Sriram Renuka, Gordon Jeremy, Baligand Celine, Ahamed Fayyaz, Delos Santos Justin, Qin Hecong, Bok Robert A, Vigneron Daniel B, Kurhanewicz John, Larson Peder E Z, Wang Zhen J
Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA 94158, USA.
Cancers (Basel). 2018 Sep 5;10(9):313. doi: 10.3390/cancers10090313.
Optimal treatment selection for localized renal tumors is challenging due to their variable biological behavior and limited ability to pre-operatively assess their aggressiveness. We investigated hyperpolarized (HP) C pyruvate MRI to noninvasively assess tumor lactate production and compartmentalization, which are strongly associated with renal tumor aggressiveness. Orthotopic tumors were created in mice using human renal cell carcinoma (RCC) lines (A498, 786-O, UOK262) with varying expression of lactate dehydrogenase A () which catalyzes the pyruvate-to-lactate conversion, and varying expression of monocarboxylate transporter 4 () which mediates lactate export out of the cells. Dynamic HP C pyruvate MRI showed that the A498 tumors had significantly higher C pyruvate-to-lactate conversion than the UOK262 and 786-O tumors, corresponding to higher A498 tumor LDHA expression. Additionally, diffusion-weighted HP C pyruvate MRI showed that the A498 tumors had significantly higher C lactate apparent diffusion coefficients compared to 786-O tumors, with corresponding higher MCT4 expression, which likely reflects more rapid lactate export in the A498 tumors. Our data demonstrate the feasibility of HP C pyruvate MRI to inform on tumor lactate production and compartmentalization, and provide the scientific premise for future clinical investigation into the utility of this technique to noninvasively interrogate renal tumor aggressiveness and to guide treatment selection.
由于局部肾肿瘤具有可变的生物学行为且术前评估其侵袭性的能力有限，因此选择最佳治疗方案具有挑战性。我们研究了超极化（HP）13C 丙酮酸磁共振成像（MRI），以无创评估肿瘤乳酸生成和分布情况，这些与肾肿瘤侵袭性密切相关。使用具有不同乳酸脱氢酶 A（LDHA）表达（催化丙酮酸向乳酸转化）和不同单羧酸转运蛋白 4（MCT4）表达（介导乳酸从细胞中输出）的人肾细胞癌（RCC）系（A498、786 - O、UOK262）在小鼠体内创建原位肿瘤。动态 HP 13C 丙酮酸 MRI 显示，A498 肿瘤的 13C 丙酮酸向乳酸的转化率显著高于 UOK262 和 786 - O 肿瘤，这与 A498 肿瘤较高的 LDHA 表达相对应。此外，扩散加权 HP 13C 丙酮酸 MRI 显示，与 786 - O 肿瘤相比，A498 肿瘤的 13C 乳酸表观扩散系数显著更高，其 MCT4 表达也相应更高，这可能反映了 A498 肿瘤中乳酸输出更快。我们的数据证明了 HP 13C 丙酮酸 MRI 在了解肿瘤乳酸生成和分布方面的可行性，并为未来临床研究该技术在无创评估肾肿瘤侵袭性及指导治疗选择方面的实用性提供了科学依据。
