated a limited number of DNA strand breaks. Advanced dark cells possessed the nuclear features of both apoptosis and necrosis. Besides chromomeric-chromonemic compaction, a chromatin arrangement similar to that of prometaphase and metaphase, as well as amitotic nuclear segregation, all of them degenerative, were found. Our interpretation is that the dark chondrocytes undergo an aberrant type of cell death which may be combined with aberrant cell cycle. Cell death of dark chondrocytes is preceded by a pre-mortal burst of secretion.

Acta Histochemica, 1981

Rat liver and hepatoma cells fixed with formaldehyd e, e mbedded into Epon and treated on section... more Rat liver and hepatoma cells fixed with formaldehyd e, e mbedded into Epon and treated on sections with 5 n HCl and then with aqueous uranylacetate show preferential DNase-sensitive reaction. The reaction is highly d e pendent upon proper fixation, hydrolysis improves its specificity. The binding of the contl'astant with DNA is of ionic nature. B ecause of its simplicity, sufficient contrast and resolution the suggest ed technique is r eco mmended [or ultrastructural sturlies of D NA-containing substrates.

PloS one, 2015

The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue ... more The underlying mechanism of dynamic control of the genome-wide expression is a fundamental issue in bioscience. We addressed it in terms of phase transition by a systemic approach based on both density analysis and characteristics of temporal fluctuation for the time-course mRNA expression in differentiating MCF-7 breast cancer cells. In a recent work, we suggested criticality as an essential aspect of dynamic control of genome-wide gene expression. Criticality was evident by a unimodal-bimodal transition through flattened unimodal expression profile. The flatness on the transition suggests the existence of a critical transition at which up- and down-regulated expression is balanced. Mean field (averaging) behavior of mRNAs based on the temporal expression changes reveals a sandpile type of transition in the flattened profile. Furthermore, around the transition, a self-similar unimodal-bimodal transition of the whole expression occurs in the density profile of an ensemble of mRNA ex...

Indian journal of experimental biology

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences

Proceedings of the Latvian Academy of Sciences Section B Natural Exact and Applied Sciences

European journal of histochemistry: EJH

Currently we experience crisis of the concept on the origin of cancer. The reductionistic theory ... more Currently we experience crisis of the concept on the origin of cancer. The reductionistic theory of cancer origin from stochastic somatic mutations is stagnating and the best witness of its failure are the patients, which continue to die from advanced cancer. The concept of cancer stem cell (CSC), which appeared relatively recently as a complementation to somatic mutation theory needs to be put into the evolutionary biological context. This commentary is an attempt to return through CSC bridge to the most old embryological theory of cancer origin proposed in the 19th century. This theory postulates that immortality of cancer cells is achieved through the ontogenetic cycle of reproduction. It may represent the evolutionary primitive life-cycle which remained preserved in the genome memory of higher organisms and is recapitulated in their early embryogenesis and cancer.

Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a ... more Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for amechanism for genomere duction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the subcellular localisation of REC8 in the resulting ETCs.We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to...

Acta Crystallographica Section A Foundations of Crystallography, 2008

Cell Cycle, 2015

Tumour cellular senescence induced by genotoxic treatments has recently been found to be paradoxi... more Tumour cellular senescence induced by genotoxic treatments has recently been found to be paradoxically linked to the induction of "stemness". This observation is critical as it directly impinges upon the response of tumours to current chemoradio-therapy treatment regimens. Previously, we showed that following etoposide (ETO) treatment embryonal carcinoma PA-1 cells undergo a p53-dependent upregulation of OCT4A and p21Cip1 (governing self-renewal and regulating cell cycle inhibition and senescence, respectively). Here we report further detail on the relationship between these and other critical cell-fate regulators. PA-1 cells treated with ETO display highly heterogeneous increases in OCT4A and p21Cip1

Experimental oncology, 2014

Worldwide, breast cancer in women remains to be the most common malignancy that in a considerable... more Worldwide, breast cancer in women remains to be the most common malignancy that in a considerable proportion shows the resistance to genotoxic treatments and poor outcome. Chromosomal instability manifested as aneuploidy represents an integral cha-racteristics of the malignant genotype not only because of the selection of mutated aneuploid sub-clones that stipulate the tumor progression, but also because of the reversible endopolyploidy of tumor cells that serves for the endless maintenance of therapy-resistant tumor stem cells. Therefore, cytometric determination of DNA content in tissue samples for detecting malignancy, monitoring responses to therapy, and prognosing disease outcome needs to be revived. Both flow and image cytometry are most frequently used for generation of DNA content profiles (histograms), interpretation of which, however, may have some caveats. This review presents the major characterization criteria and analysis tools for breast cancer DNA histograms.

Cancer cell international, Jan 16, 2005

Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes - CTA)... more Genes expressed both in normal testis and in malignancies (Cancer/ Testis associated genes - CTA) have become the most extensively studied antigen group in the field of tumour immunology. Despite this, many fundamentally important questions remain unanswered: what is the connection between germ-cell specific genes and tumours? Is the expression of these genes yet another proof for the importance of genome destabilisation in the process of tumorigenesis?, or maybe activation of these genes is not quite random but instead related to some programme giving tumours a survival advantage?This review collates most of the recent information available about CTAs expression, function, and regulation. The data suggests a programme related to ontogenesis, mostly to gametogenesis. In the "brain-storming" part, facts in conflict with the hypothesis of random CTA gene activation are discussed. We propose a programme borrowed from organisms phylogenetically much older than humans, which ex...

Journal of andrology

Controversy exists over levels of DNA integrity in the sperm of fertile and infertile men. In add... more Controversy exists over levels of DNA integrity in the sperm of fertile and infertile men. In addition, the effect of leukocytospermia on sperm DNA in these 2 groups is unclear. We decided to address these questions by collecting semen samples from men known or presumed to be fertile and men from infertile couples. Samples were analyzed and assessed for sperm concentration, motility, and morphology. Samples failing to meet World Health Organization (WHO) standards in one or more of these parameters were judged abnormal. Samples were then arbitrarily assigned normalized scores in each of the above parameters, and scores were summed to give a normalized value for overall sperm quality. DNA abnormality was determined by an in situ DNA denaturation test with acridine orange and expressed as a percentage of cells with abnormal DNA integrity (ADI). Assessment of 187 samples revealed a moderate inverse correlation between ADI and sperm quality (r =.58), although a large degree of ADI dispe...

Journal of andrology

Tests were carried out on sperm from 40 fertile and infertile men to evaluate 2 DNA in situ denat... more Tests were carried out on sperm from 40 fertile and infertile men to evaluate 2 DNA in situ denaturation methods using acridine orange (AO; the modified Rigler-Roschlau method and the Tejada method), alongside routine aniline blue (AB) and toluidine blue (TB) tests in our modification, and in order to estimate and compare the practical value of different in situ cytochemical tests for sperm chromatin structure. In addition, the methods were applied to rat and boar spermiogenesis models. The sperm heads with abnormal versus normal chromatin structure were specified as orange-red versus green by the AO method, blue versus uncolored by the AB method, and purple-violet versus light blue by the TB method. A good correlation for the proportion of sperm heads with abnormal chromatin structure was found among all the methods (r = .63-.70; P < .01), which characterized all 4 techniques as sensitive enough to estimate in situ sperm DNA integrity. In our study, the average value of abnormal...

Journal of Aging Research, 2011

Endopolyploidy and genomic instability are shared features of both stress-induced cellular senesc... more Endopolyploidy and genomic instability are shared features of both stress-induced cellular senescence and malignant growth. Here, we examined these facets in the widely used normal human fibroblast model of senescence, IMR90. At the presenescence stage, a small (2-7%) proportion of cells overcome the 4n-G1 checkpoint, simultaneously inducing self-renewal (NANOG-positivity), the DNA damage response (DDR; γ-H2AX-positive foci), and senescence (p16inka4a-and p21CIP1-positivity) signalling, some cells reach octoploid DNA content and divide. All of these markers initially appear and partially colocalise in the perinucleolar compartment. Further, with development of senescence and accumulation of p16inka4a and p21CIP1, NANOG is downregulated in most cells. The cells increasingly arrest in the 4n-G1 fraction, completely halt divisions and ultimately degenerate. A positive link between DDR, self-renewal, and senescence signalling is initiated in the cells overcoming the tetraploidy barrier, indicating that cellular and molecular context of induced tetraploidy during this period of presenescence is favourable for carcinogenesis.

Evolutionary Biology from Concept to Application, 2008