Key Points
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It is increasingly recognized that the tumour microenvironment has a crucial role in modulating tumour sensitivity to drugs.
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Stromal influence can render cancer cells more resistant to particular drugs, but can also enhance the responsiveness of tumour cells to other drugs.
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The interplay between tumour cells and stromal cells is complex and mediated by a range of soluble factors and cell–cell interactions.
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Understanding these interactions opens a host of opportunities for drug discovery. However, it is important that relevant in vivo models are used that faithfully replicate interactions between tumour cells and their microenvironment.
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Orthotopic and orthometastatic xenograft mouse models allow for an assessment of the impact of the tumour microenvironment on therapeutic efficacy.
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Such advances should help to bridge the gap between preclinical studies and clinical trials of anticancer agents.
Abstract
The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour–stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer — to tumour cells — resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents.
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Acknowledgements
The authors thank A. L. Kung and N. S. Gray for their suggestions during the preparation of this manuscript. This study was supported by the US National Institutes of Health (grant RO1-50947 to C.S.M.).
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D.W.M. is an equity holder in Axios Biosciences.
C.S.M. has received consultant honouraria from Millennium, Celgene, Novartis, Bristol-Myers Squibb, Merck & Co., Kosan, Pharmion, Centocor and Arno Therapeutics; licensing royalties from PharmaMar; research funding from Amgen, AVEO Pharma, OSI, EMD Serono, Sunesis, Gloucester Pharmaceuticals, Genzyme and Johnson & Johnson; and serves as a pro bono scientific advisor for Axios Biosciences.
J.M.N. declares no competing financial interests.
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McMillin, D., Negri, J. & Mitsiades, C. The role of tumour–stromal interactions in modifying drug response: challenges and opportunities. Nat Rev Drug Discov 12, 217–228 (2013). https://doi.org/10.1038/nrd3870
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DOI: https://doi.org/10.1038/nrd3870
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