Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes
Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, th...
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| Format: | Article |
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MDPI AG
2022-02-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/4/1039 |
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| author | Meshach Asare-Werehene Hideaki Tsuyoshi Huilin Zhang Reza Salehi Chia-Yu Chang Euridice Carmona Clifford L. Librach Anne-Marie Mes-Masson Chia-Ching Chang Dylan Burger Yoshio Yoshida Benjamin K. Tsang |
| author_facet | Meshach Asare-Werehene Hideaki Tsuyoshi Huilin Zhang Reza Salehi Chia-Yu Chang Euridice Carmona Clifford L. Librach Anne-Marie Mes-Masson Chia-Ching Chang Dylan Burger Yoshio Yoshida Benjamin K. Tsang |
| author_sort | Meshach Asare-Werehene |
| collection | DOAJ |
| description | Ovarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA. |
| first_indexed | 2024-03-09T22:23:19Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T22:23:19Z |
| publishDate | 2022-02-01 |
| publisher | MDPI AG |
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| series | Cancers |
| spelling | doaj.art-a14b45357f8d418aa1bc6f7162b43a192023-11-23T19:10:30ZengMDPI AGCancers2072-66942022-02-01144103910.3390/cancers14041039Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage SubtypesMeshach Asare-Werehene0Hideaki Tsuyoshi1Huilin Zhang2Reza Salehi3Chia-Yu Chang4Euridice Carmona5Clifford L. Librach6Anne-Marie Mes-Masson7Chia-Ching Chang8Dylan Burger9Yoshio Yoshida10Benjamin K. Tsang11Department of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, CanadaDepartment of Obstetrics and Gynecology, University of Fukui, Fukui 910-8507, JapanChronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, CanadaDepartment of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, CanadaDepartment of Biological Science and Technology, Department of Electrophysics and Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30068, TaiwanCentre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, CanadaCReATe Fertility Centre, 790 Bay Street, Suite 1100, Toronto, ON M5G 1N8, CanadaCentre de Recherche du Centre Hospitalier de l’Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, CanadaDepartment of Biological Science and Technology, Department of Electrophysics and Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30068, TaiwanDepartment of Cellular and Molecular Medicine & The Centre for Infection, Immunity and Inflammation (CI3), Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, CanadaDepartment of Obstetrics and Gynecology, University of Fukui, Fukui 910-8507, JapanDepartment of Obstetrics & Gynecology, Faculty of Medicine & Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, ON K1H 8L1, CanadaOvarian cancer (OVCA) is the most lethal gynaecological cancer with a 5-year survival rate less than 50%. Despite new therapeutic strategies, such as immune checkpoint blockers (ICBs), tumor recurrence and drug resistance remain key obstacles in achieving long-term therapeutic success. Therefore, there is an urgent need to understand the cellular mechanisms of immune dysregulation in chemoresistant OVCA in order to harness the host’s immune system to improve survival. The over-expression of plasma gelsolin (pGSN) mRNA is associated with a poorer prognosis in OVCA patients; however, its immuno-modulatory role has not been elucidated. In this study, for the first time, we report pGSN as an inhibitor of M1 macrophage anti-tumor functions in OVCA chemoresistance. Increased epithelial pGSN expression was associated with the loss of chemoresponsiveness and poor survival. While patients with increased M1 macrophage infiltration exhibited better survival due to nitric-oxide-induced ROS accumulation in OVCA cells, cohorts with poor survival had a higher infiltration of M2 macrophages. Interestingly, increased epithelial pGSN expression was significantly associated with the reduced survival benefits of infiltrated M1 macrophages, through apoptosis via increased caspase-3 activation and reduced production of iNOS and TNFα. Additionally, epithelial pGSN expression was an independent prognostic marker in predicting progression-free survival. These findings support our hypothesis that pGSN is a modulator of inflammation and confers chemoresistance in OVCA, in part by resetting the relative abundance and function of macrophage subtypes in the ovarian tumor microenvironment. Our findings raise the possibility that pGSN may be a potential therapeutic target for immune-mediated chemoresistance in OVCA.https://www.mdpi.com/2072-6694/14/4/1039tumor-associated macrophages (TAMs)plasma gelsolin (pGSN)ovarian cancer (OVCA)small extracellular vesicles (sEV)chemoresistance |
| spellingShingle | Meshach Asare-Werehene Hideaki Tsuyoshi Huilin Zhang Reza Salehi Chia-Yu Chang Euridice Carmona Clifford L. Librach Anne-Marie Mes-Masson Chia-Ching Chang Dylan Burger Yoshio Yoshida Benjamin K. Tsang Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes Cancers tumor-associated macrophages (TAMs) plasma gelsolin (pGSN) ovarian cancer (OVCA) small extracellular vesicles (sEV) chemoresistance |
| title | Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes |
| title_full | Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes |
| title_fullStr | Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes |
| title_full_unstemmed | Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes |
| title_short | Plasma Gelsolin Confers Chemoresistance in Ovarian Cancer by Resetting the Relative Abundance and Function of Macrophage Subtypes |
| title_sort | plasma gelsolin confers chemoresistance in ovarian cancer by resetting the relative abundance and function of macrophage subtypes |
| topic | tumor-associated macrophages (TAMs) plasma gelsolin (pGSN) ovarian cancer (OVCA) small extracellular vesicles (sEV) chemoresistance |
| url | https://www.mdpi.com/2072-6694/14/4/1039 |
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