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Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma

SIMPLE SUMMARY: Ovulation is regarded as the culprit of ovarian high-grade serous carcinoma (HGSC). Previously, we discovered IGF2 in the ovulatory follicular fluid (FF), which bathe fallopian tube epithelium (FTE) during ovulation, promotes malignant transformation through the IGF-1R/AKT pathway. T...

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Autores principales: Hsu, Che-Fang, Chen, Pao-Chu, Seenan, Vaishnavi, Ding, Dah-Ching, Chu, Tang-Yuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865564/
https://www.ncbi.nlm.nih.gov/pubmed/33530497
http://dx.doi.org/10.3390/cancers13030468
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author Hsu, Che-Fang
Chen, Pao-Chu
Seenan, Vaishnavi
Ding, Dah-Ching
Chu, Tang-Yuan
author_facet Hsu, Che-Fang
Chen, Pao-Chu
Seenan, Vaishnavi
Ding, Dah-Ching
Chu, Tang-Yuan
author_sort Hsu, Che-Fang
collection PubMed
description SIMPLE SUMMARY: Ovulation is regarded as the culprit of ovarian high-grade serous carcinoma (HGSC). Previously, we discovered IGF2 in the ovulatory follicular fluid (FF), which bathe fallopian tube epithelium (FTE) during ovulation, promotes malignant transformation through the IGF-1R/AKT pathway. Transformed FTE cells then exfoliate and metastasize to the ovary and peritoneum to grow overt HGSC. In this study, we utilized immortalized FTE cells and HGSC cells carrying accumulating severity of driver mutations to explore FF’s role in the development of HGSC. We found FF promotes (by order of magnitude) migration, anchorage-independent growth (AIG), invasion, peritoneum attachment, anoikis resistance, and proliferation of the full panel of tested cells. The AIG activity largely depends on IGF-1R/AKT signaling, and both AKT- and non-AKT-mediated signals are responsible for other phenotypes. The results demonstrated an extensive transformation activity of FF in the full journey of HGSC development from FTE. ABSTRACT: Background: High-grade serous carcinoma (HGSC) is mainly derived from the stepwise accumulation of driver mutations in the fallopian tube epithelium (FTE), and it subsequently metastasizes to the ovary and peritoneum that develops into a clinically evident ovarian carcinoma. The developmental process involves cell proliferation/clonal expansion, cell migration, anoikis resistance, anchorage-independent growth (AIG), peritoneum attachment, and cell invasion. Previously, we discovered FTE could be transformed by follicular fluid (FF) released from ovulation, the most crucial risk factor of ovarian cancer, and IGF axis proteins in FF confers stemness activation and clonal expansion via IGF-1R/AKT pathway. However, whether other phenotypes in advanced cancer development are involved is unknown. Methods: A panel of FTE and ovarian HGSC cell lines with different severity of transformation were treated with FF with or without IGF-1R and AKT inhibitors and analyzed for the transformation phenotypes in vitro, ex vivo, and in vivo. Results: FF largely promotes (by order of magnitude) cell migration, AIG, cell invasion, peritoneum attachment, anoikis resistance, and cell proliferation. Most of these activities worked in the full panel of cell lines. The AIG activity largely depends on IGF-1R/AKT phosphorylation, and the proliferation activity depends on an AKT phosphorylation not mediated by IGF-1R. In contrast, both AKT- and non-AKT-mediated signals are responsible for the other transformation activities. Conclusions: Our data demonstrate an extensive transformation activity of FF in the full journey of carcinogenesis, and endorsed ovulation-inhibition for the prevention and AKT-inhibition for the treatment of ovarian HGSC.
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spelling pubmed-78655642021-02-07 Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma Hsu, Che-Fang Chen, Pao-Chu Seenan, Vaishnavi Ding, Dah-Ching Chu, Tang-Yuan Cancers (Basel) Article SIMPLE SUMMARY: Ovulation is regarded as the culprit of ovarian high-grade serous carcinoma (HGSC). Previously, we discovered IGF2 in the ovulatory follicular fluid (FF), which bathe fallopian tube epithelium (FTE) during ovulation, promotes malignant transformation through the IGF-1R/AKT pathway. Transformed FTE cells then exfoliate and metastasize to the ovary and peritoneum to grow overt HGSC. In this study, we utilized immortalized FTE cells and HGSC cells carrying accumulating severity of driver mutations to explore FF’s role in the development of HGSC. We found FF promotes (by order of magnitude) migration, anchorage-independent growth (AIG), invasion, peritoneum attachment, anoikis resistance, and proliferation of the full panel of tested cells. The AIG activity largely depends on IGF-1R/AKT signaling, and both AKT- and non-AKT-mediated signals are responsible for other phenotypes. The results demonstrated an extensive transformation activity of FF in the full journey of HGSC development from FTE. ABSTRACT: Background: High-grade serous carcinoma (HGSC) is mainly derived from the stepwise accumulation of driver mutations in the fallopian tube epithelium (FTE), and it subsequently metastasizes to the ovary and peritoneum that develops into a clinically evident ovarian carcinoma. The developmental process involves cell proliferation/clonal expansion, cell migration, anoikis resistance, anchorage-independent growth (AIG), peritoneum attachment, and cell invasion. Previously, we discovered FTE could be transformed by follicular fluid (FF) released from ovulation, the most crucial risk factor of ovarian cancer, and IGF axis proteins in FF confers stemness activation and clonal expansion via IGF-1R/AKT pathway. However, whether other phenotypes in advanced cancer development are involved is unknown. Methods: A panel of FTE and ovarian HGSC cell lines with different severity of transformation were treated with FF with or without IGF-1R and AKT inhibitors and analyzed for the transformation phenotypes in vitro, ex vivo, and in vivo. Results: FF largely promotes (by order of magnitude) cell migration, AIG, cell invasion, peritoneum attachment, anoikis resistance, and cell proliferation. Most of these activities worked in the full panel of cell lines. The AIG activity largely depends on IGF-1R/AKT phosphorylation, and the proliferation activity depends on an AKT phosphorylation not mediated by IGF-1R. In contrast, both AKT- and non-AKT-mediated signals are responsible for the other transformation activities. Conclusions: Our data demonstrate an extensive transformation activity of FF in the full journey of carcinogenesis, and endorsed ovulation-inhibition for the prevention and AKT-inhibition for the treatment of ovarian HGSC. MDPI 2021-01-26 /pmc/articles/PMC7865564/ /pubmed/33530497 http://dx.doi.org/10.3390/cancers13030468 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hsu, Che-Fang
Chen, Pao-Chu
Seenan, Vaishnavi
Ding, Dah-Ching
Chu, Tang-Yuan
Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title_full Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title_fullStr Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title_full_unstemmed Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title_short Ovulatory Follicular Fluid Facilitates the Full Transformation Process for the Development of High-Grade Serous Carcinoma
title_sort ovulatory follicular fluid facilitates the full transformation process for the development of high-grade serous carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865564/
https://www.ncbi.nlm.nih.gov/pubmed/33530497
http://dx.doi.org/10.3390/cancers13030468
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