High metastatic efficiency of human sarcoma cells in Rag2/γc double knockout mice provides a powerful test system for antimetastatic targeted therapy

被引：26

作者：

Nanni, Patrizia ^{[1
,2
]}

Nicoletti, Giordano ^{[3
]}

Landuzzi, Lorena ^{[3
]}

Croci, Stefania ^{[1
]}

Murgo, Annalisa ^{[1
]}

Palladini, Arianna ^{[1
]}

Antognoli, Agnese ^{[1
]}

Ianzano, Marianna L. ^{[1
]}

Stivani, Valeria ^{[1
]}

Grosso, Valentina ^{[1
]}

Maira, Sauveur-Michel ^{[4
]}

Garcia-Echeverria, Carlos ^{[4
]}

Scotlandi, Katia ^{[3
]}

De Giovanni, Carla ^{[1
,2
]}

Lollini, Pier-Luigi ^{[2
,5
]}

机构：

[1] Univ Bologna, Canc Res Sect, Dept Expt Pathol, I-40126 Bologna, Italy

[2] Univ Bologna, Interdepartmental Ctr Canc Res Giorgio Prodi, I-40126 Bologna, Italy

[3] Rizzoli Orthoped Inst, Expt Oncol Lab, Bologna, Italy

[4] Novartis Pharma AG, Novartis Inst BioMed Res, Basel, Switzerland

[5] Univ Bologna, Dept Hematol & Oncol Sci L&A Seragnoli, I-40126 Bologna, Italy

来源：

EUROPEAN JOURNAL OF CANCER | 2010年 / 46卷 / 03期

关键词：

Metastasis; Immunodepressed mice; Xenotransplants; Animal models; Sarcoma; HUMAN RHABDOMYOSARCOMA CELLS; NK CELLS; IN-VIVO; LIVER; MODELS; GROWTH; CANCER; EXPRESSION; NUDE; PARACRINE;

D O I：

10.1016/j.ejca.2009.11.018

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 all improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lilies was studied in double knockout Rag2(-/-);gamma c(-/-) mice in comparison with NK-depleted nude mice. Rag2(-/-),gamma c(-/-) mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2(-/-);gamma c(-/-) was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2(-/-);gamma c(-/-) mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2(-/-);gamma c(-/-) mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lilies failed to colonise the liver of Rag2(-/-);gamma c(-/-) 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(-/-);gamma c(-/-) mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：659 / 668

页数：10

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