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Mouse models of advanced spontaneous metastasis for experimental therapeutics

Nature Reviews Cancer volume 11, pages 135–141 (2011)Cite this article

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Abstract

An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain _targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models.

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Figure 1: The metastatic cascade.
Figure 2: The selection of metastatically aggressive subpopulations of tumour cells often requires rounds of in vivo selection.
Figure 3: Differential response of metastases and primary tumours to therapy.
Figure 4: Treatment of visceral metastatic disease can result in the appearance of metastases to the brain.

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Acknowledgements

The authors would like to thank C. Cheng for her excellent secretarial assistance; L. Ellis, I. Hart, I. J. Fidler, C. Hackl and U. Emmenegger for their comments, past and present. R.S.K.'s metastasis therapy studies are supported by grants from the US National Institutes of Health (NIH)(CA-41233), Canadian Cancer Society Research Institute (CCSRI), Canadian Institutes of Health Research (CIHR) and the Ontario Institute for Cancer Research (OICR), as well as past or present sponsored research agreements with Taiho Pharmaceuticals, Tokyo, Japan, ImClone Systems, New York, GSK, Philadelphia and Pfizer, La Jolla, USA. R.S.K. holds a Tier I Canada Research Chair in Tumour Biology, Angiogenesis and Antiangiogenic Therapy.

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  1. Giulio Francia, William Cruz-Munoz, Shan Man, Ping Xu and Robert S. Kerbel are at The Molecular & Cellular Biology Research, Sunnybrook Health Science Centre, S-217 Research Building, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.,

    Giulio Francia, William Cruz-Munoz, Shan Man, Ping Xu & Robert S. Kerbel

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  1. Giulio Francia
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Correspondence to Giulio Francia or Robert S. Kerbel.

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R.S.K. is a consultant at Taiho Pharmaceuticals, Japan, and a member of the Scientific Advisory Board at MetronomX, USA.

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Clinicaltrails.gov Identifier NCT01131195

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Francia, G., Cruz-Munoz, W., Man, S. et al. Mouse models of advanced spontaneous metastasis for experimental therapeutics. Nat Rev Cancer 11, 135–141 (2011). https://doi.org/10.1038/nrc3001

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