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Polyamines in cancer: integrating organismal metabolism and antitumour immunity

Nature Reviews Cancer volume 22, pages 467–480 (2022)Cite this article

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Abstract

The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically ‘cold’ tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.

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Fig. 1: Oncogenic regulation of polyamine metabolism and uptake and sources of extracellular polyamines in the TME.
Fig. 2: Influence of polyamines and their modulation on immune cells in the TME.
Fig. 3: Hypoxic and chronic infection/inflammatory microenvironments promote carcinogenic polyamine metabolism.

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Acknowledgements

Work in the Casero and Stewart laboratory is supported by grants from the US National Institutes of Health (CA204345 and CA235863), the Samuel Waxman Cancer Research Foundation, the University of Pennsylvania Orphan Disease Center Million Dollar Bike Ride (MDBR-20-135-SRS), the Chan Zuckerberg Initiative and a research contract with Panbela Therapeutics Inc.

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  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Cassandra E. Holbert, Robert A. Casero Jr & Tracy Murray Stewart

  2. Panbela Therapeutics Inc., Waconia, MN, USA

    Michael T. Cullen

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The authors contributed equally to all aspects of the article.

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The Casero and Stewart laboratory and Johns Hopkins University receive research funding from Panbela Therapeutics Inc., of which M.T.C. is an employee.

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Glossary

Azoxymethane–dextran sodium sulfate model

A common murine model of inflammation-associated colorectal cancer that incorporates chemical initiation of DNA adducts combined with induction of colitis.

Biofilm

A structure formed by a community of the microbiota that adheres to and lines a surface such as the colonic lumen.

M1 macrophage

A pro-inflammatory type of macrophage that mediates pathogen resistance but can also exacerbate inflammatory conditions and cause tissue damage.

M2 macrophages

Anti-inflammatory macrophage population characterized by expression of arginase 1 (ARG1) and associated with tissue repair and immunosuppressive microenvironments.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of immature myeloid cells that have immunosuppressive function and undergo systemic expansion in association with cancer.

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Holbert, C.E., Cullen, M.T., Casero, R.A. et al. Polyamines in cancer: integrating organismal metabolism and antitumour immunity. Nat Rev Cancer 22, 467–480 (2022). https://doi.org/10.1038/s41568-022-00473-2

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