Is Higher Lactate an Indicator of Tumor Metastatic Risk? A Pilot MRS Study Using Hyperpolarized 13C-Pyruvate

Abstract

Rationale and Objectives Cancer cells generate more lactate than normal cells under aerobic and hypoxic conditions – exhibiting the so-called Warburg effect. However, the relationship between the Warburg effect and tumor metastatic potential remains controversial. We intend to investigate whether the higher lactate reflects higher tumor metastatic potential. Materials and Methods We employed hyperpolarized 13C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate 13C-labeling in vivo in breast cancer mouse xenografts of highly metastatic (MDA-MB-231) and relatively indolent (MCF-7) human cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of analysis including the differential equation (DE) fit, q-ratio (qR) fit, and ratio fit (RF) methods. Results Consistent results from the three methods showed that the highly metastatic breast tumors exhibited a smaller apparent forward rate constant (k+ = 0.060 ± .004 s−1) than the relatively indolent tumors (k+ = 0.097 ± .013 s−1). The RF fit generates the highest statistical significance for the difference (p=0.02). No significant difference is found for the reverse rate constant. Conclusion The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected 13C-pyruvate, and supports the viewpoint that breast tumor metastatic risk is not necessarily associated with the high levels of glycolysis and lactate production. More studies are needed to confirm whether and how much the measured apparent rate constants are affected by the membrane transporter activity and whether they are primarily determined by the LDH activity or not.

Acute Tumor Lactate Perturbations as a Biomarker of Genotoxic Stress: Development of a Biochemical Model

“…(16, 48, 49) Xu et al utilized this imaging platform to differentiate between cell lines with high and low metastatic potential. (15) Thind et al demonstrated that HP-MRI can be used to detect acute normal tissue radiation toxicity in a lung model. (50)…”

“…(14) On the basis of this and other promising pre-clinical data, Le et al conducted a potentially paradigm changing clinical trial, testing the potential of tumor lactate levels to predict treatment response in head and neck tumors. (15, 16) Unfortunately, data generated by this trial failed to demonstrate a correlation between proton magnetic resonance spectroscopic measurements of lactate signal intensity and clinical outcomes. (16)…”

Multiparametric MRI of the breast: A review

“…Different investigations on animals have confirmed that the real‐time measurement of the conversion of pyruvate to lactate and alanine is particularly high in tumor tissue with high lactate dehydrogenase (LDH) activity and abundant membrane transporters of monocarboxylates. Thereby, HP MRI can allow a differentiation of benign and malignant tissue and has potential in the assessment of cancer progression . Recently, other promising novel probes for redox ( 13 C dehydroascorbate), necrosis ( 13 C fumarate), and glutamine metabolism ( 13 C glutamine) have been studied to investigate other metabolic pathways .…”

The value of prognostic factors in Chinese patients with small cell lung cancer: A retrospective study of 999 patients

“…[19][20][21][22][23][24][25] Furthermore, several studies have suggested that elevated LDH levels are correlated with radio/chemoresistance in several malignancies. LDH is essential for anaerobic glycolysis and converts pyruvate to lactate reversibly.…”