Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer
Abstract Background Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatmen...
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doaj-54100735275e43a68b56e72bbf77364b2020-11-25T04:09:12ZengBMCJournal of Ovarian Research1757-22152019-11-0112111110.1186/s13048-019-0590-5Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancerElizabeth V. Connor0Caner Saygin1Chad Braley2Andrew C. Wiechert3Sheelarani Karunanithi4Katie Crean-Tate5Fadi W. Abdul-Karim6Chad M. Michener7Peter G. Rose8Justin D. Lathia9Ofer Reizes10Division of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland ClinicCancer Impact Area, Lerner Research Institute, Cleveland ClinicCancer Impact Area, Lerner Research Institute, Cleveland ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland ClinicCancer Impact Area, Lerner Research Institute, Cleveland ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland ClinicDepartment of Anatomic Pathology, Cleveland ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland ClinicDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology and Women’s Health Institute, Cleveland ClinicCancer Impact Area, Lerner Research Institute, Cleveland ClinicCancer Impact Area, Lerner Research Institute, Cleveland ClinicAbstract Background Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target. Results Kaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens. Conclusions Thy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target.http://link.springer.com/article/10.1186/s13048-019-0590-5Ovarian cancerThy-1CD90Cancer stem cellsBiomarkerSelf-renewal |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Elizabeth V. Connor Caner Saygin Chad Braley Andrew C. Wiechert Sheelarani Karunanithi Katie Crean-Tate Fadi W. Abdul-Karim Chad M. Michener Peter G. Rose Justin D. Lathia Ofer Reizes |
spellingShingle |
Elizabeth V. Connor Caner Saygin Chad Braley Andrew C. Wiechert Sheelarani Karunanithi Katie Crean-Tate Fadi W. Abdul-Karim Chad M. Michener Peter G. Rose Justin D. Lathia Ofer Reizes Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer Journal of Ovarian Research Ovarian cancer Thy-1 CD90 Cancer stem cells Biomarker Self-renewal |
author_facet |
Elizabeth V. Connor Caner Saygin Chad Braley Andrew C. Wiechert Sheelarani Karunanithi Katie Crean-Tate Fadi W. Abdul-Karim Chad M. Michener Peter G. Rose Justin D. Lathia Ofer Reizes |
author_sort |
Elizabeth V. Connor |
title |
Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
title_short |
Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
title_full |
Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
title_fullStr |
Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
title_full_unstemmed |
Thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
title_sort |
thy-1 predicts poor prognosis and is associated with self-renewal in ovarian cancer |
publisher |
BMC |
series |
Journal of Ovarian Research |
issn |
1757-2215 |
publishDate |
2019-11-01 |
description |
Abstract Background Ovarian cancer is the leading cause of gynecologic cancer death in the United States despite effective first-line systemic chemotherapy. Cancer stem cells (CSCs) retain the ability to self-renew and proliferate and may be a means of harboring disease that evades standard treatment strategies. We previously performed a high-throughput screen to assess differential protein expression in ovarian CSCs compared to non-CSCs and observed that Thy-1 was more highly expressed in CSCs. Our primary aim was to validate Thy-1 (CD90) as a cancer stem cell (CSC) marker in epithelial ovarian cancer (EOC), correlate with clinical outcomes, and assess as a potential therapeutic target. Results Kaplan Meier (KM) Plotter data were correlated with survival outcomes. Quantitative real-time PCR, flow cytometry, and immunoblots assessed RNA and protein expression. Limiting dilution assays assessed self-renewal capacity and proliferation assays assessed proliferative capacity. RNA in-situ hybridization was performed on patient specimens to assess feasibility. Thy-1 (CD90) is more highly expressed in ovarian CSCs than non-CSCs, in EOC compared to benign ovarian epithelium (P < 0.001), and is highest in serous EOC (P < 0.05). Serous ovarian cancers with high Thy-1 expression have poorer outcomes (median PFS 15.8 vs. 18.3 months, P = 0 < 0.001; median OS 40.1 v. 45.8 months, P = 0.036). Endometrioid ovarian cancers with high Thy-1 have poorer PFS, but no difference in OS (upper quartile PFS 34 v. 11 months, P = 0.013; quartile OS not reached, P = 0.69). In vitro, Thy-1 expression is higher in CSCs versus non-CSCs. EOC cells with high Thy-1 expression demonstrate increased proliferation and self-renewal. Thy-1 knockdown in EOC cells decreases proliferative capacity and self-renewal capacity, and knockdown is associated with decreased expression of stem cell transcription factors NANOG and SOX2. RNA in situ hybridization is feasible in ovarian cancer tissue specimens. Conclusions Thy-1 is a marker of ovarian CSCs. Increased expression of Thy-1 in EOC predicts poor prognosis and is associated with increased proliferative and self-renewal capacity. Thy-1 knockdown decreases proliferative and self-renewal capacity, and represents a potential therapeutic target. |
topic |
Ovarian cancer Thy-1 CD90 Cancer stem cells Biomarker Self-renewal |
url |
http://link.springer.com/article/10.1186/s13048-019-0590-5 |
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