Mackay C L Logan, Soltwisch Jens, Heijs Bram, Smith Karl W, Cruickshank Faye L, Nyhuis Annika, Dreisewerd Klaus, Cobice Diego
SIRCAMS, EastChem School of Chemistry, University of Edinburgh Scotland UK.
Institute of Hygiene, University of Münster Münster Germany.
RSC Adv. 2021 Oct 18;11(54):33916-33925. doi: 10.1039/d1ra06086d.
Prostate cancer is initially treated androgen deprivation therapy (ADT), a highly successful treatment in the initial pursuit of tumour regression, but commonly restricted by the eventual emergence of a more lethal 'castrate resistant' (CRPC) form of the disease. Intracrine pathways that utilize dehydroepiandrosterone (DHEA) or other circulatory precursor steroids are thought to generate relevant levels of growth-stimulating androgens such as testosterone (T) and dihydrotestosterone (DHT). Decoding this tissue-specific metabolic pathway is key for the development of novel therapeutic treatments. Mass spectrometry imaging (MSI) is an analytical technique that allows the visualization of the distribution of numerous classes of biomolecules within tissue sections. The analysis of androgens by liquid chromatography mass spectrometry (LC/MS)-based methods however presents a challenge due to their generally poor ionization efficiency and low physiological endogenous levels. In MSI, on-tissue chemical derivatization (OTCD) has enabled the limits of steroids to be imaged within tissues to be pushed by overcoming poor ionization performance. However, isobaric interference of key androgen derivatives such as T and DHEA can severely hamper studying the intracrinology in several diseases. Here, we have evaluated the use of laser induced post-ionization (MALDI-2) combined with trapped ion mobility separation (TIMS) and orthogonal time-of-flight (QTOF) MS for the visualization of isobaric derivatized androgens in murine tumour xenograft at about 50 μm spatial resolution. With this combination, isobaric T and DHEA were separated in tissue sections and the signals of derivatized steroids enhanced by about 20 times. The combination of TIMS and MALDI-2 thus shows unique potential to study tissue intracrinology within target tissues. This could offer the opportunity for many novel insights into tissue-specific androgen biology.
前列腺癌最初采用雄激素剥夺疗法（ADT）进行治疗，这是一种在最初追求肿瘤消退方面非常成功的治疗方法，但通常会受到最终出现更具致命性的“去势抵抗性”（CRPC）疾病形式的限制。利用脱氢表雄酮（DHEA）或其他循环前体类固醇的内分泌途径被认为会产生相关水平的生长刺激雄激素，如睾酮（T）和二氢睾酮（DHT）。解码这种组织特异性代谢途径是开发新型治疗方法的关键。质谱成像（MSI）是一种分析技术，可使组织切片内多种生物分子的分布可视化。然而，基于液相色谱质谱（LC/MS）的方法分析雄激素存在挑战，因为它们的电离效率普遍较差且生理内源性水平较低。在MSI中，组织上化学衍生化（OTCD）通过克服电离性能差的问题，使得能够在组织内对类固醇的成像极限得到突破。然而，关键雄激素衍生物如T和DHEA的等压干扰会严重阻碍对几种疾病内分泌学的研究。在此，我们评估了激光诱导后电离（MALDI-2）结合捕集离子淌度分离（TIMS）和正交飞行时间（QTOF）质谱在小鼠肿瘤异种移植中以约50μm空间分辨率可视化等压衍生化雄激素的应用。通过这种组合，等压的T和DHEA在组织切片中得以分离，衍生化类固醇的信号增强了约20倍。因此，TIMS和MALDI-2的组合显示出在研究靶组织内组织内分泌学方面的独特潜力。这可能为深入了解组织特异性雄激素生物学提供许多新的见解。
