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Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype

Nature Reviews Cardiology volume 17, pages 523–531 (2020)Cite this article

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Abstract

A prolonged state of left ventricular pressure overload, commonly caused by hypertension and aortic valve disease, promotes remodelling of the myocardium that can progress to heart failure with preserved ejection fraction (HFpEF). In animal models, a major factor driving progression from pressure-overload hypertrophy (POH) to HFpEF is the activation and proliferation of an abnormal fibroblast phenotype that is resistant to apoptosis, degrades normal stromal matrix and is replaced with a fibrotic matrix structure. A similar fibroblast phenotype has been identified in the stroma of solid cancers. This cancer-associated fibroblast drives tumour growth and invasion. The proliferation and expansion of these abnormal fibroblast populations in both HFpEF and cancer contribute to progression of disease. In early-phase clinical trials, chemotherapeutic agents targeting cancer-associated fibroblasts had antitumour properties. In this Perspectives article, we postulate that, because the abnormal fibroblast populations in POH and cancer have identical characteristics, chemotherapeutic agents targeting the POH-related fibroblast might attenuate the development of myocardial fibrosis, a pathophysiological hallmark of HFpEF. These agents must be designed to target the abnormal fibroblasts with high specificity because many classes of chemotherapeutic drugs can themselves cause myocardial dysfunction and heart failure.

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Fig. 1: Parallels in the phenotypes of abnormal fibroblasts in cancer and POH.
Fig. 2: Regulation of the abnormal fibroblast by TGFβ.
Fig. 3: Abnormal growth and proliferation of fibroblasts in pressure-overload hypertrophy.

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Acknowledgements

The authors are supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award numbers R01HL130972 and 3R01HL130972-01A1S1 and a Merit Award from the Veterans Affairs Health Administration. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Veterans Affairs Health Administration. The authors thank R. Sargent, Sargent Illustration & Design, LLC, and S. Riffle, University of South Carolina School of Medicine, for assistance with the figures.

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Authors and Affiliations

  1. Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia, SC, USA

    Kelsie E. Oatmen & Francis G. Spinale

  2. Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA

    Kelsie E. Oatmen & Francis G. Spinale

  3. Columbia VA Health Care System, Columbia, SC, USA

    Kelsie E. Oatmen & Francis G. Spinale

  4. Prisma Health AYA Oncology Program, Greenville Memorial Medical Campus, Greenville, SC, USA

    Elizabeth Cull

  5. University of South Carolina School of Medicine Greenville, Greenville, SC, USA

    Elizabeth Cull

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  1. Kelsie E. Oatmen
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K.E.O. and F.G.S. made substantial contributions to researching data for the article, discussions of content and the writing of the manuscript. All the authors reviewed and edited the manuscript before submission.

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Correspondence to Francis G. Spinale.

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Nature Reviews Cardiology thanks I. Dixon, Z. Kassiri and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Oatmen, K.E., Cull, E. & Spinale, F.G. Heart failure as interstitial cancer: emergence of a malignant fibroblast phenotype. Nat Rev Cardiol 17, 523–531 (2020). https://doi.org/10.1038/s41569-019-0286-y

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