Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Polyamines in cancer: integrating organismal metabolism and antitumour immunity

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Pegg, A. E. Mammalian polyamine metabolism and function. IUBMB Life 61, 880–894 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Smirnov, I. V., Dimitrov, S. I. & Makarov, V. L. Polyamine-DNA interactions. Condensation of chromatin and naked DNA. J. Biomol. Struct. Dyn. 5, 1149–1161 (1988).

    Article  CAS  PubMed  Google Scholar 

  3. Igarashi, K. & Kashiwagi, K. Polyamines: mysterious modulators of cellular functions. Biochem. Biophys. Res. Commun. 271, 559–564 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Dever, T. E. & Ivanov, I. P. Roles of polyamines in translation. J. Biol. Chem. 293, 18719–18729 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pegg, A. E. Functions of polyamines in mammals. J. Biol. Chem. 291, 14904–14912 (2016). This Review provides a comprehensive overview of polyamine metabolism, regulation of the individual enzymes and the roles of polyamines in disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hesterberg, R. S., Cleveland, J. L. & Epling-Burnette, P. K. Role of polyamines in immune cell functions. Med. Sci. (Basel) 6, 22 (2018).

    Google Scholar 

  7. Sjögren, T. et al. The structure of murine N1-acetylspermine oxidase reveals molecular details of vertebrate polyamine catabolism. Biochemistry 56, 458–467 (2017).

    Article  PubMed  CAS  Google Scholar 

  8. Igarashi, K. & Kashiwagi, K. Characteristics of cellular polyamine transport in prokaryotes and eukaryotes. Plant Physiol. Biochem. 48, 506–512 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Poulin, R., Casero, R. A. & Soulet, D. Recent advances in the molecular biology of metazoan polyamine transport. Amino Acids 42, 711–723 (2012).

    Article  CAS  PubMed  Google Scholar 

  10. Reguera, R. M., Tekwani, B. L. & Balaña-Fouce, R. Polyamine transport in parasites: a potential target for new antiparasitic drug development. Comp. Biochem. Physiol. C. Toxicol. Pharmacol. 140, 151–164 (2005).

    Article  PubMed  CAS  Google Scholar 

  11. Abdulhussein, A. A. & Wallace, H. M. Polyamines and membrane transporters. Amino Acids 46, 655–660 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Moriyama, Y., Hatano, R., Moriyama, S. & Uehara, S. Vesicular polyamine transporter as a novel player in amine-mediated chemical transmission. Biochim. Biophys. Acta Biomembr. 1862, 183208 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Soulet, D., Gagnon, B., Rivest, S., Audette, M. & Poulin, R. A fluorescent probe of polyamine transport accumulates into intracellular acidic vesicles via a two-step mechanism. J. Biol. Chem. 279, 49355–49366 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Belting, M. et al. Glypican-1 is a vehicle for polyamine uptake in mammalian cells: a pivital role for nitrosothiol-derived nitric oxide. J. Biol. Chem. 278, 47181–47189 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Uemura, T., Stringer, D. E., Blohm-Mangone, K. A. & Gerner, E. W. Polyamine transport is mediated by both endocytic and solute carrier transport mechanisms in the gastrointestinal tract. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G517–G522 (2010). This study investigates the roles of caveolin 1, NOS2 and SLC3A2 in the transport of exogenous putrescine in colorectal cancer cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hamouda, N. N. et al. ATP13A3 is a major component of the enigmatic mammalian polyamine transport system. J. Biol. Chem. 296, 100182 (2021).

    Article  CAS  PubMed  Google Scholar 

  17. van Veen, S. et al. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature 578, 419–424 (2020). ATP13A2 is identified as a lysosomal polyamine exporter with preferred substrate specificity for spermine and the ability to promote endocytic polyamine uptake.

    Article  PubMed  CAS  Google Scholar 

  18. Vrijsen, S. et al. ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress. Proc. Natl Acad. Sci. USA 117, 31198–31207 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Casero, R. A. Jr., Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681–695 (2018). This Review focuses on the interplay between polyamine metabolism and oncogenic pathways and provides a synopsis of recent treatment strategies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bello-Fernandez, C., Packham, G. & Cleveland, J. L. The ornithine decarboxylase gene is a transcriptional target of c-Myc. Proc. Natl Acad. Sci. USA 90, 7804–7808 (1993). This study first identifies ODC1 as a target of MYC.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peters, M. C., Minton, A., Phanstiel, O. IV & Gilmour, S. K. A novel polyamine-targeted therapy for BRAF mutant melanoma tumors. Med. Sci. 6, 3 (2018).

    CAS  Google Scholar 

  22. Alexander, E. T. et al. Harnessing the polyamine transport system to treat BRAF inhibitor-resistant melanoma. Cancer Biol. Ther. 22, 225–237 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Roy, U. K., Rial, N. S., Kachel, K. L. & Gerner, E. W. Activated K-RAS increases polyamine uptake in human colon cancer cells through modulation of caveolar endocytosis. Mol. Carcinog. 47, 538–553 (2008).

    Article  CAS  PubMed  Google Scholar 

  24. Ignatenko, N. A., Babbar, N., Mehta, D., Casero, R. A. Jr. & Gerner, E. W. Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells. Mol. Carcinog. 39, 91–102 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Tomasi, M. L. et al. Polyamine and methionine adenosyltransferase 2A crosstalk in human colon and liver cancer. Exp. Cell Res. 319, 1902–1911 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bachmann, A. S. & Geerts, D. Polyamine synthesis as a target of MYC oncogenes. J. Biol. Chem. 293, 18757–18769 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Flynn, A. T. & Hogarty, M. D. Myc, oncogenic protein translation, and the role of polyamines. Med. Sci. (Basel) 6, 41 (2018).

    Google Scholar 

  28. Nakanishi, S. & Cleveland, J. L. Polyamine homeostasis in development and disease. Med. Sci. (Basel) 9, 28 (2021).

    CAS  Google Scholar 

  29. Arruabarrena-Aristorena, A., Zabala-Letona, A. & Carracedo, A. Oil for the cancer engine: The cross-talk between oncogenic signaling and polyamine metabolism. Sci. Adv. 4, eaar2606 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Benamouzig, R., Mahé, S., Luengo, C., Rautureau, J. & Tomé, D. Fasting and postprandial polyamine concentrations in the human digestive lumen. Am. J. Clin. Nutr. 65, 766–770 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Ramos-Molina, B., Queipo-Ortuño, M. I., Lambertos, A., Tinahones, F. J. & Peñafiel, R. Dietary and gut microbiota polyamines in obesity- and age-related diseases. Front. Nutr. 6, 24 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Gerner, E. W., Bruckheimer, E. & Cohen, A. Cancer pharmacoprevention: Targeting polyamine metabolism to manage risk factors for colon cancer. J. Biol. Chem. 293, 18770–18778 (2018). This minireview focuses on the roles of polyamines in colon cancer and related chemopreventive strategies to reduce the risk of occurrence in predisposed patient populations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Muñoz-Esparza, N. C. et al. Polyamines in food. Front. Nutr. 6, 108 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Soda, K. et al. Long-term oral polyamine intake increases blood polyamine concentrations. J. Nutr. Sci. Vitaminol. 55, 361–366 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Minois, N., Carmona-Gutierrez, D. & Madeo, F. Polyamines in aging and disease. Aging 3, 716–732 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Soda, K., Dobashi, Y., Kano, Y., Tsujinaka, S. & Konishi, F. Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Exp. Gerontol. 44, 727–732 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Soda, K., Kano, Y., Chiba, F., Koizumi, K. & Miyaki, Y. Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis. PLoS ONE 8, e64357 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hirano, R., Shirasawa, H. & Kurihara, S. Health-promoting effects of dietary polyamines. Med. Sci. (Basel) 9, 8 (2021).

    CAS  Google Scholar 

  39. Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    Article  CAS  PubMed  Google Scholar 

  40. Minois, N. Molecular basis of the ‘anti-aging’ effect of spermidine and other natural polyamines - a mini-review. Gerontology 60, 319–326 (2014).

    Article  CAS  PubMed  Google Scholar 

  41. Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    Article  PubMed  CAS  Google Scholar 

  42. Holbert, C. E. et al. Autophagy induction by exogenous polyamines is an artifact of bovine serum amine oxidase activity in culture serum. J. Biol. Chem. 295, 9061–9068 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Okumura, S. et al. Oral administration of polyamines ameliorates liver ischemia/reperfusion injury and promotes liver regeneration in rats. Liver Transpl. 22, 1231–1244 (2016).

    Article  PubMed  Google Scholar 

  45. Sarhan, S., Knodgen, B. & Seiler, N. The gastrointestinal tract as polyamine source for tumor growth. Anticancer. Res. 9, 215–223 (1989).

    CAS  PubMed  Google Scholar 

  46. Raj, K. P. et al. Role of dietary polyamines in a phase III clinical trial of difluoromethylornithine (DFMO) and sulindac for prevention of sporadic colorectal adenomas. Br. J. Cancer 108, 512–518 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wallace, H. M. & Caslake, R. Polyamines and colon cancer. Eur. J. Gastroenterol. Hepatol. 13, 1033–1039 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Quemener, V., Moulinoux, J., Havouis, R. & Seiler, N. Polyamine deprivation enhances antitumoral efficacy of chemotherapy. Anticancer. Res. 12, 1447–1453 (1992).

    CAS  PubMed  Google Scholar 

  49. Corral, M. & Wallace, H. M. Upregulation of polyamine transport in human colorectal cancer cells. Biomolecules 10, 499 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  50. Berg, G. et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome 8, 103 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Johnson, C. H., Spilker, M. E., Goetz, L., Peterson, S. N. & Siuzdak, G. Metabolite and microbiome interplay in cancer immunotherapy. Cancer Res. 76, 6146–6152 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Seiler, N. et al. Endogenous and exogenous polyamines in support of tumor growth. Cancer Res. 50, 5077–5083 (1990).

    CAS  PubMed  Google Scholar 

  53. Matsumoto, M., Kurihara, S., Kibe, R., Ashida, H. & Benno, Y. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS ONE 6, e23652 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yoshimoto, S., Mitsuyama, E., Yoshida, K., Odamaki, T. & Xiao, J. Z. Enriched metabolites that potentially promote age-associated diseases in subjects with an elderly-type gut microbiota. Gut Microbes 13, 1–11 (2021). This study identifies N8 -acetylspermidine as a microbiota component that may contribute to age-related inflammatory conditions.

    Article  PubMed  CAS  Google Scholar 

  56. Johnson, C. H. et al. Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab. 21, 891–897 (2015). This study identifies increased production of N1,N12-diacetylspermine in colonic biofilm-positive patients with cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mu, T., Chu, T., Li, W., Dong, Q. & Liu, Y. N1, N12-diacetylspermine is elevated in colorectal cancer and promotes proliferation through the miR-559/CBS axis in cancer cell lines. J. Oncol. 2021, 6665704 (2021).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Tomkovich, S. et al. Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic. J. Clin. Invest. 129, 1699–1712 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018). This study identifies enrichment of tumorigenic bacterium-containing biofilms in early neoplasms of patients with familial adenomatous polyposis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Giardiello, F. M. et al. Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer Res. 57, 199–201 (1997).

    CAS  PubMed  Google Scholar 

  61. Wikoff, W. R. et al. Diacetylspermine is a novel prediagnostic serum biomarker for non-small-cell lung cancer and has additive performance with pro-surfactant protein B. J. Clin. Oncol. 33, 3880–3886 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kato, M. et al. Prognostic significance of urine N1, N12-diacetylspermine in patients with non-small cell lung cancer. Anticancer. Res. 34, 3053–3059 (2014).

    CAS  PubMed  Google Scholar 

  63. Fahrmann, J. F. et al. Association between plasma diacetylspermine and tumor spermine synthase with outcome in triple-negative breast cancer. J. Natl Cancer Inst. 112, 607–616 (2020).

    Article  PubMed  Google Scholar 

  64. Fahrmann, J. F. et al. A MYC-driven plasma polyamine signature for early detection of ovarian cancer. Cancers (Basel) 13, 913 (2021).

    Article  CAS  Google Scholar 

  65. Quinn, R. A. et al. Global chemical effects of the microbiome include new bile-acid conjugations. Nature 579, 123–129 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Singh, R. K. et al. Influence of diet on the gut microbiome and implications for human health. J. Transl. Med. 15, 73 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Parida, S. et al. A procarcinogenic colon microbe promotes breast tumorigenesis and metastatic progression and concomitantly activates Notch and β-catenin axes. Cancer Discov. 11, 1138–1157 (2021). Results of this study demonstrate that the colonic microbiota can have systemic effects in promoting tumorigenesis at distant sites.

    Article  CAS  PubMed  Google Scholar 

  68. Murray Stewart, T., Dunston, T. T., Woster, P. M. & Casero, R. A. Jr. Polyamine catabolism and oxidative damage. J. Biol. Chem. 293, 18736–18745 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yuen, G. J., Demissie, E. & Pillai, S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer 2, 747–757 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Gong, S. & Nussenzweig, M. C. Regulation of an early developmental checkpoint in the B cell pathway by Ig beta. Science 272, 411–414 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Nitta, T., Igarashi, K., Yamashita, A., Yamamoto, M. & Yamamoto, N. Involvement of polyamines in B cell receptor-mediated apoptosis: spermine functions as a negative modulator. Exp. Cell Res. 265, 174–183 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Shima, Y. et al. l-arginine import via cationic amino acid transporter CAT1 is essential for both differentiation and proliferation of erythrocytes. Blood 107, 1352–1356 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Bachrach, U. & Persky, S. Interaction of oxidized polyamines with DNA. V. Inhibition of nucleic acid synthesis. Biochim. Biophys. Acta 179, 484–493 (1969).

    Article  CAS  PubMed  Google Scholar 

  74. Carr, E. L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037–1044 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Choi, B. S. et al. Differential impact of l-arginine deprivation on the activation and effector functions of T cells and macrophages. J. Leukoc. Biol. 85, 268–277 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829–842.e813 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Gnanaprakasam, J. N. & Wang, R. MYC in regulating immunity: metabolism and beyond. Genes (Basel) 8, 88 (2017).

    Article  CAS  Google Scholar 

  79. Bowlin, T. L., McKown, B. J. & Sunkara, P. S. Increased ornithine decarboxylase activity and polyamine biosynthesis are required for optimal cytolytic T lymphocyte induction. Cell. Immunol. 105, 110–117 (1987).

    Article  CAS  PubMed  Google Scholar 

  80. Carriche, G. M. et al. Regulating T-cell differentiation through the polyamine spermidine. J. Allergy Clin. Immunol. 147, 335–348.e311 (2021).

    Article  CAS  PubMed  Google Scholar 

  81. Puleston, D. J. et al. Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell 184, 4186–4202.e4120 (2021). Results of this study implicate polyamines as mediators of TH cell differentiation into functional subsets via epigenetic regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Wagner, A. et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184, 4168–4185.e4121 (2021).

    Article  CAS  PubMed  Google Scholar 

  83. Nagaraj, S., Schrum, A. G., Cho, H. I., Celis, E. & Gabrilovich, D. I. Mechanism of T cell tolerance induced by myeloid-derived suppressor cells. J. Immunol. 184, 3106–3116 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Keough, M. P., Hayes, C. S., DeFeo, K. & Gilmour, S. K. Elevated epidermal ornithine decarboxylase activity suppresses contact hypersensitivity. J. Invest. Dermatol. 131, 158–166 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389–393 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Youn, J. I., Collazo, M., Shalova, I. N., Biswas, S. K. & Gabrilovich, D. I. Characterization of the nature of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. J. Leukoc. Biol. 91, 167–181 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Bronte, V. & Zanovello, P. Regulation of immune responses by l-arginine metabolism. Nat. Rev. Immunol. 5, 641–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Latour, Y. L., Gobert, A. P. & Wilson, K. T. The role of polyamines in the regulation of macrophage polarization and function. Amino Acids 52, 151–160 (2020).

    Article  CAS  PubMed  Google Scholar 

  89. Hardbower, D. M. et al. Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications. Proc. Natl Acad. Sci. USA 114, E751–E760 (2017). This study implicates the biosynthetic activity of myeloid cell-specific ODC in tempering the antimicrobial M1 macrophage response during infection with H. pylori and C. rodentium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Singh, K. et al. Ornithine decarboxylase in macrophages exacerbates colitis and promotes colitis-associated colon carcinogenesis by impairing M1 immune responses. Cancer Res. 78, 4303–4315 (2018). This study expands the study of myeloid-specific ODC by Hardbower et al. (2017) to identify its role in the pathology of colitis-associated cancer that is not associated with infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Miao, H. et al. Macrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM. Nat. Commun. 7, 11716 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Miska, J. et al. Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma. Sci. Adv. 7, eabc8929 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Alexander, E. T., Mariner, K., Donnelly, J., Phanstiel, O. & Gilmour, S. K. Polyamine blocking therapy decreases survival of tumor-infiltrating immunosuppressive myeloid cells and enhances the antitumor efficacy of PD-1 blockade. Mol. Cancer Ther. 19, 2012–2022 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Bussière, F. I. et al. Spermine causes loss of innate immune response to Helicobacter pylori by inhibition of inducible nitric-oxide synthase translation. J. Biol. Chem. 280, 2409–2412 (2005).

    Article  PubMed  CAS  Google Scholar 

  95. Yang, Q. et al. Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages. Cell Death Differ. 23, 1850–1861 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Mondanelli, G. et al. A relay pathway between arginine and tryptophan metabolism confers immunosuppressive properties on dendritic cells. Immunity 46, 233–244 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Proietti, E., Rossini, S., Grohmann, U. & Mondanelli, G. Polyamines and kynurenines at the intersection of immune modulation. Trends Immunol. 41, 1037–1050 (2020).

    Article  CAS  PubMed  Google Scholar 

  98. Svensson, K. J. et al. Hypoxia-mediated induction of the polyamine system provides opportunities for tumor growth inhibition by combined targeting of vascular endothelial growth factor and ornithine decarboxylase. Cancer Res. 68, 9291–9301 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Tsujinaka, S., Soda, K., Kano, Y. & Konishi, F. Spermine accelerates hypoxia-initiated cancer cell migration. Int. J. Oncol. 38, 305–312 (2011).

    CAS  PubMed  Google Scholar 

  100. Baek, J. H. et al. Spermidine/spermine N1-acetyltransferase-1 binds to hypoxia-inducible factor-1α (HIF-1α) and RACK1 and promotes ubiquitination and degradation of HIF-1α. J. Biol. Chem. 282, 33358–33366 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Dredge, K., Kink, J. A., Johnson, R. M., Bytheway, I. & Marton, L. J. The polyamine analog PG11047 potentiates the antitumor activity of cisplatin and bevacizumab in preclinical models of lung and prostate cancer. Cancer Chemother. Pharmacol. 65, 191–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Murray Stewart, T. et al. A phase Ib multicenter, dose-escalation study of the polyamine analogue PG-11047 in combination with gemcitabine, docetaxel, bevacizumab, erlotinib, cisplatin, 5-fluorouracil, or sunitinib in patients with advanced solid tumors or lymphoma. Cancer Chemother. Pharmacol. 87, 135–144 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Wu, D. et al. Regulation of spermine oxidase through hypoxia-inducible factor-1α signaling in retinal glial cells under hypoxic conditions. Invest. Ophthalmol. Vis. Sci. 61, 52 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Murata, M. et al. Unsaturated aldehyde acrolein promotes retinal glial cell migration. Invest. Ophthalmol. Vis. Sci. 60, 4425–4435 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Susek, K. H., Karvouni, M., Alici, E. & Lundqvist, A. The role of CXC chemokine receptors 1-4 on immune cells in the tumor microenvironment. Front. Immunol. 9, 2159 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Murray-Stewart, T. et al. Epigenetic silencing of miR-124 prevents spermine oxidase regulation: implications for Helicobacter pylori-induced gastric cancer. Oncogene 35, 5480–5488 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Mucaj, V. et al. MicroRNA-124 expression counteracts pro-survival stress responses in glioblastoma. Oncogene 34, 2204–2214 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Ghafouri-Fard, S. et al. An update on the role of miR-124 in the pathogenesis of human disorders. Biomed. Pharmacother. 135, 111198 (2021).

    Article  CAS  PubMed  Google Scholar 

  109. Abou Khouzam, R. et al. Tumor hypoxia regulates immune escape/invasion: influence on angiogenesis and potential impact of hypoxic biomarkers on cancer therapies. Front. Immunol. 11, 613114 (2020).

    Article  PubMed  CAS  Google Scholar 

  110. Greten, F. R. & Grivennikov, S. I. Inflammation and cancer: triggers, mechanisms, and consequences. Immunity 51, 27–41 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Shalapour, S. & Karin, M. Pas de deux: control of anti-tumor immunity by cancer-associated inflammation. Immunity 51, 15–26 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Murata, M. Inflammation and cancer. Env. Health Prev. Med. 23, 50 (2018).

    Article  CAS  Google Scholar 

  113. Ha, H. C. et al. The natural polyamine spermine functions directly as a free radical scavenger. Proc. Natl Acad. Sci. USA 95, 11140–11145 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Morón, B. et al. Activation of protein tyrosine phosphatase non-receptor type 2 by spermidine exerts anti-inflammatory effects in human THP-1 monocytes and in a mouse model of acute colitis. PLoS ONE 8, e73703 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Ma, L. et al. Preventive and therapeutic spermidine treatment attenuates acute colitis in mice. J. Agric. Food Chem. 69, 1864–1876 (2021).

    Article  CAS  PubMed  Google Scholar 

  116. Li, G. et al. Spermidine suppresses inflammatory DC function by activating the FOXO3 pathway and counteracts autoimmunity. iScience 23, 100807 (2020).

    Article  CAS  PubMed  Google Scholar 

  117. McNamara, K. M., Gobert, A. P. & Wilson, K. T. The role of polyamines in gastric cancer. Oncogene 40, 4399–4412 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Murray-Stewart, T. R., Woster, P. M. & Casero, R. A. Jr. Targeting polyamine metabolism for cancer therapy and prevention. Biochem. J. 473, 2937–2953 (2016).

    Article  CAS  PubMed  Google Scholar 

  119. Dunston, T. T. et al. Identification of a novel substrate-derived spermine oxidase inhibitor. Acta Nat. 12, 140–144 (2020).

    Article  CAS  Google Scholar 

  120. Metcalf, B. W. et al. Catalytic irreversible inhibition of mammalian ornithine decarboxylase (E.C.4.1.1.17) by substrate and product analogs. J. Amer. Chem. Soc. 100, 2551-2553 (1978).

    Article  CAS  Google Scholar 

  121. Casero, R. A. & Marton, L. J. Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases. Nat. Rev. Drug Discov. 6, 373–390 (2007).

    Article  CAS  PubMed  Google Scholar 

  122. Pegg, A. E. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 48, 759–774 (1988).

    CAS  PubMed  Google Scholar 

  123. LoGiudice, N., Le, L., Abuan, I., Leizorek, Y. & Roberts, S. C. Alpha-difluoromethylornithine, an irreversible inhibitor of polyamine biosynthesis, as a therapeutic strategy against hyperproliferative and infectious diseases. Med. Sci. (Basel) 6, 12 (2018).

    Google Scholar 

  124. Simoneau, A. R. et al. The effect of difluoromethylornithine on decreasing prostate size and polyamines in men: results of a year-long phase IIb randomized placebo-controlled chemoprevention trial. Cancer Epidemiol. Biomark. Prev. 17, 292–299 (2008).

    Article  CAS  Google Scholar 

  125. Sholler, G. L. S. et al. Maintenance DFMO increases survival in high risk neuroblastoma. Sci. Rep. 8, 14445 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. McCann, P. P. & Pegg, A. E. Ornithine decarboxylase as an enzyme target for therapy. Pharmacol. Ther. 54, 195–215 (1992).

    Article  CAS  PubMed  Google Scholar 

  127. Meyskens, F. L. et al. Effect of alpha-difluoromethylornithine on rectal mucosal levels of polyamines in a randomized, double-blinded trial for colon cancer prevention. J. Natl Cancer Inst. 90, 1212–1218 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Hessels, J. et al. Microbial flora in the gastrointestinal tract abolishes cytostatic effects of alpha-difluoromethylornithine in vivo. Int. J. Cancer 43, 1155–1164 (1989).

    Article  CAS  PubMed  Google Scholar 

  129. Levêque, J., Burtin, F., Catros-Quemener, V., Havouis, R. & Moulinoux, J. P. The gastrointestinal polyamine source depletion enhances DFMO induced polyamine depletion in MCF-7 human breast cancer cells in vivo. Anticancer. Res. 18, 2663–2668 (1998).

    PubMed  Google Scholar 

  130. Huber, M. et al. 2,2’-Dithiobis(N-ethyl-spermine-5-carboxamide) is a high affinity, membrane-impermeant antagonist of the mammalian polyamine transport system. J. Biol. Chem. 271, 27556–27563 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Muth, A. et al. Polyamine transport inhibitors: design, synthesis, and combination therapies with difluoromethylornithine. J. Med. Chem. 57, 348–363 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Burns, M. R., Graminski, G. F., Weeks, R. S., Chen, Y. & O’Brien, T. G. Lipophilic lysine-spermine conjugates are potent polyamine transport inhibitors for use in combination with a polyamine biosynthesis inhibitor. J. Med. Chem. 52, 1983–1993 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Weeks, R. S. et al. Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO. Exp. Cell Res. 261, 293–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Gamble, L. D. et al. Inhibition of polyamine synthesis and uptake reduces tumor progression and prolongs survival in mouse models of neuroblastoma. Sci. Transl. Med. 11, eaau1099 (2019).

    Article  PubMed  Google Scholar 

  135. Hayes, C. S. et al. Polyamine-blocking therapy reverses immunosuppression in the tumor microenvironment. Cancer Immunol. Res. 2, 274–285 (2014). This study demonstrates that PBT affects cancer cell proliferation by affecting both tumour cell metabolism and the tumour immune microenvironment.

    Article  CAS  PubMed  Google Scholar 

  136. Gitto, S. B. et al. Difluoromethylornithine combined with a polyamine transport inhibitor is effective against gemcitabine resistant pancreatic cancer. Mol. Pharm. 15, 369–376 (2018).

    Article  CAS  PubMed  Google Scholar 

  137. Alexander, E. T., Minton, A., Peters, M. C., Phanstiel, O. & Gilmour, S. K. A novel polyamine blockade therapy activates an anti-tumor immune response. Oncotarget 8, 84140–84152 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Khan, A. et al. Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas. Nat. Commun. 12, 971 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Spranger, S. & Gajewski, T. F. Impact of oncogenic pathways on evasion of antitumour immune responses. Nat. Rev. Cancer 18, 139–147 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Cancer Genome Atlas Research Network. Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012).

    Article  CAS  Google Scholar 

  142. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

    Article  CAS  Google Scholar 

  143. Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).

    Article  CAS  Google Scholar 

  144. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).

    Article  CAS  PubMed  Google Scholar 

  145. Witkiewicz, A. K. et al. Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets. Nat. Commun. 6, 6744 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Kalkat, M. et al. MYC deregulation in primary human cancers. Genes (Basel) 8, 151 (2017).

    Article  CAS  Google Scholar 

  147. Simanshu, D. K., Nissley, D. V. & McCormick, F. Ras proteins and their regulators in human disease. Cell 170, 17–33 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Gysin, S., Rickert, P., Kastury, K. & McMahon, M. Analysis of genomic DNA alterations and mRNA expression patterns in a panel of human pancreatic cancer cell lines. Genes. Chromosomes Cancer 44, 37–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  149. Spaans, V. M. et al. Designing a high-throughput somatic mutation profiling panel specifically for gynaecological cancers. PLoS ONE 9, e93451 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Dryja, P., Fisher, C., Woster, P. M. & Bartee, E. Inhibition of polyamine biosynthesis using difluoromethylornithine acts as a potent immune modulator and displays therapeutic synergy with PD-1-blockade. J. Immunother. 44, 283–291 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Ye, C. et al. Targeting ornithine decarboxylase by α-difluoromethylornithine inhibits tumor growth by impairing myeloid-derived suppressor cells. J. Immunol. 196, 915–923 (2016).

    Article  CAS  PubMed  Google Scholar 

  153. Li, L. et al. p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature 567, 253–256 (2019).

    Article  CAS  PubMed  Google Scholar 

  154. Lee, J. S. et al. Urea cycle dysregulation generates clinically relevant genomic and biochemical signatures. Cell 174, 1559–1570.e1522 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Dong, Z.-Y. et al. Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 23, 3012–3024 (2017).

    Article  CAS  PubMed  Google Scholar 

  156. Vadakekolathu, J. et al. TP53 abnormalities correlate with immune infiltration and associate with response to flotetuzumab immunotherapy in AML. Blood Adv. 4, 5011–5024 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Travers, M. et al. DFMO and 5-Azacytidine Increase M1 macrophages in the tumor microenvironment of murine ovarian cancer. Cancer Res. 79, 3445–3454 (2019). This study provides evidence of increased antitumour immune response following combination treatment with clinically approved inhibitors of polyamine biosynthesis and DNA methylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Witherspoon, M., Chen, Q., Kopelovich, L., Gross, S. S. & Lipkin, S. M. Unbiased metabolite profiling indicates that a diminished thymidine pool is the underlying mechanism of colon cancer chemoprevention by alpha-difluoromethylornithine. Cancer Discov. 3, 1072–1081 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Tebbutt, N. C. et al. A phase 1 safety study of SBP-101, a polyamine metabolic inhibitor, for pancreatic ductal adenocarcinoma (PDA). J. Clin. Oncol. 36, e16231 (2018).

    Article  Google Scholar 

  160. Bergeron, R. J. et al. Synthesis and evaluation of hydroxylated polyamine analogues as antiproliferatives. J. Med. Chem. 43, 224–235 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Shah, A. K., Cullen, M. T. & Baker, C. H. Abstract 3128: efficacy of diethyldihydroxyhomospermine against human pancreatic adenocarcinoma using orthotopic implantation of human pancreatic L3.6pl cells into the pancreas of nude mice. Cancer Res. 74, 3128–3128 (2014).

    Article  Google Scholar 

  162. Hurta, R. A., Huang, A. & Wright, J. A. Basic fibroblast growth factor selectively regulates ornithine decarboxylase gene expression in malignant H-ras transformed cells. J. Cell Biochem. 60, 572–583 (1996).

    Article  CAS  PubMed  Google Scholar 

  163. Soda, K. The mechanisms by which polyamines accelerate tumor spread. J. Exp. Clin. Cancer Res. 30, 95 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Dai, F. et al. Extracellular polyamines-induced proliferation and migration of cancer cells by ODC, SSAT, and Akt1-mediated pathway. Anticancer. Drugs 28, 457–464 (2017).

    Article  CAS  PubMed  Google Scholar 

  165. Kucharzewska, P., Welch, J. E., Svensson, K. J. & Belting, M. The polyamines regulate endothelial cell survival during hypoxic stress through PI3K/AKT and MCL-1. Biochem. Biophys. Res. Commun. 380, 413–418 (2009).

    Article  CAS  PubMed  Google Scholar 

  166. Lewis, E. C. et al. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma. Int. J. Cancer 147, 3152–3159 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Bassiri, H. et al. Translational development of difluoromethylornithine (DFMO) for the treatment of neuroblastoma. Transl. Pediatr. 4, 226–238 (2015).

    PubMed  PubMed Central  Google Scholar 

  168. Levin, V. A., Ictech, S. E. & Hess, K. R. Clinical importance of eflornithine (α-difluoromethylornithine) for the treatment of malignant gliomas. CNS Oncol. 7, CNS16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Meyskens, F. L., Simoneau, A. R. & Gerner, E. W. Chemoprevention of prostate cancer with the polyamine synthesis inhibitor difluoromethylornithine. Recent. Results Cancer Res. 202, 115–120 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Bacchi, C. J. Chemotherapy of human African trypanosomiasis. Interdiscip. Perspect. Infect. Dis. 2009, 195040 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Xie, Y. et al. Self-immolative nanoparticles for simultaneous delivery of microRNA and targeting of polyamine metabolism in combination cancer therapy. J. Control. Rel. 246, 110–119 (2017).

    Article  CAS  Google Scholar 

  172. Goyal, L. et al. Phase 1 study of N1,N11-diethylnorspermine (DENSPM) in patients with advanced hepatocellular carcinoma. Cancer Chemother. Pharmacol. 72, 1305–1314 (2013).

    Article  CAS  PubMed  Google Scholar 

  173. Hahm, H. A. et al. Phase I study of N1,N11-diethylnorspermine in patients with non-small cell lung cancer. Clin. Cancer Res. 8, 684–690 (2002).

    CAS  PubMed  Google Scholar 

  174. Streiff, R. R. & Bender, J. F. Phase 1 study of N1-N11-diethylnorspermine (DENSPM) administered TID for 6 days in patients with advanced malignancies. Invest. N. Drugs 19, 29–39 (2001).

    Article  CAS  Google Scholar 

  175. Wolff, A. C. et al. A phase II study of the polyamine analog N1,N11-diethylnorspermine (DENSpm) daily for five days every 21 days in patients with previously treated metastatic breast cancer. Clin. Cancer Res. 9, 5922–5928 (2003).

    CAS  PubMed  Google Scholar 

  176. Hacker, A., Marton, L. J., Sobolewski, M. & Casero, R. A. Jr. In vitro and in vivo effects of the conformationally restricted polyamine analogue CGC-11047 on small cell and non-small cell lung cancer cells. Cancer Chemother. Pharmacol. 63, 45–53 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Murray-Stewart, T. et al. Biochemical evaluation of the anticancer potential of the polyamine-based nanocarrier Nano11047. PLoS ONE 12, e0175917 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Murray Stewart, T., Desai, A. A., Fitzgerald, M. L., Marton, L. J. & Casero, R. A. Jr. A phase I dose-escalation study of the polyamine analog PG-11047 in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 85, 1089–1096 (2020).

    Article  CAS  PubMed  Google Scholar 

  179. Muth, A. et al. Development of polyamine transport ligands with improved metabolic stability and selectivity against specific human cancers. J. Med. Chem. 56, 5819–5828 (2013).

    Article  CAS  PubMed  Google Scholar 

  180. Seiler, N. How important is the oxidative degradation of spermine?: minireview article. Amino Acids 26, 317–319 (2004).

    CAS  PubMed  Google Scholar 

  181. Casero, R. A. & Pegg, A. E. Polyamine catabolism and disease. Biochem. J. 421, 323–338 (2009).

    Article  CAS  PubMed  Google Scholar 

  182. Gill, J. E., Christian, J. F. & Seidel, E. R. Antizyme mRNA distribution and regulation in rat small intestinal enterocytes. Dig. Dis. Sci. 47, 1458–1464 (2002).

    Article  CAS  PubMed  Google Scholar 

  183. Hayes, C. S., Burns, M. R. & Gilmour, S. K. Polyamine blockade promotes antitumor immunity. Oncoimmunology 3, e27360 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Nagaraj, S. et al. Antigen-specific CD4+ T cells regulate function of myeloid-derived suppressor cells in cancer via retrograde MHC class II signaling. Cancer Res. 72, 928–938 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Kumar, V., Patel, S., Tcyganov, E. & Gabrilovich, D. I. The nature of myeloid-derived suppressor cells in the tumor microenvironment. Trends Immunol. 37, 208–220 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Nagaraj, S. et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 13, 828–835 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Tillinghast, J., Drury, S., Bowser, D., Benn, A. & Lee, K. P. K. Structural mechanisms for gating and ion selectivity of the human polyamine transporter ATP13A2. Mol. Cell 81, 4650–4662 e4654 (2021).

    Article  CAS  PubMed  Google Scholar 

  189. Madan, M. et al. ATP13A3 and caveolin-1 as potential biomarkers for difluoromethylornithine-based therapies in pancreatic cancers. Am. J. Cancer Res. 6, 1231–1252 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Hiasa, M. et al. Identification of a mammalian vesicular polyamine transporter. Sci. Rep. 4, 6836 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Takeuchi, T. et al. Vesicular polyamine transporter mediates vesicular storage and release of polyamine from mast cells. J. Biol. Chem. 292, 3909–3918 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Lichterman, J. N. & Reddy, S. M. Mast cells: a new frontier for cancer immunotherapy. Cells 10, 1270 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Park, S. J. et al. Imaging inflammation using an activated macrophage probe with Slc18b1 as the activation-selective gating target. Nat. Commun. 10, 1111 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Robert A. Casero Jr or Tracy Murray Stewart.

Ethics declarations

Competing interests

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

Peer review

Peer review information

Nature Reviews Cancer thanks Susan Gilmour, Chaim Kahana and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-022-00473-2

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer