The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary
Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, he...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Sneha, Smarakan [verfasserIn] Nagare, Rohit P. [verfasserIn] Sidhanth, Chirukandath [verfasserIn] Krishnapriya, Syama [verfasserIn] Garg, Manoj [verfasserIn] Ramachandran, Balaji [verfasserIn] Murhekar, Kanchan [verfasserIn] Sundersingh, Shirley [verfasserIn] Ganesan, Trivadi S. [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Cellular oncology - Amsterdam [u.a.] : IOS Press, 2004, 43(2020), 4 vom: 08. Mai, Seite 601-616 |
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| Übergeordnetes Werk: |
volume:43 ; year:2020 ; number:4 ; day:08 ; month:05 ; pages:601-616 |
| Links: |
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| DOI / URN: |
10.1007/s13402-020-00504-w |
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SPR040352315 |
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| 245 | 1 | 4 | |a The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary |
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| 520 | |a Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. | ||
| 650 | 4 | |a Serous adenocarcinoma of ovary |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Cancer stem cells |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a pathway |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Spheroids |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a Malignant ascites |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Nagare, Rohit P. |e verfasserin |4 aut | |
| 700 | 1 | |a Sidhanth, Chirukandath |e verfasserin |4 aut | |
| 700 | 1 | |a Krishnapriya, Syama |e verfasserin |4 aut | |
| 700 | 1 | |a Garg, Manoj |e verfasserin |4 aut | |
| 700 | 1 | |a Ramachandran, Balaji |e verfasserin |4 aut | |
| 700 | 1 | |a Murhekar, Kanchan |e verfasserin |4 aut | |
| 700 | 1 | |a Sundersingh, Shirley |e verfasserin |4 aut | |
| 700 | 1 | |a Ganesan, Trivadi S. |e verfasserin |4 aut | |
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10.1007/s13402-020-00504-w doi (DE-627)SPR040352315 (SPR)s13402-020-00504-w-e DE-627 ger DE-627 rakwb eng 610 570 ASE Sneha, Smarakan verfasserin aut The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. Serous adenocarcinoma of ovary (dpeaa)DE-He213 Cancer stem cells (dpeaa)DE-He213 pathway (dpeaa)DE-He213 Spheroids (dpeaa)DE-He213 Malignant ascites (dpeaa)DE-He213 Nagare, Rohit P. verfasserin aut Sidhanth, Chirukandath verfasserin aut Krishnapriya, Syama verfasserin aut Garg, Manoj verfasserin aut Ramachandran, Balaji verfasserin aut Murhekar, Kanchan verfasserin aut Sundersingh, Shirley verfasserin aut Ganesan, Trivadi S. verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 43(2020), 4 vom: 08. Mai, Seite 601-616 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:43 year:2020 number:4 day:08 month:05 pages:601-616 https://dx.doi.org/10.1007/s13402-020-00504-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 43 2020 4 08 05 601-616 |
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10.1007/s13402-020-00504-w doi (DE-627)SPR040352315 (SPR)s13402-020-00504-w-e DE-627 ger DE-627 rakwb eng 610 570 ASE Sneha, Smarakan verfasserin aut The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. Serous adenocarcinoma of ovary (dpeaa)DE-He213 Cancer stem cells (dpeaa)DE-He213 pathway (dpeaa)DE-He213 Spheroids (dpeaa)DE-He213 Malignant ascites (dpeaa)DE-He213 Nagare, Rohit P. verfasserin aut Sidhanth, Chirukandath verfasserin aut Krishnapriya, Syama verfasserin aut Garg, Manoj verfasserin aut Ramachandran, Balaji verfasserin aut Murhekar, Kanchan verfasserin aut Sundersingh, Shirley verfasserin aut Ganesan, Trivadi S. verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 43(2020), 4 vom: 08. Mai, Seite 601-616 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:43 year:2020 number:4 day:08 month:05 pages:601-616 https://dx.doi.org/10.1007/s13402-020-00504-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 43 2020 4 08 05 601-616 |
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10.1007/s13402-020-00504-w doi (DE-627)SPR040352315 (SPR)s13402-020-00504-w-e DE-627 ger DE-627 rakwb eng 610 570 ASE Sneha, Smarakan verfasserin aut The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. Serous adenocarcinoma of ovary (dpeaa)DE-He213 Cancer stem cells (dpeaa)DE-He213 pathway (dpeaa)DE-He213 Spheroids (dpeaa)DE-He213 Malignant ascites (dpeaa)DE-He213 Nagare, Rohit P. verfasserin aut Sidhanth, Chirukandath verfasserin aut Krishnapriya, Syama verfasserin aut Garg, Manoj verfasserin aut Ramachandran, Balaji verfasserin aut Murhekar, Kanchan verfasserin aut Sundersingh, Shirley verfasserin aut Ganesan, Trivadi S. verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 43(2020), 4 vom: 08. Mai, Seite 601-616 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:43 year:2020 number:4 day:08 month:05 pages:601-616 https://dx.doi.org/10.1007/s13402-020-00504-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 43 2020 4 08 05 601-616 |
| allfieldsGer |
10.1007/s13402-020-00504-w doi (DE-627)SPR040352315 (SPR)s13402-020-00504-w-e DE-627 ger DE-627 rakwb eng 610 570 ASE Sneha, Smarakan verfasserin aut The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. Serous adenocarcinoma of ovary (dpeaa)DE-He213 Cancer stem cells (dpeaa)DE-He213 pathway (dpeaa)DE-He213 Spheroids (dpeaa)DE-He213 Malignant ascites (dpeaa)DE-He213 Nagare, Rohit P. verfasserin aut Sidhanth, Chirukandath verfasserin aut Krishnapriya, Syama verfasserin aut Garg, Manoj verfasserin aut Ramachandran, Balaji verfasserin aut Murhekar, Kanchan verfasserin aut Sundersingh, Shirley verfasserin aut Ganesan, Trivadi S. verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 43(2020), 4 vom: 08. Mai, Seite 601-616 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:43 year:2020 number:4 day:08 month:05 pages:601-616 https://dx.doi.org/10.1007/s13402-020-00504-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 43 2020 4 08 05 601-616 |
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10.1007/s13402-020-00504-w doi (DE-627)SPR040352315 (SPR)s13402-020-00504-w-e DE-627 ger DE-627 rakwb eng 610 570 ASE Sneha, Smarakan verfasserin aut The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. Serous adenocarcinoma of ovary (dpeaa)DE-He213 Cancer stem cells (dpeaa)DE-He213 pathway (dpeaa)DE-He213 Spheroids (dpeaa)DE-He213 Malignant ascites (dpeaa)DE-He213 Nagare, Rohit P. verfasserin aut Sidhanth, Chirukandath verfasserin aut Krishnapriya, Syama verfasserin aut Garg, Manoj verfasserin aut Ramachandran, Balaji verfasserin aut Murhekar, Kanchan verfasserin aut Sundersingh, Shirley verfasserin aut Ganesan, Trivadi S. verfasserin aut Enthalten in Cellular oncology Amsterdam [u.a.] : IOS Press, 2004 43(2020), 4 vom: 08. Mai, Seite 601-616 (DE-627)392964430 (DE-600)2158254-3 1875-8606 nnns volume:43 year:2020 number:4 day:08 month:05 pages:601-616 https://dx.doi.org/10.1007/s13402-020-00504-w lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 AR 43 2020 4 08 05 601-616 |
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Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. 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Sneha, Smarakan Nagare, Rohit P. Sidhanth, Chirukandath Krishnapriya, Syama Garg, Manoj Ramachandran, Balaji Murhekar, Kanchan Sundersingh, Shirley Ganesan, Trivadi S. |
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hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary |
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The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary |
| abstract |
Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. |
| abstractGer |
Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. |
| abstract_unstemmed |
Purpose Signaling by cancer stem cells (CSCs) is known to occur at least in part through conserved developmental pathways. Here, the role of one of these pathways, i.e., the hedgehog pathway, was evaluated in high-grade serous ovarian carcinoma (HGSOC). Methods and results We found that in HGSOC, hedgehog inhibitors (HHIs) GANT61, LDE225 and GDC0449 reduced or inhibited the formation of spheroids enriched in CSCs. Primary malignant cells (PMCs) in ascites from HGSOC patients cultured in the presence of HHIs showed significant reduction in CSCs. Sonic hedgehog (SHH) significantly increased the expression of ALDH1A1, which was inhibited by GANT61. In the presence of a SHH neutralizing antibody (5E1), a significant reduction in the number of spheroids was observed in HGSOC-derived cell lines. Further, the motility, migration and clonogenic growth of the cells were significantly reduced by HHIs. In the presence of GANT61, a reduction of cells from PMCs in the G0 phase of the cell cycle was observed. The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. Conclusions Our results indicate that the hedgehog pathway plays an important role in maintaining the integrity of CSCs in HGSOC and could be a potential therapeutic target. |
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The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary |
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Nagare, Rohit P. Sidhanth, Chirukandath Krishnapriya, Syama Garg, Manoj Ramachandran, Balaji Murhekar, Kanchan Sundersingh, Shirley Ganesan, Trivadi S. |
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The magnitude of difference in expression of Gli1 in tumors from the same HGSOC patients at presentation and at interval debulking surgery was greater in patients who had a recurrence on follow up. GANT61 also significantly inhibited the growth of CSCs in nude mice. Finally, RNA sequencing of HGSOC cells treated with GANT61 showed a significantly reduced expression of CSC markers. 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