Dataset Information

PTTG1: a Unique Regulator of Stem/Cancer Stem Cells in the Ovary and Ovarian Cancer.

ABSTRACT: Origin of cancer stem cells (CSCs) and mechanisms by which oncogene PTTG1 contributes to tumor progression via CSCs is not known. Ovarian CSCs exhibit characteristics of self-renewal, tumor-initiation, growth, differentiation, drug resistance, and tumor relapse. A common location of putative origin, namely the ovarian surface epithelium, is shared between the normal stem and CSC compartments. Existence of ovarian stem cells and their co-expression with CSC signatures suggests a strong correlation between origin of epithelial cancer and CSCs. We hereby explored a putative oncogene PTTG1 (Securin), reported to be overexpressed in various tumors, including ovarian. We report a previously overlooked role of PTTG1 as a marker of CSCs thereby modulating CSC, germline, and stemness-related genes. We further characterized PTTG1's ability to regulate (cancer) stem cell-associated self-renewal and epithelial-mesenchymal transition pathways. Collectively, the data sheds light on a potential target expressed during ovarian tumorigenesis and metastatically disseminated ascites CSCs in the peritoneal cavity. Present study highlights this unconventional, under-explored role of PTTG1 in regulation of stem and CSC compartments in ovary, ovarian cancer and ascites and highlights it as a potential candidate for developing CSC specific targeted therapeutics.

SUBMITTER: Parte S

PROVIDER: S-EPMC10723898 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PTTG1: a Unique Regulator of Stem/Cancer Stem Cells in the Ovary and Ovarian Cancer.

Parte Seema S Virant-Klun Irma I Patankar Manish M Batra Surinder K SK Straughn Alex A Kakar Sham S SS

Stem cell reviews and reports 20191201 6

Origin of cancer stem cells (CSCs) and mechanisms by which oncogene PTTG1 contributes to tumor progression via CSCs is not known. Ovarian CSCs exhibit characteristics of self-renewal, tumor-initiation, growth, differentiation, drug resistance, and tumor relapse. A common location of putative origin, namely the ovarian surface epithelium, is shared between the normal stem and CSC compartments. Existence of ovarian stem cells and their co-expression with CSC signatures suggests a strong correlatio ...[more]

PMID: 31482269

Similar Datasets

Project description:BackgroundOvarian cancer is a complicated malady associated with cancer stem cells (CSCs) contributing to 238,700 estimated new cases and 151,900 deaths per year, worldwide. CSCs comprise a tiny fraction of tumor-bulk responsible for cancer recurrence and eventual mortality. CSCs or tumor initiating cells are responsible for self-renewal, differentiation and proliferative potential, tumor initiation capability, its progression, drug resistance and metastatic spread. Although several biomarkers are implicated in these processes, their distribution within the ovary and association with single cell type has neither been established nor demonstrated across ovarian tumor developmental stages. Therefore, precise identification, thorough characterization and effective targeted destruction of dormant and highly proliferating potent CSC populations is an immediate need.ResultsIn view of this, distribution of various CSC (ALDH1/2, C-KIT, CD133, CD24 and CD44) and cell proliferation (KI67) specific markers in the ovarian surface epithelium (OSE) and cortex regions in normal ovary, and benign, borderline and high grade metastatic ovarian tumors by immuno-histochemistry and confocal microscopy was studied. We further confirmed their expression by RT-PCR analysis. Co-expression analysis of stem cell (OCT4, SSEA4) and CSC (ALDH1/2, CD44 and LGR5) markers with proliferation marker (KI67) in HG tumors revealed dual positive proliferating stem and CSCs, few non-proliferating stem/CSC (SSEA4+/KI67- and ALDH1/2+/KI67-) and only KI67+ cells in cortex, signifying dynamic populations and interesting cellular hierarchy in cortex region. Smaller spherical (≤ 5 μm) and larger spindle/elliptical shaped (~ 10 μm) cell populations with high nucleo-cytoplasmic ratio were detected across all samples (including normal ovaries) but with variable distribution and characteristic stage-wise marker expression across different tumor stages.ConclusionsDiverse stem and CSC populations expressing characteristic markers revealing distinct phenotypes (spherical ≤5 μm and spindle/elliptical ~ 10 μm) were distributed within different tumor stages studied signifying dynamic and probable functional hierarchy within these cell types. Involvement of extra-ovarian sites of origin of stem and CSCs requires rigorous evaluation. Quantitative analysis of potent CSC populations, their mechanisms and pathways for self-renewal, chemo-resistance, metastatic spread etc. with respect to various markers studied, will provide better insights and targets for developing effective therapeutics to prevent metastasis and eventually help improve patient mortality.

Project description:Ovarian Cancer is the fifth most common cancer in females and remains the most lethal gynecological malignancy as most patients are diagnosed at late stages of the disease. Despite initial responses to therapy, recurrence of chemo-resistant disease is common. The presence of residual cancer stem cells (CSCs) with the unique ability to adapt to several metabolic and signaling pathways represents a major challenge in developing novel targeted therapies. The objective of this study is to investigate the transcripts of putative ovarian cancer stem cell (OCSC) markers in correlation with transcripts of receptors, transporters, and enzymes of the energy generating metabolic pathways involved in high grade serous ovarian cancer (HGSOC). We conducted correlative analysis in data downloaded from The Cancer Genome Atlas (TCGA), studies of experimental OCSCs and their parental lines from Gene Expression Omnibus (GEO), and Cancer Cell Line Encyclopedia (CCLE). We found positive correlations between the transcripts of OCSC markers, specifically CD44, and glycolytic markers. TCGA datasets revealed that NOTCH1, CD133, CD44, CD24, and ALDH1A1, positively and significantly correlated with tricarboxylic acid cycle (TCA) enzymes. OVCAR3-OCSCs (cancer stem cells derived from a well-established epithelial ovarian cancer cell line) exhibited enrichment of the electron transport chain (ETC) mainly in complexes I, III, IV, and V, further supporting reliance on the oxidative phosphorylation (OXPHOS) phenotype. OVCAR3-OCSCs also exhibited significant increase in CD36, ACACA, SCD, and CPT1A, with CD44, CD133, and ALDH1A1 exhibiting positive correlations with lipid metabolic enzymes. TCGA data show positive correlations between OCSC markers and glutamine metabolism enzymes, whereas in OCSC experimental models of GSE64999, GSE28799, and CCLE, the number of positive and negative correlations observed was significantly lower and was different between model systems. Appropriate integration and validation of data model systems with those in patients' specimens is needed not only to bridge our knowledge gap of metabolic programing of OCSCs, but also in designing novel strategies to target the metabolic plasticity of dormant, resistant, and CSCs.

Project description:Ovarian cancer is most lethal among gynecological cancers with often fatal consequences due to lack of effective biomarkers and relapse, which propels ovarian cancer research into unique directions to establish solid targeted therapeutics. "Ovarian stem cells" expressing germline pluripotent markers serve as novel paradigm with potential to address infertility, menopause, and probably influence tumor initiation. Cancer stem cells (CSCs) pose vital role in tumor recurrence and hence it is extremely important to study them with respect to ovarian stem cells across various cancer stages and normal ovaries. Pluripotent (OCT4, NANOG, SOX2, SSEA1, and SSEA4), germline (IFITM3, VASA/DDX4), and cancer stem (CD44, LGR5) cell specific markers were characterized for protein and mRNA expression in tumor tissues to understand their distribution in the surface epithelium and ovarian cortex in benign, borderline, and high-grade malignant stages. To elucidate whether pluripotent ovarian germline stem cells and CSCs are common subset of stem cells in tumor tissues, VASA was colocalized with known pluripotent stem (OCT4, SSEA1, SSEA4) and CSC (CD44, LGR5) specific markers by confocal microscopy. Single, smaller spherical (≤5 μm), and larger elliptical fibroblast like (≥10 μm) cells (also in clusters or multiples) were detected implying probable functional behavioral significance of cells in tumor initiation and metastasis across various cancer stages. Cells revealed characteristic staining pattern in ovarian surface epithelium (OSE) and cortex regions exclusive for each marker. Co-expression studies revealed specific subpopulations existing simultaneously in OSE and cortex and that a dynamic hierarchy of (cancer) stem cells with germline properties prevails in normal ovaries and cancer stages. Novel insights into CSC biology with respect to ovarian and germline stem cell perspective were obtained. Understanding molecular signatures and distribution within ovarian tissue may enable identification of precise tumor-initiating CSC populations and signaling pathways thus improving their efficient targeting and strategies to prevent their dissemination causing fatal relapse.

Dataset Information

PTTG1: a Unique Regulator of Stem/Cancer Stem Cells in the Ovary and Ovarian Cancer.

Publications

PTTG1: a Unique Regulator of Stem/Cancer Stem Cells in the Ovary and Ovarian Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets