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How the ageing microenvironment influences tumour progression

Nature Reviews Cancer volume 20, pages 89–106 (2020)Cite this article

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Abstract

Most cancers arise in individuals over the age of 60. As the world population is living longer and reaching older ages, cancer is becoming a substantial public health problem. It is estimated that, by 2050, more than 20% of the world’s population will be over the age of 60 — the economic, healthcare and financial burdens this may place on society are far from trivial. In this Review, we address the role of the ageing microenvironment in the promotion of tumour progression. Specifically, we discuss the cellular and molecular changes in non-cancerous cells during ageing, and how these may contribute towards a tumour permissive microenvironment; these changes encompass biophysical alterations in the extracellular matrix, changes in secreted factors and changes in the immune system. We also discuss the contribution of these changes to responses to cancer therapy as ageing predicts outcomes of therapy, including survival. Yet, in preclinical studies, the contribution of the aged microenvironment to therapy response is largely ignored, with most studies designed in 8-week-old mice rather than older mice that reflect an age appropriate to the disease being modelled. This may explain, in part, the failure of many successful preclinical therapies upon their translation to the clinic. Overall, the intention of this Review is to provide an overview of the interplay that occurs between ageing cell types in the microenvironment and cancer cells and how this is likely to impact tumour metastasis and therapy response.

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Fig. 1: Stromal deregulation in the aged microenvironment drives tumorigenesis and progression.
Fig. 2: Age-induced contextual changes in extracellular matrix structure and function in the tumour microenvironment.
Fig. 3: Immune cell switching, inflammaging and immunosenescence as drivers of age-induced tumour progression.

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Acknowledgements

This review is dedicated to the memory of Dr Aarti Hurria, a prominent geriatric oncologist at the City of Hope, Los Angeles, CA. Dr Hurria was a loving mentor to so many, a pioneer in the field of geriatric oncology, and a positive force in the field of ageing and cancer. This review was supported by research grants from the National Cancer Institute R01CA1746046 (ATW) and R01CA207935 (ATW, MEF).

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Authors and Affiliations

  1. The Wistar Institute, Immunology, Microenvironment and Metastasis Program, Philadelphia, PA, USA

    Mitchell Fane & Ashani T. Weeraratna

  2. Department of Biochemistry and Molecular Biology, Johns Hopkins School of Public Health, Baltimore, MD, USA

    Mitchell Fane & Ashani T. Weeraratna

  3. Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Ashani T. Weeraratna

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A.T.W. contributed substantially to the discussions and subject matter. M.E.F. researched the data for the article. A.T.W and M.E.F. contributed equally to writing the article and to reviewing and/or editing of the manuscript before submission.

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Correspondence to Mitchell Fane or Ashani T. Weeraratna.

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Nature Reviews Cancer thanks J. DeGregori, S. McAllister and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Proteostasis

The homeostatic maintenance of protein folding for proper structure and function.

Cellular senescence

Refers to the potentially irreversible arrest of cell proliferation (growth) that occurs when cells experience certain stressors.

Osteoclastogenesis

The process by which stem cells or stromal cells commit towards an osteoclast lineage.

Strain-stiffening

The property of increasing stiffness with increasing deformation.

Thymic atrophy

The loss in cellularity of the thymus.

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Fane, M., Weeraratna, A.T. How the ageing microenvironment influences tumour progression. Nat Rev Cancer 20, 89–106 (2020). https://doi.org/10.1038/s41568-019-0222-9

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