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High metastatic efficiency of human sarcoma cells in Rag2/gammac double knockout mice provides a powerful test system
Patrizia Nanni1, Giordano Nicoletti, Lorena Landuzzi
1Cancer Research Section, Department of Experimental Pathology, Viale Filopanti 22, University of Bologna, 40126 Bologna, Italy.
Abstract:
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.
Insights
A novel mouse model lacking T, B, and NK cell immunity significantly enhances human tumor metastasis, enabling better study of cancer spread and drug efficacy.
Area of Science:
- Oncology
- Immunology
- Animal Models
Background:
- Immunodeficient animal models are crucial for studying human tumor metastasis.
- Residual immune responses, particularly natural killer (NK) cells, can limit the metastatic potential of human tumors in these models.
Purpose of the Study:
- To investigate if a genetically modified mouse lacking T, B, and NK cell immunity (Rag2(-/-);gammac(-/-)) improves the metastatic phenotype expression of human tumors.
- To compare the metastatic efficiency of human sarcoma cell lines in Rag2(-/-);gammac(-/-) mice versus NK-depleted nude mice.
- To evaluate the potential of this model for preclinical testing of targeted therapies.
Main Methods:
- Human sarcoma cell lines were administered intravenously (i.v.) or subcutaneously (s.c.) into Rag2(-/-);gammac(-/-) mice and NK-depleted nude mice.
- Metastatic spread, organ preference, and growth kinetics were analyzed.
- In vitro studies investigated molecular mechanisms of liver metastasis, including the insulin-like growth factor (IGF) axis.
- The efficacy of NVP-BEZ235, a PI3K/mTOR inhibitor, was tested against liver metastasis.
Main Results:
- Rag2(-/-);gammac(-/-) mice exhibited significantly enhanced multiorgan metastasis of human sarcoma cell lines compared to nude mice.
- Metastatic growth was faster in Rag2(-/-);gammac(-/-) mice, allowing earlier evaluation.
- Sarcomas preferentially metastasized to the liver in Rag2(-/-);gammac(-/-) mice, an organ preference not observed in nude mice.
- NVP-BEZ235 treatment strongly inhibited liver metastasis.
Conclusions:
- The Rag2(-/-);gammac(-/-) mouse model effectively recapitulates human metastatic phenotypes that are often suppressed in conventional immunodeficient models.
- This model provides a superior platform for studying tumor metastasis and for preclinical evaluation of targeted therapies, particularly for sarcomas.
- The findings highlight the role of the IGF axis in sarcoma liver metastasis and the therapeutic potential of PI3K/mTOR inhibitors.
