The PSA-/lo prostate cancer cells harbor self-renewing long-term tumor-propagating cells that resist castration
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Dean Tang
PROVIDER: E-GEOD-35814 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Prostate cancer (PCa) is heterogeneous containing both phenotypically differentiated and undifferentiated tumor cells. An important unanswered question is whether these two populations of PCa cells are functionally different. Here we report the distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (i.e., PSA+) and low (PSA-/lo) levels of the differentiation marker PSA (prostatespecific antigen). PSA-/lo PCa cells are quiescent and resistant to multiple stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity in male mice. They preferentially express stem cell-associated genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA-/lo PCa cells can initiate robust tumor development in castrated hosts, survive androgen deprivation, and harbor highly tumorigenic castration-resistant PCa cells that can be further enriched using the ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, mainly undergo symmetric division, and are sensitive to castration. Together, our study suggests that PSA-/lo and PSA+ PCa cells are functionally distinct and PSA-/lo cells may represent one critical source of castration-resistant PCa cells. There are 4 sets of human samples in this study corresponding to 4 different prostate cancer patients labeled as HPCa46T, HPCa47T, HPCa49T and HPCa51T. Each set includes 3 technical triplicates (except HPCa46T) that were performed on dual color arrays and each individual array includes comparisons between PSA- (Cy5) and PSA+ (Cy3) cells of the respective patient prostate tumor.
2012-05-09 | E-GEOD-35733 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) is heterogeneous containing both phenotypically differentiated and undifferentiated tumor cells. An important unanswered question is whether these two populations of PCa cells are functionally different. Here we report the distinct molecular, cellular, and tumor-propagating properties of PCa cells that express high (i.e., PSA+) and low (PSA-/lo) levels of the differentiation marker PSA (prostatespecific antigen). PSA-/lo PCa cells are quiescent and resistant to multiple stresses including androgen deprivation, exhibit high clonogenic potential, and possess long-term tumor-propagating capacity in male mice. They preferentially express stem cell-associated genes and can undergo asymmetric cell division generating PSA+ cells. Importantly, PSA-/lo PCa cells can initiate robust tumor development in castrated hosts, survive androgen deprivation, and harbor highly tumorigenic castration-resistant PCa cells that can be further enriched using the ALDH+CD44+α2β1+ phenotype. In contrast, PSA+ PCa cells possess more limited tumor-propagating capacity, mainly undergo symmetric division, and are sensitive to castration. Together, our study suggests that PSA-/lo and PSA+ PCa cells are functionally distinct and PSA-/lo cells may represent one critical source of castration-resistant PCa cells. There are two sets of samples in this study corresponding to two different prostate cancer cell lines LNCaP and LAPC9. Both LNCaP and LAPC9 sets include 3 technical triplicates each that were performed onvdual color arrays and each individual array includes comparison between PSA- (Cy5) and PSA+ (Cy3) cells of the respective cell line.
2012-05-09 | E-GEOD-30114 | biostudies-arrayexpress
Project description:15-Lipoxygenase 2 (15-LOX2), a human-specific lipid-peroxidizing enzyme, is mainly expressed in luminal compartment of the normal prostate and often decreased or lost in prostate cancer (PCa). Previous studies from our lab implicate 15-LOX2 as a functional tumor suppressor. To better understand the biological role of 15-LOX2 in vivo, we established prostate-specific 15-LOX2 transgenic mice using the ARR2PB promoter. Unexpectedly, 15-LOX2 expression resulted in age-dependent prostatic hyperplasia. Interestingly, transgenic expression of 15-LOX2sv-b, a splice variant that lacks the arachidonic acid metabolizing activity, also induced hyperplasia and enlargement of the prostate. Prostatic hyperplasia induced by both 15-LOX2 and 15-LOX2sv-b was associated with an increase in proliferative (i..e., Ki67+) and luminal cells but 15-LOX2-induced hyperplasia was also accompanied by a prominent increase in basal cells. Microarray analysis revealed distinct gene expression profiles that could help explain the prostate phenotypes. Strikingly, 15-LOX2 (but not 15-LOX2sv-b) transgenic prostate showed up-regulation of several well-known stem/progenitor cell molecules including Sca-1, Trop2, p63 and Psca. Prostatic hyperplasia caused by both 15-LOX2 and 15-LOX2sv-b did not progress to PCa over >5 years of observations. Mechanistically, hyperplastic prostate lobes (especially those of the 15-LOX2 mice) showed a dramatic increase in senescent cells revealed by increased SA-ßgal, HP1, and p27Kip1 staining. Collectively, our results suggest that 15-LOX2 expression in mouse prostate leads to hyperplasia that activates the senescence checkpoint, which may in turn function as a barrier to tumor development. RNA was isolated from combined prostatic lobes of 6 mice (to reduce inter-animal variation) from ~2.5 month old (young; y) 15-LOX2 (line fl26), 15-LOX2sv-b (line svb9), wild type (wt) and ~15 month old (old; o) wt mice and hybridized onto Agilent's whole mouse genome oligoarrays arrays (G4122A) in fl26y(vs)wty, svb9y(vs)wty and wto(vs)wty combinations. The hybridizations were carried out in duplicates using an independent set of samples (biological replicates).
2010-12-16 | E-GEOD-15827 | biostudies-arrayexpress
Project description:It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear, however, whether there are any innate surveillants that ensure keratinocytes undergoing terminal differentiation, preventing the disease. IKKα induces keratinocyte terminal differentiation and its reduction promotes skin tumor development. However, its nature function in skin cancer is unknown. Here we found that mice with IKKα deletion in keratinocytes or in hair follicle keratinocytes developed a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKKα inhibited excessive mitosis, induced terminal differentiation, and prevented skin cancer through an EGFR-driven autocrine loop in mice. Thus, IKKα serves as an innate surveillant. Experiment Overall Design: The differences in gene expression profiles of CHUK deleted mouse keratinocytes compared to wild type mouse keratinocytes were analyzed using two dual-channel agilent microarrays in duplicates.
2009-08-12 | E-GEOD-12111 | biostudies-arrayexpress
Project description:1. Comparison of gene expression profiles of normal prostates, hyperplastic prostates (4-5 month old mice) and prostate tumors (>10 month old mice) isolated from PSA-Cre;Pten-loxP/loxP mice 2.Comparison of the gene expression profiles and molecular subtyping of prostate tumors isolated from targeted Pten knockout mice
2016-09-30 | E-MTAB-3970 | biostudies-arrayexpress
Project description:Naval training exercises involving live ordnance can introduce munitions constituents (MCs) such as 1,3,5-trinitro-1,3,5 triazine (RDX) into the marine environment posing a potential environmental hazard to reef organisms, including corals. We developed a bioinformatic infrastructure and high-density microarray for a coral consortium and assessed the effects of RDX bioaccumulation on gene expression related to coral and endosymbiont health in the reef building coral (Acropora formosa). High-throughput sequencing and assembly of the transcriptomes for A. formosa and all eukaryotic endosymbionts yielded 189,616 unique sequences and 25,003 significant functional matches to protein-coding genes. Functional annotation and metabolic pathway associations were also developed. The bioinformatics base was transitioned to custom 15,000 probe microarrays that were used to assess RDX effects on gene expression in the A. formosa coral consortium. Coral fragments were exposed to RDX (0.5, 1, 2, 4, and 8 mg/L) for 5d in a controlled laboratory experiment. RDX readily accumulated into coral tissues; however, bioconcentration was minimal (bioconcentration factor = 1.09-1.50). RDX caused no significant changes in zooxanthellae tissue densities, however a significant (p<0.05) 40% increase in mucocytes was observed in the 8 mg/L exposure indicating a mucosal protective response to RDX exposure. Investigation of T-RFLP profiles indicated significant differences in bacterial community composition inhabiting the coral surface microlayer of Acropora sp. between control and RDX-exposed coral as among exposure concentrations. Differential expression of transcripts increased with increasing RDX concentration where 126, 195 and 272 transcripts were differentially expressed in the 0.5, 2.0 and 8 mg/L RDX treatments, respectively. The commonality in differentially expressed transcripts (DET) among exposure concentrations ranged from 9.9 to 29.0% where the lowest commonality was observed between the most disparate RDX exposure concentrations. Increasing RDX concentrations caused an increasing proportion of the number of transcripts differentially expressed in symbionts relative to corals. Further, a trend toward decreased transcript expression in symbionts in response to increasing RDX concentration was observed where 20.0% of differentially expressed transcripts had decreased expression at the 0.5 mg/L concentration, whereas 80.4% had decreased expression at the 8 mg/L concentration. Investigation of KEGG orthology for DET indicated potential impacts of RDX on a variety of molecular pathways, predominantly in endosymbionts compared to the coral host. Prominent effects of RDX exposure on pathways included enrichment of DET involved in carbohydrate metabolism, amino acid metabolism, energy metabolism, lipid metabolism, metabolism of cofactors and vitamins, environmental information processing and cellular processes. Fragments of the living branched coral Acropora formosa were obtained from Oceans, Reefs and Aquaria (http://www.orafarm.com). Ten gallon aquaria were used to expose 5 coral fragments to control or RDX exposure conditions (0.49, 0.93, 1.77, 3.67 and 7.18 mg/L, measured concentrations). The microarray hybridization experiment included 3 biological replicates for the 0.5, 2, and 8 mg/L RDX conditions and 4 biological replicates for the control.
2014-03-26 | E-GEOD-27624 | biostudies-arrayexpress
Project description:This study shows the pronounced expansion of CD8 T cell clones at sites of active inflammation within the joints of psoriatic arthritis (PsA) patients compared to blood, and characterises the gene expression of expanded clones using droplet based single cell RNA sequencing. Mononuclear cells were separated from freshly acquired paired peripheral blood and synovial fluid samples from 3 PsA patients using density gradient separation, then enriched for CD4 and CD8 T cells using FACS. Additionally, CD45+ leukocytes were enriched by FACS from the cryopreserved synovial tissue of 2 further PsA patients. All cells were then processed using a 10x Chromium Controller and sequenced by Illumina HiSeq 4000 (peripheral blood / synovial fluid) or NovaSeq with S2 flowcell (synovial tissue).
2020-09-07 | E-MTAB-9492 | biostudies-arrayexpress
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2021-04-08 | PXD019861 | Pride
Project description:Organophosphorus compounds induce cardiotoxicity through currently unknown mechanisms, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. We used microarrays to study gene expression changes in human cardiomyocytes after exposure to VX, and identified pathways underlying these changes. Human cardiomyocytes were exposed to sublethal concentrations (0, 0.1, 10 μM) of VX. RNA were extracted at different timepoints (0, 6, 24, 72 h) after VX exposure and hybridized to Affymetrix microarrays. Four biological repeats were used for each condition.
2011-10-28 | E-GEOD-33325 | biostudies-arrayexpress
Project description:Organophosphorus compounds induce hepatotoxicity through currently unknown mechanisms, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. We used microarrays to study gene expression changes in human hepatocytes after exposure to VX, and identified pathways underlying these changes. Human hepatocytes were exposed to sublethal concentrations (0, 0.1, 10 μM) of VX. RNA were extracted at different timepoints (0, 6 h) after VX exposure and hybridized to Affymetrix microarrays. Four biological repeats were used for each condition.
2011-11-11 | E-GEOD-33606 | biostudies-arrayexpress