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Control of cancer formation by intrinsic genetic noise and microenvironmental cues

Nature Reviews Cancer volume 15, pages 499–509 (2015)Cite this article

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Abstract

Differentiation therapies that induce malignant cells to stop growing and revert to normal tissue-specific differentiated cell types are successful in the treatment of a few specific haematological tumours. However, this approach has not been widely applied to solid tumours because their developmental origins are less well understood. Recent advances suggest that understanding tumour cell plasticity and how intrinsic factors (such as genetic noise and microenvironmental signals, including physical cues from the extracellular matrix) govern cell state switches will help in the development of clinically relevant differentiation therapies for solid cancers.

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Figure 1: Intrinsic noise gives rise to heterogeneous tumour populations.
Figure 2: Simulated intrinsic noise and extrinsic variation in cell hyperproliferation.
Figure 3: Cell intrinsic variation factors as a source of cancer cell plasticity.
Figure 4: Extrinsic cues contributing to cancer cell plasticity and reversion.

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Acknowledgements

The authors thank K. Johnson of Boston Children's Hospital for assistance with figure preparation. This work was supported by a Breast Cancer Research Foundation Translational Research Grant (14-60-26-BROC) to A.B., and a Department of Defense Breast Cancer Innovator Award (BC074986) to D.E.I. The authors apologize to the many people whose work we could not cite owing to space constraints.

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Author notes

  1. Amy Brock and Silva Krause: A.B. and S.K. contributed equally to this work.

Authors and Affiliations

  1. Department of Biomedical Engineering, Institute for Cell and Molecular Biology, The University of Texas, Austin, 78712, Texas, USA

    Amy Brock

  2. Momenta Pharmaceuticals, Cambridge, 02142, Massachusetts, USA

    Silva Krause

  3. Wyss Institute for Biologically Inspired Engineering at Harvard University, 3 Blackfan Circle, CLSB 5, Boston, 02115, Massachusetts, USA

    Donald E. Ingber

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  1. Amy Brock
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  2. Silva Krause
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  3. Donald E. Ingber
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Corresponding author

Correspondence to Donald E. Ingber.

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Competing interests

S.K. holds equity in Momenta Pharmaceuticals and D.E.I. consults to Momenta Pharmaceuticals, SynDevRx Inc. and Celgene Cellular Therapeutics, on work unrelated to the material included here. A.B. declares no competing interests as defined by Nature Publishing Group or other interests that might be perceived to influence the interpretation of the article.

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Supplementary information S1 (table)

Ongoing clinical trials phase I to III targeting tumor microenvironment (interventional) (XLSX 13 kb)

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Brock, A., Krause, S. & Ingber, D. Control of cancer formation by intrinsic genetic noise and microenvironmental cues. Nat Rev Cancer 15, 499–509 (2015). https://doi.org/10.1038/nrc3959

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