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 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.
Section of Cancer Research, Department of Experimental Pathology, University of Bologna, Bologna, Italy.
Patrizia
P
Nanni
Giordano
G
Nicoletti
Arianna
A
Palladini
Stefania
S
Croci
Annalisa
A
Murgo
Marianna L
ML
Ianzano
Valentina
V
Grosso
Valeria
V
Stivani
Agnese
A
Antognoli
Alessia
A
Lamolinara
Lorena
L
Landuzzi
Emmanuelle
E
di Tomaso
Manuela
M
Iezzi
Carla
C
De Giovanni
Pier-Luigi
PL
Lollini
D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D014018:Tissue Distribution
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D053631:Interleukin Receptor Common gamma Subunit; D009687:Nuclear Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C507941:IL2RG protein, human; C507942:Il2rg protein, mouse; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse