Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis
Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. Howev...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:8ba8c39e586b4cab9c01eff91032d3922021-12-02T00:10:45ZOvarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis2296-634X10.3389/fcell.2021.764375https://doaj.org/article/8ba8c39e586b4cab9c01eff91032d3922021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcell.2021.764375/fullhttps://doaj.org/toc/2296-634XTranscoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Here we investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes in MCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associated with the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependent MAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NF-kB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETBR or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC pro-metastatic behaviour via MMT.Danila Del RioIlenia MasiValentina CapraraFrancesca SpadaroFlavia OttaviRaffaele StrippoliPilar SandovalManuel López-CabreraRicardo Sainz de la CuestaAnna BagnatoLaura RosanòLaura RosanòFrontiers Media S.A.articlemesothelial cellsendothelin-1serous ovarian cancerβ-arrestin1mesothelial-to-mesenchymal transitionBiology (General)QH301-705.5ENFrontiers in Cell and Developmental Biology, Vol 9 (2021) |
| institution |
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| collection |
DOAJ |
| language |
EN |
| topic |
mesothelial cells endothelin-1 serous ovarian cancer β-arrestin1 mesothelial-to-mesenchymal transition Biology (General) QH301-705.5 |
| spellingShingle |
mesothelial cells endothelin-1 serous ovarian cancer β-arrestin1 mesothelial-to-mesenchymal transition Biology (General) QH301-705.5 Danila Del Rio Ilenia Masi Valentina Caprara Francesca Spadaro Flavia Ottavi Raffaele Strippoli Pilar Sandoval Manuel López-Cabrera Ricardo Sainz de la Cuesta Anna Bagnato Laura Rosanò Laura Rosanò Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| description |
Transcoelomic spread of serous ovarian cancer (SOC) results from the cooperative interactions between cancer and host components. Tumor-derived factors might allow the conversion of mesothelial cells (MCs) into tumor-associated MCs, providing a favorable environment for SOC cell dissemination. However, factors and molecular mechanisms involved in this process are largely unexplored. Here we investigated the tumor-related endothelin-1 (ET-1) as an inducer of changes in MCs supporting SOC progression. Here, we report a significant production of ET-1 from MCs associated with the expression of its cognate receptors, ETA and ETB, along with the protein β-arrestin1. ET-1 triggers MC proliferation via β-arrestin1-dependent MAPK and NF-kB pathways and increases the release of cancer-related factors. The ETA/ETB receptor activation supports the genetic reprogramming of mesothelial-to-mesenchymal transition (MMT), with upregulation of mesenchymal markers, as fibronectin, α-SMA, N-cadherin and vimentin, NF-kB-dependent Snail transcriptional activity and downregulation of E-cadherin and ZO-1, allowing to enhanced MC migration and invasion, and SOC transmesothelial migration. These effects are impaired by either blockade of ETAR and ETBR or by β-arrestin1 silencing. Notably, in peritoneal metastases both ETAR and ETBR are co-expressed with MMT markers compared to normal control peritoneum. Collectively, our report shows that the ET-1 axis may contribute to the early stage of SOC progression by modulating MC pro-metastatic behaviour via MMT. |
| format |
article |
| author |
Danila Del Rio Ilenia Masi Valentina Caprara Francesca Spadaro Flavia Ottavi Raffaele Strippoli Pilar Sandoval Manuel López-Cabrera Ricardo Sainz de la Cuesta Anna Bagnato Laura Rosanò Laura Rosanò |
| author_facet |
Danila Del Rio Ilenia Masi Valentina Caprara Francesca Spadaro Flavia Ottavi Raffaele Strippoli Pilar Sandoval Manuel López-Cabrera Ricardo Sainz de la Cuesta Anna Bagnato Laura Rosanò Laura Rosanò |
| author_sort |
Danila Del Rio |
| title |
Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| title_short |
Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| title_full |
Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| title_fullStr |
Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| title_full_unstemmed |
Ovarian Cancer-Driven Mesothelial-to-Mesenchymal Transition is Triggered by the Endothelin-1/β-arr1 Axis |
| title_sort |
ovarian cancer-driven mesothelial-to-mesenchymal transition is triggered by the endothelin-1/β-arr1 axis |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/8ba8c39e586b4cab9c01eff91032d392 |
| work_keys_str_mv |
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1718403875409494016 |