Papers by Panagiota Sotiropoulou
Cold Spring Harbor perspectives in biology, 2012
The skin epidermis is a stratified epithelium that forms a barrier that protects animals from deh... more The skin epidermis is a stratified epithelium that forms a barrier that protects animals from dehydration, mechanical stress, and infections. The epidermis encompasses different appendages, such as the hair follicle (HF), the sebaceous gland (SG), the sweat gland, and the touch dome, that are essential for thermoregulation, sensing the environment, and influencing social behavior. The epidermis undergoes a constant turnover and distinct stem cells (SCs) are responsible for the homeostasis of the different epidermal compartments. Deregulation of the signaling pathways controlling the balance between renewal and differentiation often leads to cancer formation.
British journal of cancer, Jan 15, 2003
HER-2/neu oncoprotein contains several major histocompatibility complex class I-restricted epitop... more HER-2/neu oncoprotein contains several major histocompatibility complex class I-restricted epitopes, which are recognised by cytotoxic T lymphocyte (CTL) on autologous tumours and therefore can be used in immune-based cancer therapies. Of these, the most extensively studied is HER-2(9(369)). In the present report, we used dendritic cells pulsed with HER-2(9(369)) to stimulate, in the presence of IL-7 and IL-12, the production of IFN-gamma by patients' CTL detected by the enzyme-linked immunosorbent spot-assay. Frequencies of peptide-specific precursors were estimated in HLA-A2, HLA-A3 and HLA-A26 patients with HER-2/neu-positive (+) breast, ovarian, lung, colorectal and prostate cancers and healthy individuals. We found increased percentages of such precursors in HLA-A2 (25%) and HLA-A26 (30%) patients, which were significantly higher (60%) in HLA-A3 patients. Our results demonstrate for the first time that pre-existing immunity to HER-2(9(369)) occurs in patients with colorecta...
British journal of cancer, Jan 16, 2001
HER2/neu-derived peptides inducing MHC class II-restricted CD4+ T helper lymphocyte (Th) response... more HER2/neu-derived peptides inducing MHC class II-restricted CD4+ T helper lymphocyte (Th) responses, although critical for tumour rejection, are not thoroughly characterized. Here, we report the generation and characterization of CD4+ T cell clones specifically recognizing a HER-2/neu-derived peptide (776-788) [designated HER2(776-788)]. Such clones yielded specific proliferative and cytokine [gamma-interferon(IFN)-gamma] responses when challenged with autologous dendritic cells (DCs) loaded with HER2(776-788). By performing blocking studies with monoclonal antibodies (MAbs) and by using DCs from allogeneic donors sharing certain HLA-DR alleles, we found that HER2(776-788) is a promiscuous peptide presented, at least, by DRB5*0101, DRB1*0701 and DRB1*0405 alleles. One TCRV beta 6.7+ clone recognized the HLA-DRB5*0101+ FM3 melanoma cell line transfected with a full length HER-2/neu cDNA. Moreover, this clone recognized the HER-2/neu+ SKBR3 breast cancer cell line induced to express HL...
Methods in Molecular Biology, 2007
The goal of this review is to summarize current knowledge on the immune properties of mesenchymal... more The goal of this review is to summarize current knowledge on the immune properties of mesenchymal stem cells (MSCs) and to discuss how these properties might affect clinical applications, in particular tissue regeneration. Mesenchymal Stem Cells (MSCs) are pluripotent cells with unique immune properties. They show immunoenhancing as well as immunosuppressive properties. It is the latter property that makes them stem cells of interest by scientists since they could be ideal for tissue regeneration, across allogeneic barrier. MSCs can transdifferentiate and differentiate into specialized cells. Although found mostly in the adult bone marrow, MSCs also reside in a variety of fetal tissues. In the adult bone marrow they act as "gatekeeper" cells regulating traffic in and out to the peripheral circulation and lymphatics. Their location within the vicinity of the bone marrow and periphery allows the MSCs, through their immune suppressor ability and antigen presenting property (APC) to maintain homeostasis in bone marrow function. There is potential for clinical therapy with MSCs. They have the potential to facilitate bone marrow transplantation by reducing graft-versus-host disease (GVHD). In addition, their immunosuppressive properties show promise for cell therapy across allogeneic barrier. Their role in the bone marrow, as it relates to hematological disorder is discussed.
The Journal of Cell Biology, 2013
Stem Cells, 2008
The maintenance of genome integrity in stem cells (SCs) is critical for preventing cancer formati... more The maintenance of genome integrity in stem cells (SCs) is critical for preventing cancer formation and cellular senescence. The immortal strand hypothesis postulates that SCs protect their genome by keeping the same DNA strand throughout life by asymmetrical cell divisions, thus avoiding accumulation of mutations that can arise during DNA replication. The in vivo relevance of this model remains to date a matter of intense debate. In this study, we revisited this long-standing hypothesis, by analyzing how multipotent hair follicle (HF) SCs segregate their DNA strands during morphogenesis, skin homeostasis, and SC activation. We used three different in vivo approaches to determine how HF SCs segregate their DNA strand during cell divisions. Double-labeling studies using pulse-chase experiments during morphogenesis and the first adult hair cycle showed that HF SCs incorporate two different nucleotide analogs, contradictory to the immortal strand hypothesis. The co-segregation of DNA and chromatin labeling during pulse-chase experiments demonstrated that label retention in HF SCs is rather a mark of relative quiescence. Moreover, DNA labeling of adult SCs, similar to labeling during morphogenesis, also resulted in label retention in HF SCs, indicating that chromosome segregation occurs randomly in most of these cells. Altogether, our results demonstrate that DNA strand segregation occurs randomly in the majority of HF SCs during development, tissue homeostasis, and following SC activation. STEM CELLS 2008;
Proceedings of the National Academy of Sciences, 2011
Nature Cell Biology, 2010
For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we... more For most types of cancers, the cell at the origin of tumour initiation is still unknown. Here, we used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequently occurring types of cancer in humans, and can result from the activation of the Hedgehog signalling pathway.
Nature Cell Biology, 2010
Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside... more Adult stem cells (SCs) are at high risk of accumulating deleterious mutations because they reside and self-renew in adult tissues for extended periods. Little is known about how adult SCs sense and respond to DNA damage within their natural niche. Here, using mouse epidermis as a model, we define the functional consequences and the molecular mechanisms by which adult SCs respond to DNA damage. We show that multipotent hair-follicle-bulge SCs have two important mechanisms for increasing their resistance to DNA-damage-induced cell death: higher expression of the anti-apoptotic gene Bcl-2 and transient stabilization of p53 after DNA damage in bulge SCs. The attenuated p53 activation is the consequence of a faster DNA repair activity, mediated by a higher non-homologous end joining (NHEJ) activity, induced by the key protein DNA-PK. Because NHEJ is an error-prone mechanism, this novel characteristic of adult SCs may have important implications in cancer development and ageing.
Nature, 2012
The skin interfollicular epidermis (IFE) is the first barrier against the external environment an... more The skin interfollicular epidermis (IFE) is the first barrier against the external environment and its maintenance is critical for survival. Two seemingly opposite theories have been proposed to explain IFE homeostasis. One posits that IFE is maintained by long-lived slow-cycling stem cells that give rise to transit-amplifying cell progeny, whereas the other suggests that homeostasis is achieved by a single committed progenitor population that balances stochastic fate. Here we probe the cellular heterogeneity within the IFE using two different inducible Cre recombinase–oestrogen receptor constructs targeting IFE progenitors in mice. Quantitative analysis of clonal fate data and proliferation dynamics demonstrate the existence of two distinct proliferative cell compartments arranged in a hierarchy involving slow-cycling stem cells and committed progenitor cells. After wounding, only stem cells contribute substantially to the repair and long-term regeneration of the tissue, whereas committed progenitor cells make a limited contribution.
The Journal of Immunology, 2008
HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggres... more HER-2/neu oncoprotein is overexpressed in a variety of human tumors and is associated with aggressive disease. Immunogenic HER-2/neu CTL epitopes have been used as vaccines for the treatment of HER-2/neu positive malignancies with limited success. By applying prediction algorithms for MHC class I ligands and proteosomal cleavages, in this study, we describe the identification of HER-2/neu decamer LIAHNQVRQV spanning residues 85-94 (HER-2(10 85 )). HER-2(10 85 ) proved to bind with high affinity to HLA-A2.1 and was stable for 4 h in an off-kinetics assay. This peptide was immunogenic in HLA-A2.1 transgenic (HHD) mice inducing peptide-specific CTL, which responded to tumor cell lines of various origin coexpressing human HER-2/neu and HLA-A2.1. This demonstrates that HER-2(10 85 ) is naturally processed from endogenous HER-2/neu. Five of sixteen HER-2/neu ؉ HLA-A2.1 ؉ breast cancer patients analyzed had HER-2(10 85 )-reactive T cells ranging from 0.35-0.70% of CD8 ؉ T cells. Depletion of T regulatory cells from PBMC enabled the rapid expansion of HLA-A2.1/HER-2(10 85 )pentamer ؉ /CD8 ؉ cells (PENT ؉ / CD8 ؉ ), whereas significantly lower numbers of CTL could be generated from unfractionated PBMC. HER-2(10 85 )-specific human CTL recognized the HER-2/neu ؉ HLA-A2.1 ؉ tumor cell line SKBR3.A2, as determined by IFN-␥ intracellular staining and in the high sensitivity CD107␣ degranulation assay. Finally, HER-2(10 85 ) significantly prolonged the survival of HHD mice inoculated with the transplantable ALC.A2.1.HER tumor both in prophylactic and therapeutic settings. These data demonstrate that HER-2(10 85 ) is an immunogenic peptide, capable of eliciting CD8-mediated responses in vitro and in vivo, providing the platform for further exploitation of HER-2(10 85 ) as a possible target for anticancer immunotherapy.
Journal of Biological Chemistry, 2005
The coding region determinant-binding protein/insulin-like growth factor II mRNA-binding protein ... more The coding region determinant-binding protein/insulin-like growth factor II mRNA-binding protein (CRD-BP/IMP1) is an RNA-binding protein specifically recognizing c-myc, leader 3 IGF-II and tau mRNAs, and the H19 RNA. CRD-BP/IMP1 is predominantly expressed in embryonal tissues but is de novo activated and/or overexpressed in various human neoplasias. To address the question of whether CRD-BP/IMP1 expression characterizes certain cell types displaying distinct proliferation and/or differentiation properties (i.e. stem cells), we isolated cell subpopulations from human bone marrow, mobilized peripheral blood, and cord blood, all sources known to contain stem cells, and monitored for its expression. CRD-BP/IMP1 was detected only in cord bloodderived CD34 ؉ stem cells and not in any other cell type of either adult or cord blood origin. Adult BM CD34 ؉ cells cultured in the presence of 5-azacytidine expressed de novo CRD-BP/IMP1, suggesting that epigenetic modifications may be responsible for its silencing in adult non-expressing cells. Furthermore, by applying the short interfering RNA methodology in MCF-7 cells, we observed, subsequent to knocking down CRD-BP/ IMP1, decreased c-myc expression, increased IGF-II mRNA levels, and reduced cell proliferation rates. These data 1) suggest a normal role for CRD-BP/IMP1 in pluripotent stem cells with high renewal capacity, like the CB CD34 ؉ cells, 2) indicate that altered methylation may directly or indirectly affect its expression in adult cells, 3) imply that its de novo activation in cancer cells may affect the expression of c-Myc and insulin-like growth factor II, and 4) indicate that the inhibition of CRD-BP/ IMP1 expression might affect cancer cell proliferation.
International Immunology, 2005
IL-21 plays a role in the proliferation and maturation of NK cells developed from hematopoietic s... more IL-21 plays a role in the proliferation and maturation of NK cells developed from hematopoietic stem cells. In this study, we found that IL-21, in the presence of physiological concentration of hydrocortisone (HC), has a significant impact on the functions of NK cells derived from umbilical cord blood (CB) populations. We demonstrate that IL-21, in combination with Flt3-ligand, IL-15 and HC, induces high proliferative responses and, apart from enhancing NK-mediated cytotoxicity, it also induces a significant increase in lymphokine-activated killer activity of CB/CD34 1 -derived CD56 1 cells. In addition, IL-21 induced changes in the CD56 1 cell cytokine secretion profile. Thus, we observed increased levels of IL-10 and granulocyte macrophage colony-stimulating factor, whereas tumor necrosis factor-a levels decreased. IFN-c production was also modified by IL-21, depending on the presence or absence of IL-18. CB/CD34 1 cells did not express the IL-21R ex vivo, but receptor expression was induced during their commitment to differentiation into CD56 1 cells. Our data ascribe to IL-21 an essential role on NK cell development and function under conditions similar to the in vivo CB microenvironment.
Genes & Development, 2013
The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation o... more The accurate maintenance of genomic integrity is essential for tissue homeostasis. Deregulation of this process leads to cancer and aging. BRCA1 is a critical mediator of this process. Here, we performed conditional deletion of Brca1 during epidermal development and found that BRCA1 is specifically required for hair follicle (HF) formation and for development of adult HF stem cells (SCs). Mice deficient for Brca1 in the epidermis are hairless and display a reduced number of HFs that degenerate progressively. Surprisingly, the interfollicular epidermis and the sebaceous glands remain unaffected by Brca1 deletion. Interestingly, HF matrix transient amplifying progenitors present increased DNA damage, p53 stabilization, and caspase-dependent apoptosis compared with the interfollicular and sebaceous progenitors, leading to hyperproliferation, apoptosis, and subsequent depletion of the prospective adult HF SCs. Concomitant deletion of p53 and Brca1 rescues the defect of HF morphogenesis and loss of HF SCs. During adult homeostasis, BRCA1 is dispensable for quiescent bulge SCs, but upon their activation during HF regeneration, Brca1 deletion causes apoptosis and depletion of Brca1-deficient bulge SCs. Our data reveal a major difference in the requirement of BRCA1 between different types of epidermal SCs and progenitors and during the different activation stages of adult HF SCs.
Europace, 2007
Aims Autologous stem cell transplantation has been successfully used for repair of infarcted myoc... more Aims Autologous stem cell transplantation has been successfully used for repair of infarcted myocardium, but concerns have been raised regarding its pro-arrhythmic potential. This study aimed at using electrophysiological assessment, and the monitoring and data storage capacity of implanted cardioverter defibrillators (ICDs), in order to evaluate the possible proarrhythmic potential of stem cell transplantation.
Cell Stem Cell, 2011
Recent studies have shown that tissue-specific stem cells (SCs) found throughout the body respond... more Recent studies have shown that tissue-specific stem cells (SCs) found throughout the body respond differentially to DNA damage. In this review, we will discuss how different SC populations sense and functionally respond to DNA damage, identify various common and distinct mechanisms utilized by tissue-specific SCs to address DNA damage, and describe how these mechanisms can impact SC genomic integrity by potentially promoting aging, tissue atrophy, and/or cancer development. Finally, we will discuss how similar mechanisms operate in cancer stem cells (CSCs) and can mediate resistance to chemo-and radiotherapy.
Cancer Immunology, Immunotherapy, 2004
HER-2/neu (also known as HER2 or c-erb-B2) is a 185-kDa protein receptor with tyrosine kinase act... more HER-2/neu (also known as HER2 or c-erb-B2) is a 185-kDa protein receptor with tyrosine kinase activity and extensive homology to the epidermal growth factor (EGF) receptor. HER-2/neu is expressed in many epithelial tumors and known to be overexpressed in approximately 20-25% of all ovarian and breast cancers, 35-45% of all pancreatic adenocarcinomas, and up to 90% of colorectal carcinomas. HER-2/neu overexpression represents a marker of poor prognosis. HER-2/ neu-positive tumor cells are potentially good targets for tumor-reactive cytotoxic T lymphocytes which have been utilized in immunotherapeutic trials. In addition, the ''humanized'' monoclonal antibody Herceptin has been tested in several clinical trials and proved to be an effective adjuvant therapy for HER-2/neu-positive breast and ovarian cancers. Vaccinations aiming at generating T-cell responses are being examined in both experimental and clinical trials. Natural immunity at the level of T and B cells has been observed in patients with HER-2/neu-positive tumors confirming the immunogenicity of HER-2/neu and encouraging vaccination trials with HER-2 protein-derived subunits or synthetic peptides. This review summarizes recent data from patients with various types of HER-2/neu-overexpressing cancers carrying different HLA alleles and exhibiting preexistent immunity to HER-2/neu-derived synthetic peptides. It also discusses potential advantages of the various vaccination approaches to immunotherapy targeting the HER-2/neu molecule.
Blood, 2005
Although glucocorticoids (GCs) have been described as acting mainly as antiinflammatory and immun... more Although glucocorticoids (GCs) have been described as acting mainly as antiinflammatory and immunosuppressive drugs, they may also positively influence the immune system. In the present study, we demonstrate for the first time that hydrocortisone (HC), in synergy with interleukin-15 (IL-15), induces a dramatic increase in the expansion of peripheral blood-derived CD56 ؉ cells, favoring the preferential outgrowth of classical natural killer (CD56 ؉ CD3 ؊ NK) over CD56 ؉ CD3 ؉ natural killer T (NKT) cells. HC plus IL-15-driven CD56 ؉ cells exhibited an increased potential for cytokine production with no impairment in their NK-and lymphokine-activated killer
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Papers by Panagiota Sotiropoulou