High metastatic efficiency of human sarcoma cells in Rag2/gammac double knockout mice provides a powerful test system for antimetastatic targeted therapy.
Immunodeficient animal models are invaluable tools to investigate the metastatic propensity of human tumours. However residual immune responses, in particular natural killer (NK) cells, severely hamper the traffic and growth of human tumour cells. We studied whether a genetically modified mouse host lacking T, B and NK immunity allowed an improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lines was studied in double knockout Rag2(-/-);gammac(-/-) mice in comparison with NK-depleted nude mice. Rag2(-/-);gammac(-/-) mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2(-/-);gammac(-/-) was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2(-/-);gammac(-/-) mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2(-/-);gammac(-/-) mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lines failed to colonise the liver of Rag2(-/-);gammac(-/-) mice, independently of their metastatic spread to other sites. In vitro analysis of the molecular mechanisms of liver metastasis of sarcomas implicated liver-produced growth and motility factors, in particular the insulin-like growth factor (IGF) axis. NVP-BEZ235, a specific inhibitor of downstream signal transduction targeting PI3K and mTOR, strongly inhibited liver metastasis of human sarcoma cells. In conclusion, the Rag2(-/-);gammac(-/-) mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies.
Nanni
Patrizia
P
Cancer Research Section, Department of Experimental Pathology, Viale Filopanti 22, University of Bologna, 40126 Bologna, Italy.
Nicoletti
Giordano
G
Landuzzi
Lorena
L
Croci
Stefania
S
Murgo
Annalisa
A
Palladini
Arianna
A
Antognoli
Agnese
A
Ianzano
Marianna L
ML
Stivani
Valeria
V
Grosso
Valentina
V
Maira
Sauveur-Michel
SM
García-Echeverría
Carlos
C
Scotlandi
Katia
K
De Giovanni
Carla
C
Lollini
Pier-Luigi
PL
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002633:Chemotaxis / Q000276:immunology; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007108:Immune Tolerance; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary; D008175:Lung Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D014183:Transplantation, Heterologous; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C499308:Rag2 protein, mouse; C531198:dactolisib