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Modeling hyperpolarized lactate signal dynamics in cells, patient‐derived tissue slice cultures and murine models
NMR in Biomedicine ( IF 2.7 ) Pub Date : 2021-01-07 , DOI: 10.1002/nbm.4467
Fayyaz Ahamed 1 , Mark Van Criekinge 2 , Zhen J Wang 2 , John Kurhanewicz 2 , Peder Larson 2 , Renuka Sriram 2
Affiliation  

Determining the aggressiveness of renal cell carcinoma (RCC) noninvasively is a critical part of the diagnostic workup for treating this disease that kills more than 15,000 people annually in the USA. Recently, we have shown that not only the amount of lactate produced, as a consequence of the Warburg effect, but also its efflux out of the cell, is a critical marker of RCC aggressiveness and differentiating RCCs from benign renal tumors. Enzymatic conversions can now be measured in situ with hyperpolarized (HP) 13C magnetic resonance (MR) on a sub‐minute time scale. Using RCC models, we have shown that this technology can interrogate in real time both lactate production and compartmentalization, which are associated with tumor aggressiveness. The dynamic HP MR data have enabled us to robustly characterize parameters that have been elusive to measure directly in intact living cells and murine tumors thus far. Specifically, we were able to measure the same intracellular lactate longitudinal relaxation time in three RCC cell lines of 16.42 s, and lactate efflux rate ranging from 0.14 to 0.8 s−1 in the least to the most aggressive RCC cell lines and correlate it to monocarboxylate transporter isoform 4 expression. We also analyzed dynamic HP lactate and pyruvate data from orthotopic murine RCC tumors using a simplified one‐compartment model, and showed comparable apparent pyruvate to lactate conversion rate (kPL) values with those measured in vitro. This kinetic modeling was then extended to characterize the lactate dynamics in patient‐derived living RCC tissue slices; and even without direct measurement of the extracellular lactate signal the efflux parameter was still assessed and was distinct between the benign renal tumors and RCCs. Across all these preclinical models, the rate parameters of kPL and lactate efflux correlated to cancer aggressiveness, demonstrating the validity of our modeling approach for noninvasive assessment of RCC aggressiveness.

中文翻译:

模拟细胞、患者来源的组织切片培养物和鼠模型中的超极化乳酸信号动力学

以无创方式确定肾细胞癌 (RCC) 的侵袭性是治疗这种疾病的诊断检查的关键部分,这种疾病在美国每年导致 15,000 多人死亡。最近,我们已经表明,不仅作为 Warburg 效应的结果产生的乳酸量,而且其流出细胞外,也是 RCC 侵袭性和区分 RCC 与良性肾肿瘤的关键标志物。现在可以使用超极化 (HP) 13原位测量酶促转化亚分​​钟时间尺度上的 C 磁共振(MR)。使用 RCC 模型,我们已经表明该技术可以实时询问乳酸产生和区室化,这与肿瘤侵袭性有关。动态 HP MR 数据使我们能够稳健地表征迄今为止难以直接在完整活细胞和鼠肿瘤中测量的参数。具体而言,我们能够测量三个 RCC 细胞系中相同的细胞内乳酸纵向弛豫时间为 16.42 s,乳酸流出率范围为 0.14 至 0.8 s -1至少与最具侵略性的 RCC 细胞系相关,并将其与单羧酸转运蛋白同种型 4 表达相关联。我们还使用简化的单室模型分析了来自原位鼠 RCC 肿瘤的动态 HP 乳酸和丙酮酸数据,并显示了与体外测量的表观丙酮酸到乳酸转化率 ( k PL ) 值相当的值。然后将该动力学模型扩展到表征患者来源的活 RCC 组织切片中的乳酸动力学;即使没有直接测量细胞外乳酸信号,仍会评估流出参数,并且在良性肾肿瘤和 RCC 之间是不同的。在所有这些临床前模型中,k PL的速率参数 和乳酸流出与癌症侵袭性相关,证明了我们的建模方法对 RCC 侵袭性的无创评估的有效性。
更新日期:2021-02-04
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