Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Panbela Therapeutics Inc., Waconia, MN, USA.
Nat Rev Cancer. 2022 Aug;22(8):467-480. doi: 10.1038/s41568-022-00473-2. Epub 2022 Apr 27.
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.
天然哺乳动物多胺腐胺、精脒和精胺对于正常和肿瘤细胞的功能和复制都是必不可少的。多胺代谢及其需求的失调在许多癌症中很常见。临床和实验性的多胺耗竭都证明了它们的代谢是治疗的合理靶点；然而，多胺如何能够建立一个肿瘤允许的微环境的机制现在才刚刚出现。最近的数据表明，多胺可以在调节抗肿瘤免疫反应中发挥重要作用，因此可能有助于存在免疫“冷”肿瘤，这些肿瘤对免疫检查点阻断没有反应。此外，微生物群及其相关组织之间的相互作用创造了一个肿瘤微环境，其中多胺代谢、含量和功能都可以根据微生物群组成、饮食中多胺的可用性以及组织对周围微环境的反应而发生显著改变。本观点的目的是向读者介绍多胺、多胺代谢、微生物群和饮食相互作用的多种方式，以建立一个促进癌症发生和发展的肿瘤微环境。它还详细介绍了多胺代谢和功能可以成功靶向治疗的方法，包括特异性增强抗肿瘤免疫反应。
