Pavel Sova

Wisconsin National Primate Research Center, Madison, Wisconsin, United States

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Publications (23)119.47 Total impact

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    ABSTRACT: HIV-1 replication requires the insertion of viral DNA into the host genome, which is catalyzed by HIV-1 integrase. This integration event can lead to vast changes in the chromatin landscape and gene transcription. In this study, we sought to correlate the extensive changes of histone post-translation modification (PTM) abundances with the equally dynamic shifts in host transcriptional activity. To fully capture the changes that were occurring during the course of HIV-infection, we performed time-courses in which we extracted both histones and mRNA from HIV-infected, UV-inactivated HIV-infected and mock-infected SUP-T1 cells. We then analyzed the alterations to histone PTM profiles using nanoLC-MS/MS, as well as the expression of chromatin-associated enzymes, such as histone deacetylases, acetyltransferases, demethylases, methyltransferases and histone chaperone proteins. As expected, we observed major changes in histone PTM abundances, which we linked to massive fluctuations in mRNA expression of associated chromatin enzymes. However, we find few differences between HIV and HIVUV (UV-inactivated) infection, which suggests that initial histone PTM changes during HIV infection are from the host in response to the infection, and not due to the HIV virus manipulating the transcriptional machinery. We believe that these preliminary experiments can provide a basis for future forays into targeted manipulations of histone PTM-regulated aspects of HIV progression through its replication cycle.This article is protected by copyright. All rights reserved
    Proteomics 08/2014; · 4.43 Impact Factor
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    ABSTRACT: Polyadenylated mature mRNAs are the focus of standard transcriptome analyses. However, the profiling of nascent transcripts, which often include non-polyadenylated RNAs, can unveil novel insights into transcriptional regulation. Here, we separately sequenced Total RNAs (Total RNAseq) and mRNAs (mRNAseq) from the same HIV-1 infected human CD4+ T cells. We found that many non-polyadenylated RNAs were differentially expressed upon HIV-1 infection, and we identified 8 times more differentially expressed genes at 12 hours post-infection by Total RNAseq than by mRNAseq. These expression changes were also evident by concurrent changes in introns and were recapitulated by later mRNA changes, revealing an unexpectedly significant delay between transcriptional initiation and mature mRNA production early after HIV-1 infection. We computationally derived and validated the underlying regulatory programs, and we predicted drugs capable of reversing these HIV-1 induced expression changes followed by experimental confirmation. Our results show that combined total and mRNA transcriptome analysis is essential for fully capturing the early host response to virus infection and provide a framework for identifying candidate drugs for host-directed therapy against HIV/AIDS.
    Journal of virology. 05/2014;
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    ABSTRACT: ABSTRACT HIV infection of CD4(+) T cells induces a range of host transcriptional changes in mRNAs as well as microRNAs that may coordinate changes in mRNAs. To survey these dynamic changes, we applied next-generation sequencing, analyzing the small RNA fraction of HIV-infected cells at 5, 12, and 24 h postinfection (RNA-Seq). These time points afforded a view of the transcriptomic changes occurring both before and during viral replication. In the resulting small RNA-Seq data set, we detected a phased pattern of microRNA expression. Largely distinct sets of microRNAs were found to be suppressed at 5 and 12 h postinfection, and both sets of changes rebounded later in infection. A larger set of microRNA changes was observed at 24 h postinfection. When integrated with mRNA expression data, the small RNA-Seq data indicated a role for microRNAs in transcriptional regulation, T cell activation, and cell cycle during HIV infection. As a unique benefit of next-generation sequencing, we also detected candidate novel host microRNAs differentially expressed during infection, including one whose downregulation at 24 h postinfection may allow full replication of HIV to proceed. Collectively, our data provide a uniquely comprehensive view of the changes in host microRNAs induced by HIV during cellular infection. IMPORTANCE New sequencing technologies allow unprecedented views into changes occurring in virus-infected cells, including comprehensive and largely unbiased measurements of different types of RNA. In this study, we used next-generation sequencing to profile dynamic changes in cellular microRNAs occurring in HIV-infected cells. The sensitivity afforded by sequencing allowed us to detect changes in microRNA expression early in infection, before the onset of viral replication. A phased pattern of expression was evident among these microRNAs, and many that were initially suppressed were later overexpressed at the height of infection, providing unique signatures of infection. By integrating additional mRNA data with the microRNA data, we identified a role for microRNAs in transcriptional regulation during infection and specifically a network of microRNAs involved in the expression of a known HIV cofactor. Finally, as a distinct benefit of sequencing, we identified candidate nonannotated microRNAs, including one whose downregulation may allow HIV-1 replication to proceed fully.
    mBio 01/2013; 4(1). · 6.88 Impact Factor
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    ABSTRACT: ABSTRACT A novel human coronavirus (HCoV-EMC) was recently identified in the Middle East as the causative agent of a severe acute respiratory syndrome (SARS) resembling the illness caused by SARS coronavirus (SARS-CoV). Although derived from the CoV family, the two viruses are genetically distinct and do not use the same receptor. Here, we investigated whether HCoV-EMC and SARS-CoV induce similar or distinct host responses after infection of a human lung epithelial cell line. HCoV-EMC was able to replicate as efficiently as SARS-CoV in Calu-3 cells and similarly induced minimal transcriptomic changes before 12 h postinfection. Later in infection, HCoV-EMC induced a massive dysregulation of the host transcriptome, to a much greater extent than SARS-CoV. Both viruses induced a similar activation of pattern recognition receptors and the interleukin 17 (IL-17) pathway, but HCoV-EMC specifically down-regulated the expression of several genes within the antigen presentation pathway, including both type I and II major histocompatibility complex (MHC) genes. This could have an important impact on the ability of the host to mount an adaptive host response. A unique set of 207 genes was dysregulated early and permanently throughout infection with HCoV-EMC, and was used in a computational screen to predict potential antiviral compounds, including kinase inhibitors and glucocorticoids. Overall, HCoV-EMC and SARS-CoV elicit distinct host gene expression responses, which might impact in vivo pathogenesis and could orient therapeutic strategies against that emergent virus. IMPORTANCE Identification of a novel coronavirus causing fatal respiratory infection in humans raises concerns about a possible widespread outbreak of severe respiratory infection similar to the one caused by SARS-CoV. Using a human lung epithelial cell line and global transcriptomic profiling, we identified differences in the host response between HCoV-EMC and SARS-CoV. This enables rapid assessment of viral properties and the ability to anticipate possible differences in human clinical responses to HCoV-EMC and SARS-CoV. We used this information to predict potential effective drugs against HCoV-EMC, a method that could be more generally used to identify candidate therapeutics in future disease outbreaks. These data will help to generate hypotheses and make rapid advancements in characterizing this new virus.
    mBio 01/2013; 4(3). · 6.88 Impact Factor
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    ABSTRACT: Human immunodeficiency virus (HIV-1) depends upon host-encoded proteins to facilitate its replication while at the same time inhibiting critical components of innate and/or intrinsic immune response pathways. To characterize the host cell response on protein levels in CD4+ lymphoblastoid SUP-T1 cells after infection with HIV-1 strain LAI, we used mass spectrometry (MS)-based global quantitation with iTRAQ (isobaric tag for relative and absolute quantification). We found 266, 60 and 22 proteins differentially expressed (DE) (P-value ≤ 0.05) at 4, 8, and 20 hours post-infection (hpi), respectively, compared to time-matched mock-infected samples. The majority of changes in protein abundance occurred at an early stage of infection well before the de novo production of viral proteins. Functional analyses of these DE proteins showed enrichment in several biological pathways including protein synthesis, cell proliferation, and T-cell activation. Importantly, these early changes before the time of robust viral production have not been described before.
    Virology 04/2012; 429(1):37-46. · 3.35 Impact Factor
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    ABSTRACT: DNA methylation analysis is emerging as a new technique with potential capabilities for early cancer detection. However, current state-of-the-art techniques are not easily translatable into routine clinical methods. Herein we describe a bead-based flow cytometry assay which combines DNA hybridization to microparticles with 5MeC-specific proteins/antibodies. These assays can be used to study the binding properties of current and emerging 5MeC-binding proteins and may also have potential in the measurement of 5MeC density in clinical samples for cancer detection.
    The Analyst 02/2011; 136(4):688-91. · 4.23 Impact Factor
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    ABSTRACT: In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy.
    PLoS ONE 01/2011; 6(1):e16186. · 3.53 Impact Factor
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    ABSTRACT: [This corrects the article on p. e16186 in vol. 6.].
    PLoS ONE 01/2011; 6(2). · 3.53 Impact Factor
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    ABSTRACT: Next-generation sequencing (NGS) enables the highly sensitive measurement of whole transcriptomes. We report the first application to our knowledge of this technology to the analysis of RNA from a CD4+ T cell line infected with intact HIV. We sequenced the total mRNA from infected cells and detected differences in the expression of both host and viral mRNA. Viral reads represented a large portion of the total mapped sequencing reads: approximately 20% at 12 h postinfection (hpi) and 40% at 24 hpi. We also detected a small but significant suppression of T cell activation-related genes at 12 hpi. This suppression persisted and expanded by 24 hpi, providing new possible markers of virus-induced T cell cytopathology. By 24 hpi, the expression of over 50% of detectable host loci was also altered, indicating widespread alteration of host processes, including RNA processing, splicing, and transport to an extent not previously reported. In addition, next-generation sequencing provided insights into alternative viral RNA splice events and the expression of noncoding RNAs, including microRNA host genes. IMPORTANCE: Recent advances in sequencing technology now allow the measurement of effectively all the RNA in a cell. This approach is especially useful for studying models of virus infection, as it allows the simultaneous measurement of both host and viral RNA. Using next-generation sequencing (NGS), we measured changes in total mRNA from a HIV-infected T cell line. To our knowledge, this is the first application of this technology to the investigation of HIV-host interactions involving intact HIV. We directly measured the amount of viral mRNA in infected cells and detected novel viral RNA splice variants and changes in the host expression of noncoding RNA species. We also detected small changes in T cell activation and other host processes during the early stages of viral replication that increased near the peak of viral replication, providing new candidate biomarkers of T cell death.
    mBio 01/2011; 2(5). · 6.88 Impact Factor
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    ABSTRACT: We studied the susceptibility of primary ovarian cancer cells to oncolytic adenoviruses. Using gene expression profiling of cancer cells either resistant or susceptible to viral oncolysis, we discovered that the epithelial phenotype of ovarian cancer represents a barrier to infection by commonly used oncolytic adenoviruses targeted to coxsackie-adenovirus receptor or CD46. Specifically, we found that these adenovirus receptors were trapped in tight junctions and not accessible for virus binding. Accessibility to viral receptors was critically linked to depolarization and the loss of tight and adherens junctions, both hallmarks of epithelial-to-mesenchymal transition (EMT). We showed that specific, thus far little-explored adenovirus serotypes (Ad3, Ad7, Ad11, and Ad14) that use receptor(s) other than coxsackie-adenovirus receptor and CD46 were able to trigger EMT in epithelial ovarian cancer cells and cause efficient oncolysis. Our studies on ovarian cancer cultures and xenografts also revealed several interesting cancer cell biology features. Tumors in situ as well as tumor xenografts in mice mostly contained epithelial cells and cells that were in a hybrid stage where they expressed both epithelial and mesenchymal markers (epithelial/mesenchymal cells). These epithelial/mesenchymal cells are the only xenograft-derived cells that can be cultured and with passaging undergo EMT and differentiate into mesenchymal cells. Our study provides a venue for improved virotherapy of cancer as well as new insights into cancer cell biology.
    Cancer Research 07/2009; 69(12):5115-25. · 9.28 Impact Factor
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    ABSTRACT: Herein we report a method for the detection of methylated CpG dinucleotides located within CpG islands in genomic DNA using multiplexed bead-based assays and standard flow cytometry instrumentation. Four CpG "clusters" were identified in the TFPI2 and SPARC CpG islands whose methylation status was highly correlated with the incidence of invasive cervical cancer in our previous studies. Eight probes in total were designed for both the methylated and unmethylated forms of each cluster and attached to different fluorescently-encoded organosilica bead sets. Probe design was investigated by changing either the length of probes whilst keeping the melting temperature constant, or changing the melting temperature and keeping the probe length constant. Asymmetric polymerase chain reaction (PCR) methods designed without methylation-specific primers were used to prepare fluorescently-labelled targets based on bisulfite-converted genomic DNA. After investigating the specificity of the probes in a model system using fluorescently-labelled synthetic oligonucleotides, cancer cell-line DNA was analysed and the constant length probe design facilitated the correct genotyping of all clusters with respect to negative controls.
    Molecular BioSystems 04/2009; 5(3):262-8. · 3.35 Impact Factor
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    ABSTRACT: We constructed helper-dependent, fiber-chimeric adenoviral vectors that efficiently transduce human hematopoietic stem cells. We found that vectors carrying a 23-kb fragment of the beta-globin locus control region (LCR) flanked by adeno-associated virus inverted terminal repeats (Ad.LCR) preferentially integrated into the chromosomal beta-globin LCR of human erythroid Mo7e cells. We hypothesized that this targeted integration involves beta-globin LCR-specific chromatin structures. Chromatin immunoprecipitation assays of the beta-globin LCR revealed active chromatin within, and immediately downstream of, DNase hypersensitivity region 2 (HS2) in erythroid Mo7e cells, but not in nonerythroid cells. Importantly, most of the Ad.LCR integrations in Mo7e cells were found within this area. We provide further data indicating tethering of incoming Ad.LCR genomes to the chromosomal LCR. We also provide data that suggest a role for active chromatin in AAV Rep78-mediated Ad.LCR integration. Our findings support a new strategy for achieving targeted integration through chromatin tethering of vector DNA.
    Human Gene Therapy 03/2008; 19(2):153-66. · 4.02 Impact Factor
  • Blood Cells Molecules and Diseases - BLOOD CELLS MOLECULES DIS. 01/2008; 40(2):273-274.
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    ABSTRACT: We examined the feasibility of using detection of high-risk human papillomavirus (HPV) DNA in combination with the presence of aberrantly methylated genes (DAPK1, RARB, TWIST1, and CDH13) for urine-based cervical cancer screening. Urine samples from 129 Senegalese women, aged 35 years or older, 110 with (same day) biopsy-proven cervical neoplasia [cervical intraepithelial neoplasia grade 1 (CIN-1): n = 9; CIN-2-3/carcinoma in situ (CIS): n = 29; invasive cervical cancer (ICC): n = 72], and 19 without cervical neoplasia on biopsy were examined. Hypermethylation of at least one of the four genes identified 62% of ICC and 28% of CIN-2-3/CIS and was present in only 4% of CIN-1 or normal urines. High-risk HPV DNA was detected in urine in 70% of those with biopsy-proven ICC, 59% of those with CIN-2-3/CIS on biopsy, 44% of those with CIN-1 on biopsy, and only 11% of women negative for cervical neoplasia on biopsy. Urine-based detection of either high-risk HPV or hypermethylation of any of the four genes identified 84% of ICC, 64% of CIN-2-3/CIS, 44% of CIN-1, but only 19% of women negative for cervical neoplasia. The sensitivity for detection of CIN-2-3/CIS/ICC by high-risk HPV DNA or aberrant DNA methylation of four genes seems to be comparable to that of an exfoliated cervical cytology. This study shows the potential feasibility of using molecular markers detected in urine for cervical cancer screening.
    Cancer Epidemiology Biomarkers &amp Prevention 07/2007; 16(6):1178-84. · 4.56 Impact Factor
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    ABSTRACT: There is growing evidence from in vitro studies that subgroup B adenoviruses (Ad) can overcome the limitations in safety and tumor transduction efficiency seen with commonly used subgroup C serotype 5-based vectors. In this study, we confirm that the expression level of the B-group Ad receptor, CD46, correlates with the grade of malignancy of cervical cancer in situ. We also demonstrate the in vivo properties of Ad5-based vectors that contain the B-group Ad serotype 35 fiber (Ad5/35) in transgenic mice that express CD46 in a pattern and at a level similar to humans. Upon intravenous and intraperitoneal injection, an Ad5/35 vector did not efficiently transduce normal tissue, but was able to target metastatic or intraperitoneal tumors that express CD46 at levels comparable to human tumors. When an oncolytic Ad5/35-based vector was employed, in both tumor models antitumor effects were observed. Furthermore, injection of Ad5/35 vectors into CD46 transgenic mice caused less innate toxicity than Ad5 vectors. Our data demonstrate that Ad vectors that target CD46 offer advantages over Ad5-based vectors for treatment of cancer.
    Cancer Gene Therapy 01/2007; 13(12):1072-81. · 2.95 Impact Factor
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    ABSTRACT: Molecular Therapy (2006) 13, S299|[ndash]|S300; doi: 10.1016/j.ymthe.2006.08.860 774. Evaluation of Adenovirus Vectors Containing Serotype 35 Fibers for Gene Therapy of Cervical Cancer Ying Liu1, Pavel Sova2, Robert Strauss1, Sebastian Tuve1, Janice Morihara2, Nancy Kiviat2, Papa Toure3, Salif Sow3 and Andre Lieber1,21Division of Medical Genetics, University of Washington, Seattle, WA2Department of Pathology, University of Washington, Seattle, WA3Department of Infectious Diseases, University of Dakar, Dakar, Senegal
    Molecular Therapy 04/2006; · 7.04 Impact Factor
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    ABSTRACT: Molecular Therapy (2006) 13, S18|[ndash]|S18; doi: 10.1016/j.ymthe.2006.08.056 42. Resistance of Primary Ovarian Cancer Cells to Viral Oncolysis Robert Strauss1, Pavel Sova2, Ying Liu1, Zong Yi Li1, Nicole Urban3, Charles Drescher3, Nancy Kiviat2 and Andre Lieber1,21Division of Medical Genetics, University of Washington, Seattle, WA2Department of Pathology, University of Washington, Seattle, WA3Fred Hutchinson Cancer Research Center, Seattle, WA
    Molecular Therapy 04/2006; · 7.04 Impact Factor
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    ABSTRACT: A genome-wide screening study for identification of hypermethylated genes in invasive cervical cancer (ICC) was carried out to augment our previously discovered panel of three genes found to be useful for detection of ICC and its precursor neoplasia. Putatively hypermethylated and silenced genes were reactivated in four ICC cell lines by treatment with 5-aza-2'-deoxycytidine and trichostatin A and identified on expression microarrays. Thirty-nine of the 235 genes up-regulated in multiple ICC cell lines were further examined to determine the methylation status of associated CpG islands. The diagnostic use of 23 genes that were aberrantly methylated in multiple ICC cell lines were then analyzed in DNA from exfoliated cells obtained from patients with or without ICC. We show, for the first time, that aberrant methylation of six genes (SPARC, TFPI2, RRAD, SFRP1, MT1G, and NMES1) is present in a high proportion of ICC clinical samples but not in normal samples. Of these genes, SPARC and TFPI2 showed the highest frequency of aberrant methylation in ICC specimens (86.4% for either) and together were hypermethylated in all but one ICC cases examined. We conclude that expression profiling of epigenetically reactivated genes followed by methylation analysis in clinical samples is a powerful tool for comprehensive identification of methylation markers. Several novel genes identified in our study may be clinically useful for detection or stratification of ICC and/or of its precursor lesions and provide a basis for better understanding of mechanisms involved in development of ICC.
    Cancer Epidemiology Biomarkers &amp Prevention 02/2006; 15(1):114-23. · 4.56 Impact Factor
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    ABSTRACT: Chromatin immunoprecipitation (ChIP) is a widely used method to explore in vivo interactions between proteins and DNA. The ChIP assay takes several days to complete, involves several tube transfers and uses either phenol-chlorophorm or spin columns to purify DNA. The traditional ChIP method becomes a challenge when handling multiple samples. We have developed an efficient and rapid Chelex resin-based ChIP procedure that dramatically reduces time of the assay and uses only a single tube to isolate PCR-ready DNA. This method greatly facilitates the probing of chromatin changes over many time points with several antibodies in one experiment.
    Nucleic Acids Research 02/2006; 34(1):e2. · 8.81 Impact Factor
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    ABSTRACT: Cancer stem cells, e.g. cells with a capacity to self-renew and undergo pluripotential differentiation, have been identified in malignancies of hematopoietic origin and in solid breast and brain tumors. We have established primary cultures from 40 ovarian cancer biopsies. After in vitro culture, tumor cells were expanded in immunodeficient mice. Cells from an explanted xenograft were then cloned. Of these clones, 40% contained subsets of cells with different morphology, size, and expression of surface markers, indicating that the cells from which these clones originated were pluripotent. When injected into mice, clonal cultures formed tumors with different histological components that stained with surface markers for human cells. Among the histological features were poorly differentiated malignant cells and structures that resemble the ovarian follicles. The ability of a clonal culture to give rise to different phenotypes further indicates the presence of pluripotent stem cells. Tumors also had clearly developed ECM and vasculature derived from mouse tissue. We then attempted to separate different cell fractions from clonal cultures with polymorphic morphology using FACS for marker expression. Immediately after sorting, different fractions were separated into three parts: i) cells were set aside for RNA isolation and expression array studies, ii) cells were subjected to clonogeneic assays and the percentage of polymorphic colonies that developed was used as a parameter to assess whether a given subfraction contains pluripotent cells. iii) different cell numbers of each fraction were injected into mice and tumor formation and histology was monitored. Among the markers used for sorting were tumor-associated antigens (CEA, CA125, HE-4), epithelial cell markers (CD44, CD133. αvβ3, ESA, AE1/AE3), embryonic stem cell markers (laminin receptor), and hematopietic stem cell markers (SLAM receptors, aldehyde dehydrogenase). We also sorted cells based on their ability to exclude the fluorescent dye Hoechst 33342. [It is thought that hematopoietic stem cells reside in a Hoechst 33342 negative side population (SP) based on a high activity of ATP-binding cassette drug transporters such as ABCG2.] We found that the fraction of ovarian cancer SP cells contained the highest percentage of pluripotent cells among all fractions analyzed. Other fractions that were enriched for pluripotent stem cells included the fractions of small cells, of cells that were relatively resistant to trypsin, and of cells that were ALDH-/low. Notably, markers that have been described for breast or brain cancer stem cells, such as CD133 and CD44, did not discriminate cell fractions containing pluripotent cells. Furthermore, putative ovarian cancer stem cells were negative for CD31 and CD45 but expressed high levels of the B-group adenovirus receptor CD46. We are currently analyzing expression microarray data from different sorted cell fractions for new markers for ovarian cancer stem cells and the results will be presented.
    Molecular Therapy 01/2006; 13. · 7.04 Impact Factor

Publication Stats

413 Citations
119.47 Total Impact Points

Institutions

  • 2014
    • Wisconsin National Primate Research Center
      Madison, Wisconsin, United States
  • 2004–2014
    • University of Washington Seattle
      • • Department of Microbiology
      • • Division of Medical Genetics
      • • Department of Pathology
      Seattle, Washington, United States