TIMELINE

A history of exploring cancer in context

Abstract

The concept that progression of cancer is regulated by interactions of cancer cells with their microenvironment was postulated by Stephen Paget over a century ago. Contemporary tumour microenvironment (TME) research focuses on the identification of tumour-interacting microenvironmental constituents, such as resident or infiltrating non-tumour cells, soluble factors and extracellular matrix components, and the large variety of mechanisms by which these constituents regulate and shape the malignant phenotype of tumour cells. In this Timeline article, we review the developmental phases of the TME paradigm since its initial description. While illuminating controversies, we discuss the importance of interactions between various microenvironmental components and tumour cells and provide an overview and assessment of therapeutic opportunities and modalities by which the TME can be targeted.

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Fig. 1: Timeline of tumour microenvironment research.
Fig. 2: The primary tumour and metastatic microenvironments regulate tumour progression by distinct pathways.
Fig. 3: The deleterious influence of tumour–tumour microenvironment interactions on therapy.

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Acknowledgements

The authors thank Y. Shaked for his valuable and constructive comments on this review. The authors’ studies were supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (Needham, MA, USA), the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG)), the Sara and Natan Blutinger Foundation (West Orange, NJ, USA), the Fred August and Adele Wolpers Charitable Fund (Clifton, NJ, USA) and the James and Rita Leibman Endowment Fund for Cancer Research (New York, NY, USA).

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