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Cellular Oncology
Published in: Cellular Oncology 4/2020

01-08-2020 | Ovarian Cancer | Original paper

The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary

Authors: Smarakan Sneha, Rohit P. Nagare, Chirukandath Sidhanth, Syama Krishnapriya, Manoj Garg, Balaji Ramachandran, Kanchan Murhekar, Shirley Sundersingh, Trivadi S. Ganesan

Published in: Cellular Oncology | Issue 4/2020

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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.
Appendix
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Metadata
Title
The hedgehog pathway regulates cancer stem cells in serous adenocarcinoma of the ovary
Authors
Smarakan Sneha
Rohit P. Nagare
Chirukandath Sidhanth
Syama Krishnapriya
Manoj Garg
Balaji Ramachandran
Kanchan Murhekar
Shirley Sundersingh
Trivadi S. Ganesan
Publication date
01-08-2020
Publisher
Springer Netherlands
Published in
Cellular Oncology / Issue 4/2020
Print ISSN: 2211-3428
Electronic ISSN: 2211-3436
DOI
https://doi.org/10.1007/s13402-020-00504-w

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