Microarray analysis of PIN lesions from APT121 mouse prostate
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE50662 | GEO | 2016/09/09
SECONDARY ACCESSION(S): PRJNA218214
REPOSITORIES: GEO
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Project description:Many human cancers present as multi-focal lesions. Understanding the clonal origin of multi-focal cancers is of both etiological and clinical importance. The molecular basis of multi-focal prostate cancer has previously been explored using only a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multi-focal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 54 individual cancer and HGPIN lesions, isolated from 20 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 16 informative multi-tumor cases. In addition, both HGPIN lesions in the two multi-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 13q21.31-13q21.32, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this multi-focal prostate cancer study, occurring in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multi-focal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci, which through clonal expansion may progress to multi-focal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multi-focal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis and potentially improve clinical management of the disease. Copy number analysis of Affymetrix SNP 6.0 array was performed for a total of 48 cancer and HGPIN lesions from 18 prostate cancer cases. All samples have case-matched normal controls. PL = high grade PIN from left side, PR = high grade PIN from right side, PM = high grade PIN from middle of the tissue, TL = tumour from left side, TR = tumour from right side.
2011-12-31 | E-GEOD-29569 | biostudies-arrayexpress
Project description:We report the changes in gene expression in mouse prostate comparing normal wild type prostate to tumors generated by Cre mediated deletion of Pten or Apc, either with or without deletion of Tgfbr2. Pten single mutant tumors were isolated at either 8 weeks or 22 weeks of age, with high grade prostate intraepithelial neoplasia (HGPIN) as the main phenotype. Pten;Tgfbr2 double mutants were isolated at 8 weeks (primarily HGPIN), or at 11-14 weeks with extensive locally invasive cancer. Apc single mutants were isolated at 36 weeks old with adenosquamous HGPIN, or at 21-24 weeks of age for the Apc:Tgfbr2 double mutants, which had adenosquamous carcinoma. Ages for the two double mutant groups were based on initial signs of excess tumor burden. Wild type control prostates were isolated at around 20 weeks of age.
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Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
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Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
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Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
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Project description:Although a promotional role of the androgen receptor (AR) has been implicated in prostate tumorigenesis, the underlying mechanisms by which the AR, as a steroid-hormone receptor, induces prostatic oncogenesis still remain unknown. Conditional expression of the human AR transgene (hARtg) through Osr1 (old skipped related1) driven-Cre develops high-grade prostatic intraepithelial neoplasia (HGPIN) and adenocarcinomas in mice. Single-cell transcriptomic and genetic tracing analyses implicate the prostatic progenitor properties of prostatic Osr1-expressing cells through prostate development. Conditional expression of hARtg in Osr1-expressing basal epithelial cells elevates IGF1 signaling and initiates prostate oncogenesis and PIN formation. Aberrant IGF1 signaling further cumulates Wnt/b-catenin activation in atypical PIN cells to promote tumor development. Specific inhibition of Wnt signaling pathways significantly represses the growth of hARtg-positive prostate tumor cells in ex-vivo and xenograft models. These data elucidate a new and dynamic regulatory loop initiated by aberrant AR signaling altering IGF1 and Wnt signaling pathways in prostate oncogenesis and tumor development.
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Project description:Many human cancers present as multi-focal lesions. Understanding the clonal origin of multi-focal cancers is of both etiological and clinical importance. The molecular basis of multi-focal prostate cancer has previously been explored using only a limited number of isolated markers and, although independent origin is widely believed, the clonal origin of multi-focal prostate cancer is still debatable. We attempted to address clonal origin using a genome-wide copy-number analysis of individual cancer and high-grade prostatic intraepithelial neoplasia (HGPIN) lesions. Using Affymetrix array 6.0 copy-number analysis, we compared the genomic changes detected in 54 individual cancer and HGPIN lesions, isolated from 20 clinically localized prostate cancer cases. Identical genomic copy-number changes, shared by all same-case cancer foci, were detected in all 16 informative multi-tumor cases. In addition, both HGPIN lesions in the two multi-HGPIN cases available shared identical genomic changes. Commonly known genomic alterations, including losses at 6q15, 8p21.3-8p21.2, 10q23.2-10q23.31, 13q21.31-13q21.32, 16q22.3, 16q23.2-16q23.3 and 21q22.2-21q22.3 regions and gain of 8q24.3 were the most frequently detected changes in this multi-focal prostate cancer study, occurring in all same-case foci in at least one case. Microarray data were confirmed by fluorescence in situ hybridization in selected foci. Our high-resolution genome-wide copy-number data suggest that many multi-focal cases derive from a single prostate cancer precursor clone and that this precursor may give rise to separate HGPIN foci, which through clonal expansion may progress to multi-focal invasive prostate cancer. These findings, which demonstrate the monoclonal origin of multi-focal prostate cancer, should significantly enhance our understanding of prostate carcinogenesis and potentially improve clinical management of the disease.
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