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Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53
Ovarian cancer (OvCA) remains one of the most devastating malignancies, but treatment options are still limited. We report that amphiregulin (AREG) can serve as an effective and safe pharmacological target in a syngeneic murine model. AREG is highly abundant in abdominal fluids of patients with adva...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154589/ https://www.ncbi.nlm.nih.gov/pubmed/33941851 http://dx.doi.org/10.1038/s41388-021-01784-8 |
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author | Lindzen, Moshit Ghosh, Soma Noronha, Ashish Drago, Diana Nataraj, Nishanth Belugali Leitner, Orith Carvalho, Silvia Zmora, Einav Sapoznik, Stav Shany, Keren Bahar Levanon, Keren Aderka, Dan Ramírez, Belinda Sánchez Dahlhoff, Maik McNeish, Iain Yarden, Yosef |
author_facet | Lindzen, Moshit Ghosh, Soma Noronha, Ashish Drago, Diana Nataraj, Nishanth Belugali Leitner, Orith Carvalho, Silvia Zmora, Einav Sapoznik, Stav Shany, Keren Bahar Levanon, Keren Aderka, Dan Ramírez, Belinda Sánchez Dahlhoff, Maik McNeish, Iain Yarden, Yosef |
author_sort | Lindzen, Moshit |
collection | PubMed |
description | Ovarian cancer (OvCA) remains one of the most devastating malignancies, but treatment options are still limited. We report that amphiregulin (AREG) can serve as an effective and safe pharmacological target in a syngeneic murine model. AREG is highly abundant in abdominal fluids of patients with advanced OvCa. In immunocompetent animals, depletion or overexpression of AREG respectively prolonged or shortened animal survival. A new antibody we generated in AREG-knockout mice recognized murine AREG and reproducibly prolonged animal survival in the syngeneic model. The underlying mechanism likely involves binding of wildtype p53 to AREG’s promoter and autocrine activation of the epidermal growth factor receptor (EGFR), a step blocked by the antibody. Accordingly, depletion of p53 downregulated AREG secretion and conferred tolerance, whereas blocking an adaptive process involving CXCL1, which transactivates EGFR, might increase therapeutic efficacy. Consistent with these observations, analysis of OvCa patients revealed that high AREG correlates with poor prognosis of patients expressing wildtype TP53. In conclusion, clinical tests of the novel antibody are warranted; high AREG, normal TP53, and reduced CXCL1 activity might identify patients with OvCa who may derive therapeutic benefit. |
format | Online Article Text |
id | pubmed-8154589 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-81545892021-06-10 Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 Lindzen, Moshit Ghosh, Soma Noronha, Ashish Drago, Diana Nataraj, Nishanth Belugali Leitner, Orith Carvalho, Silvia Zmora, Einav Sapoznik, Stav Shany, Keren Bahar Levanon, Keren Aderka, Dan Ramírez, Belinda Sánchez Dahlhoff, Maik McNeish, Iain Yarden, Yosef Oncogene Article Ovarian cancer (OvCA) remains one of the most devastating malignancies, but treatment options are still limited. We report that amphiregulin (AREG) can serve as an effective and safe pharmacological target in a syngeneic murine model. AREG is highly abundant in abdominal fluids of patients with advanced OvCa. In immunocompetent animals, depletion or overexpression of AREG respectively prolonged or shortened animal survival. A new antibody we generated in AREG-knockout mice recognized murine AREG and reproducibly prolonged animal survival in the syngeneic model. The underlying mechanism likely involves binding of wildtype p53 to AREG’s promoter and autocrine activation of the epidermal growth factor receptor (EGFR), a step blocked by the antibody. Accordingly, depletion of p53 downregulated AREG secretion and conferred tolerance, whereas blocking an adaptive process involving CXCL1, which transactivates EGFR, might increase therapeutic efficacy. Consistent with these observations, analysis of OvCa patients revealed that high AREG correlates with poor prognosis of patients expressing wildtype TP53. In conclusion, clinical tests of the novel antibody are warranted; high AREG, normal TP53, and reduced CXCL1 activity might identify patients with OvCa who may derive therapeutic benefit. Nature Publishing Group UK 2021-04-30 2021 /pmc/articles/PMC8154589/ /pubmed/33941851 http://dx.doi.org/10.1038/s41388-021-01784-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lindzen, Moshit Ghosh, Soma Noronha, Ashish Drago, Diana Nataraj, Nishanth Belugali Leitner, Orith Carvalho, Silvia Zmora, Einav Sapoznik, Stav Shany, Keren Bahar Levanon, Keren Aderka, Dan Ramírez, Belinda Sánchez Dahlhoff, Maik McNeish, Iain Yarden, Yosef Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title | Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title_full | Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title_fullStr | Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title_full_unstemmed | Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title_short | Targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
title_sort | targeting autocrine amphiregulin robustly and reproducibly inhibits ovarian cancer in a syngeneic model: roles for wildtype p53 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154589/ https://www.ncbi.nlm.nih.gov/pubmed/33941851 http://dx.doi.org/10.1038/s41388-021-01784-8 |
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