Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA.
Nat Rev Cancer. 2023 Dec;23(12):863-878. doi: 10.1038/s41568-023-00632-z. Epub 2023 Oct 31.
Metabolic reprogramming is central to malignant transformation and cancer cell growth. How tumours use nutrients and the relative rates of reprogrammed pathways are areas of intense investigation. Tumour metabolism is determined by a complex and incompletely defined combination of factors intrinsic and extrinsic to cancer cells. This complexity increases the value of assessing cancer metabolism in disease-relevant microenvironments, including in patients with cancer. Stable-isotope tracing is an informative, versatile method for probing tumour metabolism in vivo. It has been used extensively in preclinical models of cancer and, with increasing frequency, in patients with cancer. In this Review, we describe approaches for using in vivo isotope tracing to define fuel preferences and pathway engagement in tumours, along with some of the principles that have emerged from this work. Stable-isotope infusions reported so far have revealed that in humans, tumours use a diverse set of nutrients to supply central metabolic pathways, including the tricarboxylic acid cycle and amino acid synthesis. Emerging data suggest that some activities detected by stable-isotope tracing correlate with poor clinical outcomes and may drive cancer progression. We also discuss current challenges in isotope tracing, including comparisons of in vivo and in vitro models, and opportunities for future discovery in tumour metabolism.
代谢重编程是恶性转化和癌细胞生长的核心。肿瘤如何利用营养物质以及重编程途径的相对速率是研究的热点领域。肿瘤代谢受癌细胞内在和外在的多种复杂且尚未完全确定的因素决定。这种复杂性增加了在与疾病相关的微环境中评估癌症代谢的价值，包括在癌症患者中。稳定同位素示踪是一种用于在体内探测肿瘤代谢的信息丰富、用途广泛的方法。它已在癌症的临床前模型中得到广泛应用，并且在癌症患者中的应用频率也在逐渐增加。在这篇综述中，我们描述了使用体内同位素示踪来定义肿瘤中燃料偏好和途径参与的方法，以及从这些工作中得出的一些原则。迄今为止报告的稳定同位素输注表明，在人类中，肿瘤利用多种营养物质来供应中央代谢途径，包括三羧酸循环和氨基酸合成。新出现的数据表明，一些通过稳定同位素示踪检测到的活性与不良临床结果相关，并可能推动癌症进展。我们还讨论了同位素示踪的当前挑战，包括体内和体外模型的比较，以及在肿瘤代谢领域未来发现的机会。
