Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers

Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic a...

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Autores principales: Stany, Michael P., Vathipadiekal, Vinod, Ozbun, Laurent, Stone, Rebecca L., Mok, Samuel C., Xue, Hui, Kagami, Takashi, Wang, Yuwei, McAlpine, Jessica N., Bowtell, David, Gout, Peter W., Miller, Dianne M., Gilks, C. Blake, Huntsman, David G., Ellard, Susan L., Wang, Yu-Zhuo, Vivas-Mejia, Pablo, Lopez-Berestein, Gabriel, Sood, Anil K., Birrer, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130734/
https://www.ncbi.nlm.nih.gov/pubmed/21754983
http://dx.doi.org/10.1371/journal.pone.0021121
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author Stany, Michael P.
Vathipadiekal, Vinod
Ozbun, Laurent
Stone, Rebecca L.
Mok, Samuel C.
Xue, Hui
Kagami, Takashi
Wang, Yuwei
McAlpine, Jessica N.
Bowtell, David
Gout, Peter W.
Miller, Dianne M.
Gilks, C. Blake
Huntsman, David G.
Ellard, Susan L.
Wang, Yu-Zhuo
Vivas-Mejia, Pablo
Lopez-Berestein, Gabriel
Sood, Anil K.
Birrer, Michael J.
author_facet Stany, Michael P.
Vathipadiekal, Vinod
Ozbun, Laurent
Stone, Rebecca L.
Mok, Samuel C.
Xue, Hui
Kagami, Takashi
Wang, Yuwei
McAlpine, Jessica N.
Bowtell, David
Gout, Peter W.
Miller, Dianne M.
Gilks, C. Blake
Huntsman, David G.
Ellard, Susan L.
Wang, Yu-Zhuo
Vivas-Mejia, Pablo
Lopez-Berestein, Gabriel
Sood, Anil K.
Birrer, Michael J.
author_sort Stany, Michael P.
collection PubMed
description Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients.
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spelling pubmed-31307342011-07-13 Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers Stany, Michael P. Vathipadiekal, Vinod Ozbun, Laurent Stone, Rebecca L. Mok, Samuel C. Xue, Hui Kagami, Takashi Wang, Yuwei McAlpine, Jessica N. Bowtell, David Gout, Peter W. Miller, Dianne M. Gilks, C. Blake Huntsman, David G. Ellard, Susan L. Wang, Yu-Zhuo Vivas-Mejia, Pablo Lopez-Berestein, Gabriel Sood, Anil K. Birrer, Michael J. PLoS One Research Article Clear cell ovarian cancer is an epithelial ovarian cancer histotype that is less responsive to chemotherapy and carries poorer prognosis than serous and endometrioid histotypes. Despite this, patients with these tumors are treated in a similar fashion as all other ovarian cancers. Previous genomic analysis has suggested that clear cell cancers represent a unique tumor subtype. Here we generated the first whole genomic expression profiling using epithelial component of clear cell ovarian cancers and normal ovarian surface specimens isolated by laser capture microdissection. All the arrays were analyzed using BRB ArrayTools and PathwayStudio software to identify the signaling pathways. Identified pathways validated using serous, clear cell cancer cell lines and RNAi technology. In vivo validations carried out using an orthotopic mouse model and liposomal encapsulated siRNA. Patient-derived clear cell and serous ovarian tumors were grafted under the renal capsule of NOD-SCID mice to evaluate the therapeutic potential of the identified pathway. We identified major activated pathways in clear cells involving in hypoxic cell growth, angiogenesis, and glucose metabolism not seen in other histotypes. Knockdown of key genes in these pathways sensitized clear cell ovarian cancer cell lines to hypoxia/glucose deprivation. In vivo experiments using patient derived tumors demonstrate that clear cell tumors are exquisitely sensitive to antiangiogenesis therapy (i.e. sunitinib) compared with serous tumors. We generated a histotype specific, gene signature associated with clear cell ovarian cancer which identifies important activated pathways critical for their clinicopathologic characteristics. These results provide a rational basis for a radically different treatment for ovarian clear cell patients. Public Library of Science 2011-07-06 /pmc/articles/PMC3130734/ /pubmed/21754983 http://dx.doi.org/10.1371/journal.pone.0021121 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Stany, Michael P.
Vathipadiekal, Vinod
Ozbun, Laurent
Stone, Rebecca L.
Mok, Samuel C.
Xue, Hui
Kagami, Takashi
Wang, Yuwei
McAlpine, Jessica N.
Bowtell, David
Gout, Peter W.
Miller, Dianne M.
Gilks, C. Blake
Huntsman, David G.
Ellard, Susan L.
Wang, Yu-Zhuo
Vivas-Mejia, Pablo
Lopez-Berestein, Gabriel
Sood, Anil K.
Birrer, Michael J.
Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title_full Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title_fullStr Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title_full_unstemmed Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title_short Identification of Novel Therapeutic Targets in Microdissected Clear Cell Ovarian Cancers
title_sort identification of novel therapeutic targets in microdissected clear cell ovarian cancers
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130734/
https://www.ncbi.nlm.nih.gov/pubmed/21754983
http://dx.doi.org/10.1371/journal.pone.0021121
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