Cancer Center Karolinska

Stockholm, Sweden

Cancer Center Karolinska

Stockholm, Sweden
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Wiman K.G.,Cancer Center Karolinska | Zhivotovsky B.,Karolinska Institutet | Zhivotovsky B.,Moscow State University
Journal of Internal Medicine | Year: 2017

Cell division, cell differentiation and cell death are the three principal physiological processes that regulate tissue homoeostasis in multicellular organisms. The growth and survival of cells as well as the integrity of the genome are regulated by a complex network of pathways, in which cell cycle checkpoints, DNA repair and programmed cell death have critical roles. Disruption of genomic integrity and impaired regulation of cell death may both lead to uncontrolled cell growth. Compromised cell death can also favour genomic instability. It is becoming increasingly clear that dysregulation of cell cycle and cell death processes plays an important role in the development of major disorders such as cancer, cardiovascular disease, infection, inflammation and neurodegenerative diseases. Research achievements in these fields have led to the development of novel approaches for treatment of various conditions associated with abnormalities in the regulation of cell cycle progression or cell death. A better understanding of how cellular life-and-death processes are regulated is essential for this development. To highlight these important advances, the Third Nobel Conference entitled ‘The Cell Cycle and Cell Death in Disease’ was organized at Karolinska Institutet in 2016. In this review we will summarize current understanding of cell cycle progression and cell death and discuss some of the recent advances in therapeutic applications in pathological conditions such as cancer, neurological disorders and inflammation. © 2017 The Association for the Publication of the Journal of Internal Medicine


Ligtenberg M.A.,Cancer Center Karolinska | Rojas-Colonelli N.,Laboratory of Gene Immunotherapy | Rojas-Colonelli N.,Andrés Bello University | Kiessling R.,Cancer Center Karolinska | And 2 more authors.
Human Vaccines and Immunotherapeutics | Year: 2013

DNA vaccines have been shown to elicit tumor-protective cytotoxic T lymphocyte (CTL) immunity in preclinical models, but have shown limited efficacy in cancer patients. Plasmids used for DNA vaccines can stimulate several innate immune receptors, triggering the activation of master transcription factors, including interferon regulatory factor 3 (IRF3) and nuclear factor k B (NF-kB). These transcription factors drive the production of type I interferons (IFNs) and pro-inflammatory cytokines, which promote the induction of CTL responses. Understanding the innate immune signaling pathways triggered by DNA vaccines that control the generation of CTL responses will increase our ability to design more effective vaccines. To gain insight into the contribution of these pathways, we vaccinated mice lacking different signaling components with plasmids encoding tyrosinase-related protein 2 (TRP2) or ovalbumin (OVA) using intradermal electroporation. Antigenspecific CTL responses were detected by intracellular IFN-7 staining and in vivo cytotoxicity. Mice lacking IRF3, IFN-a receptor, IL-1 p/IL-18, TLR9 or MyD88 showed similar CTL responses to wild-type mice, arguing that none of these molecules were required for the immunogenicity of DNA vaccines. To elucidate the role of NF-kB activation we co-vaccinated mice with pkBa-SR, a plasmid encoding a mutant IκBα that blocks NF-κB activity. Mice vaccinated with plκBα-SR and the TRP2-encoding plasmid (pTRP2) drastically reduced the frequencies of TRP2-specific CTLs and were unable to suppress lung melanoma metastasis in vivo, as compared with mice vaccinated only with pTRP2. Taken together these results indicate that the activation of NF-kB is essential for the immunogenicity of intradermal DNA vaccines. © 2013 Landes Bioscience.


Stalhammar G.,Karolinska Institutet | Stalhammar G.,Karolinska University Hospital | Rosin G.,Karolinska Institutet | Rosin G.,Cancer Center Karolinska | And 8 more authors.
Histopathology | Year: 2014

Aims: The aim of this study was to investigate in primary breast cancer the congruency of routine clinical predictive biomarker evaluations, including ER, PR and Ki67, obtained using immunocytochemistry (ICC) and immunohistochemistry (IHC). Methods and results: Clinicopathological data were collected on all women diagnosed with primary breast cancer at Karolinska University Hospital in 2011. A total of 346 patients were included in a retrospective paired comparison of predictive biomarker evaluations on direct smear ICC and IHC. This showed a low congruency between findings with the two methods, especially evident for Ki67 (κ = 0.35-0.42). By suggested adjustments to ICC cut-offs, we managed to improve the inter-rater agreement of Ki67 classification slightly to κ = 0.46. Conclusions: Our findings suggest that routine clinical ICC and IHC evaluations of predictive biomarkers produce discordant results. Consequently, basing therapeutic decisions on cytology with cut-offs defined for IHC induces a risk that patients will receive suboptimal therapy. However, our analysis shows that local adjustments to biomarker cut-off levels may improve congruency and increase the probability of correct classifications. © 2013 John Wiley & Sons Ltd.


Waraky A.,Cancer Center Karolinska | Akopyan K.,Karolinska Institutet | Parrow V.,Karolinska Institutet | Stromberg T.,Cancer Center Karolinska | And 7 more authors.
Oncotarget | Year: 2014

Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP.


D'Arcy P.,Cancer Center Karolinska | Maruwge W.,Cancer Center Karolinska | Wolahan B.,Cancer Center Karolinska | Ma L.,Cancer Center Karolinska | Brodin B.,Cancer Center Karolinska
PLoS ONE | Year: 2014

SSX is a transcription factor with elusive oncogenic functions expressed in a variety of human tumors of epithelial and mesenchymal origin. It has raised substantial interest as a target for cancer therapy since it elicits humoral responses and displays restricted expression to cancer, spermatogonia and mesenchymal stem cells. Here, we investigated the oncogenic properties of SSX by employing a RNA interference to knock-down the endogenous expression of SSX in melanoma and osteosarcoma cell lines. Depletion of SSX expression resulted in reduced proliferation with cells accumulating in the G1 phase of the cell cycle. We found that the growth promoting and survival properties of SSX are mediated in part though modulation of MAPK/Erk and Wnt signaling pathways, since SSX silencing inhibited Erk-mediated signaling and transcription of cMYC and Akt-1. We also found that SSX forms a transient complex with β-catenin at the G1-S phase boundary resulting in the altered expression of β-catenin target genes such as E-cadherin, snail-2 and vimentin, involved in epithelial- mesenchymal transitions. Importantly the silencing of SSX expression in in vivo significantly impaired the growth of melanoma tumor xenografts. Tumor biopsies from SSX silenced tumors displayed reduced cyclin A staining, indicative of low proliferation and predominantly cycloplasmic β-catenin compared to SSX expressing tumors. The present study demonstrates a previously unknown function of SSX, that as an oncogene and as a tumor target for the development of novel anti-cancer drugs. © 2014 D'Arcy et al.


Xie H.,Cancer Center Karolinska | Liu T.,Cancer Center Karolinska | Liu T.,Shandong University | Wang N.,Cancer Center Karolinska | And 5 more authors.
Oncotarget | Year: 2014

Telomerase activation through the induction of its catalytic component TERT is essential in carcinogenesis. The regulatory mechanism and clinical significance underlying cancer-specific TERT expression have been extensively investigated in various human malignancies, but little is known about these in Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin tumor. Here we addressed these issues by determining TERT promoter mutations, gene amplification, mRNA expression and association with clinical variables in MCC. TERT mRNA was expressed in 6/6 MCC cell lines and 41 of 43 tumors derived from 35 MCC patients. Telomerase activity was detectable in all 6 cell lines and 11 tumors analyzed. TERT promoter mutations were identified in 1/6 cell lines and 4/35 (11.4%) MCC cases. The mutation exhibited UV signature and occurred in sun-exposed areas. Increased TERT gene copy numbers were observed in 1/6 cell lines and 11/14 (79%) tumors, and highly correlated with its mRNA expression (r = 0.7419, P = 0.0024). Shorter overall survival was significantly associated with higher TERT mRNA levels in MCC patients (P = 0.032). Collectively, TERT expression and telomerase activity is widespread in MCC, and may be attributable to TERT promoter mutations and gene amplification. Higher TERT expression predicts poor patient outcomes.


Lichtenfels R.,Martin Luther University of Halle Wittenberg | Mougiakakos D.,Cancer Center Karolinska | Mougiakakos D.,Friedrich - Alexander - University, Erlangen - Nuremberg | Johansson C.C.,Cancer Center Karolinska | And 4 more authors.
PLoS ONE | Year: 2012

The clinical outcome of adoptive T cell transfer-based immunotherapies is often limited due to different escape mechanisms established by tumors in order to evade the hosts' immune system. The establishment of an immunosuppressive micromilieu by tumor cells along with distinct subsets of tumor-infiltrating lymphocytes is often associated with oxidative stress that can affect antigen-specific memory/effector cytotoxic T cells thereby substantially reducing their frequency and functional activation. Therefore, protection of tumor-reactive cytotoxic T lymphocytes from oxidative stress may enhance the anti-tumor-directed immune response. In order to better define the key pathways/proteins involved in the response to oxidative stress a comparative 2-DE-based proteome analysis of naïve CD45RA+ and their memory/effector CD45RO+ T cell counterparts in the presence and absence of low dose hydrogen peroxide (H2O2) was performed in this pilot study. Based on the profiling data of these T cell subpopulations under the various conditions, a series of differentially expressed spots were defined, members thereof identified by mass spectrometry and subsequently classified according to their cellular function and localization. Representative targets responding to oxidative stress including proteins involved in signaling pathways, in regulating the cellular redox status as well as in shaping/maintaining the structural cell integrity were independently verified at the transcript and protein level under the same conditions in both T cell subsets. In conclusion the resulting profiling data describe complex, oxidative stress-induced, but not strictly concordant changes within the respective expression profiles of CD45RA+ and CD45RO+ T cells. Some of the differentially expressed genes/proteins might be further exploited as potential targets toward modulating the redox capacity of the distinct lymphocyte subsets thereby providing the basis for further studies aiming at rendering them more resistant to tumor micromilieu-induced oxidative stress. © 2012 Lichtenfels et al.


Sundin M.,Karolinska University Hospital | Sundin M.,Astrid Lindgren Childrens Hospital | D'Arcy P.,Cancer Center Karolinska | Johansson C.C.,Cancer Center Karolinska | And 8 more authors.
Journal of Immunotherapy | Year: 2011

Multipotent mesenchymal stromal cells (MSCs) have immunosuppressive capacity but the exact mechanism by which they suppress proliferation of T lymphocytes is not fully understood. Recently, the characteristics and function of regulatory T lymphocytes (Tregs) have become better defined. Tregs and MSCs have immunosuppressive features in common. Here, we looked for a common basis for immunosuppression in these distinct cell types. Forkhead box P3 (FoxP3) and CD39 expression in MSCs was measured by flow cytometry and real-time quantitative polymerase chain reaction. The importance of FoxP3 in MSC-mediated immunosuppression was investigated by siRNA technology and mixed lymphocyte culture (MLC). The effect of 5-azacytidine and other immunosuppressive drugs on FoxP3 expression and immunosuppression by MSCs was explored by flow cytometry, MLC, and real-time quantitative polymerase chain reaction. MSCs express FoxP3 at variable levels, but they do not express CD39. FoxP3high MSCs suppress MLC to a greater extent than cells with lower FoxP3 expression. However, FoxP3-decreased MSCs were found to retain their immunosuppressive properties. 5-azacytitine had no effect on FoxP3 expression or MLC suppression by MSCs. However, immunosuppressive drugs led to increased FoxP3 levels and MLC inhibition in FoxP3 MSCs. This is the first demonstration of FoxP3 expression by MSCs. Although MSCs share several features with Tregs, and FoxP3low MSCs tend to be more immunosuppressive, MSCs do not require functional FoxP3 for their immunosuppressive activity. The increased MSC-mediated suppression of immune responses by immunosuppressive drugs deserves further investigation. © 2011 by Lippincott Williams and Wilkins.


PubMed | Cancer Center Karolinska, Karolinska Institutet, Visiopharm A S and Karolinska University Hospital
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

In the spectrum of breast cancers, categorization according to the four gene expression-based subtypes Luminal A, Luminal B, HER2-enriched, and Basal-like is the method of choice for prognostic and predictive value. As gene expression assays are not yet universally available, routine immunohistochemical stains act as surrogate markers for these subtypes. Thus, congruence of surrogate markers and gene expression tests is of utmost importance. In this study, 3 cohorts of primary breast cancer specimens (total n=436) with up to 28 years of survival data were scored for Ki67, ER, PR, and HER2 status manually and by digital image analysis (DIA). The results were then compared for sensitivity and specificity for the Luminal B subtype, concordance to PAM50 assays in subtype classification and prognostic power. The DIA system used was the Visiopharm Integrator System. DIA outperformed manual scoring in terms of sensitivity and specificity for the Luminal B subtype, widely considered the most challenging distinction in surrogate subclassification, and produced slightly better concordance and Cohens agreement with PAM50 gene expression assays. Manual biomarker scores and DIA essentially matched each other for Cox regression hazard ratios for all-cause mortality. When the Nottingham combined histologic grade (Elston-Ellis) was used as a prognostic surrogate, stronger Spearmans rank-order correlations were produced by DIA. Prognostic value of Ki67 scores in terms of likelihood ratio (2) (LR (2)) was higher for DIA that also added significantly more prognostic information to the manual scores (LR-(2)). In conclusion, the system for DIA evaluated here was in most aspects a superior alternative to manual biomarker scoring. It also has the potential to reduce time consumption for pathologists, as many of the steps in the workflow are either automatic or feasible to manage without pathological expertise.


PubMed | Cancer Center Karolinska, Shandong University, Karolinska University Hospital and Cancer Center Karolinska Contributed Equally To This Work
Type: Journal Article | Journal: Oncotarget | Year: 2014

Telomerase activation through the induction of its catalytic component TERT is essential in carcinogenesis. The regulatory mechanism and clinical significance underlying cancer-specific TERT expression have been extensively investigated in various human malignancies, but little is known about these in Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin tumor. Here we addressed these issues by determining TERT promoter mutations, gene amplification, mRNA expression and association with clinical variables in MCC. TERT mRNA was expressed in 6/6 MCC cell lines and 41 of 43 tumors derived from 35 MCC patients. Telomerase activity was detectable in all 6 cell lines and 11 tumors analyzed. TERT promoter mutations were identified in 1/6 cell lines and 4/35 (11.4%) MCC cases. The mutation exhibited UV signature and occurred in sun-exposed areas. Increased TERT gene copy numbers were observed in 1/6 cell lines and 11/14 (79%) tumors, and highly correlated with its mRNA expression (r = 0.7419, P = 0.0024). Shorter overall survival was significantly associated with higher TERT mRNA levels in MCC patients (P = 0.032). Collectively, TERT expression and telomerase activity is widespread in MCC, and may be attributable to TERT promoter mutations and gene amplification. Higher TERT expression predicts poor patient outcomes.

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