Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor.
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mou...
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2012
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oai:doaj.org-article:84ef216e802b4cee8d005229b86ae3542021-11-18T07:14:43ZMultiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor.1932-620310.1371/journal.pone.0039626https://doaj.org/article/84ef216e802b4cee8d005229b86ae3542012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22737248/?tool=EBIhttps://doaj.org/toc/1932-6203In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2-/-;Il2rg-/-, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2-/-;Il2rg-/- mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2-/-;Il2rg-/- mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2-/-;Il2rg-/- mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents.Patrizia NanniGiordano NicolettiArianna PalladiniStefania CrociAnnalisa MurgoMarianna L IanzanoValentina GrossoValeria StivaniAgnese AntognoliAlessia LamolinaraLorena LanduzziEmmanuelle di TomasoManuela IezziCarla De GiovanniPier-Luigi LolliniPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 6, p e39626 (2012) |
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| collection |
DOAJ |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Patrizia Nanni Giordano Nicoletti Arianna Palladini Stefania Croci Annalisa Murgo Marianna L Ianzano Valentina Grosso Valeria Stivani Agnese Antognoli Alessia Lamolinara Lorena Landuzzi Emmanuelle di Tomaso Manuela Iezzi Carla De Giovanni Pier-Luigi Lollini Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| description |
In vivo studies of the metastatic process are severely hampered by the fact that most human tumor cell lines derived from highly metastatic tumors fail to consistently metastasize in immunodeficient mice like nude mice. We describe a model system based on a highly immunodeficient double knockout mouse, Rag2-/-;Il2rg-/-, which lacks T, B and NK cell activity. In this model human metastatic HER-2+ breast cancer cells displayed their full multiorgan metastatic potential, without the need for selections or additional manipulations of the system. Human HER-2+ breast cancer cell lines MDA-MB-453 and BT-474 injected into Rag2-/-;Il2rg-/- mice faithfully reproduced human cancer dissemination, with multiple metastatic sites that included lungs, bones, brain, liver, ovaries, and others. Multiorgan metastatic spread was obtained both from local tumors, growing orthotopically or subcutaneously, and from cells injected intravenously. The problem of brain recurrencies is acutely felt in HER-2+ breast cancer, because monoclonal antibodies against HER-2 penetrate poorly the blood-brain barrier. We studied whether a novel oral small molecule inhibitor of downstream PI3K, selected for its penetration of the blood-brain barrier, could affect multiorgan metastatic spread in Rag2-/-;Il2rg-/- mice. NVP-BKM120 effectively controlled metastatic growth in multiple organs, and resulted in a significant proportion of mice free from brain and bone metastases. Human HER-2+ human breast cancer cells in Rag2-/-;Il2rg-/- mice faithfully reproduced the multiorgan metastatic pattern observed in patients, thus allowing the investigation of metastatic mechanisms and the preclinical study of novel antimetastatic agents. |
| format |
article |
| author |
Patrizia Nanni Giordano Nicoletti Arianna Palladini Stefania Croci Annalisa Murgo Marianna L Ianzano Valentina Grosso Valeria Stivani Agnese Antognoli Alessia Lamolinara Lorena Landuzzi Emmanuelle di Tomaso Manuela Iezzi Carla De Giovanni Pier-Luigi Lollini |
| author_facet |
Patrizia Nanni Giordano Nicoletti Arianna Palladini Stefania Croci Annalisa Murgo Marianna L Ianzano Valentina Grosso Valeria Stivani Agnese Antognoli Alessia Lamolinara Lorena Landuzzi Emmanuelle di Tomaso Manuela Iezzi Carla De Giovanni Pier-Luigi Lollini |
| author_sort |
Patrizia Nanni |
| title |
Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| title_short |
Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| title_full |
Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| title_fullStr |
Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| title_full_unstemmed |
Multiorgan metastasis of human HER-2+ breast cancer in Rag2-/-;Il2rg-/- mice and treatment with PI3K inhibitor. |
| title_sort |
multiorgan metastasis of human her-2+ breast cancer in rag2-/-;il2rg-/- mice and treatment with pi3k inhibitor. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/84ef216e802b4cee8d005229b86ae354 |
| work_keys_str_mv |
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