Non-Invasive Assessment of Lactate Production and Compartmentalization in Renal Cell Carcinomas Using Hyperpolarized 13C Pyruvate MRI.

Renuka Sriram,John Kurhanewicz,Robert Bok,Justin Delos Santos,Daniel Vigneron,Peder Larson,Hecong Qin,Jeremy Gordon,Zhen Wang,Celine Baligand,Fayyaz Ahamed

doi:10.3390/cancers10090313

Renuka Sriram, John Kurhanewicz + Show 9 more

Open Access

https://doi.org/10.3390/cancers10090313

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Abstract

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) 13C 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 (LDHA) which catalyzes the pyruvate-to-lactate conversion, and varying expression of monocarboxylate transporter 4 (MCT4) which mediates lactate export out of the cells. Dynamic HP 13C pyruvate MRI showed that the A498 tumors had significantly higher 13C pyruvate-to-lactate conversion than the UOK262 and 786-O tumors, corresponding to higher A498 tumor LDHA expression. Additionally, diffusion-weighted HP 13C pyruvate MRI showed that the A498 tumors had significantly higher 13C 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 13C 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.

Highlights

The increased utilization of medical imaging has led to a significant increase in the incidental detection of renal tumors, most of which are renal cell carcinomas (RCCs) [1,2]
The growth characteristics of the orthotopic tumors derived from three human RCC cell lines with varying expression of lactate dehydrogenase A (LDHA) and monocarboxylate transporter 4 (MCT4) is summarized in Supplemental Table S1
In a murine orthotopic model of human RCC, we demonstrated the feasibility of HP 13 C pyruvate magnetic resonance imaging (MRI) as a noninvasive means to inform on tumor lactate production and compartmentalization, which are strongly associated with aggressive RCCs

Summary

Introduction

The increased utilization of medical imaging has led to a significant increase in the incidental detection of renal tumors, most of which are renal cell carcinomas (RCCs) [1,2]. Many of these incidentally detected RCCs are localized small tumors, which account for 40–50% of newly diagnosed renal tumors [1]. Cancers 2018, 10, 313 can be challenging due to a lack of reliable means for estimation of the relative risks and benefits of each approach. This is largely related to the limited ability to pre-operatively predict the histology, grade and aggressiveness of renal tumors.

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