Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13)C-pyruvate.
OBJECTIVE
Cancer cells generate more lactate than normal cells under both 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.


METHODS
We used hyperpolarized (13)C-pyruvate magnetic resonance spectroscopy (MRS) to compare lactate (13)C-labeling in vivo in mouse xenografts of the highly metastatic (MDA-MB-231) and the relatively indolent (MCF-7) human breast cancer cell lines. We obtained the kinetic parameters of the lactate dehydrogenase (LDH)-catalyzed reaction by three methods of data analysis including the differential equation fit, q-ratio fit, and ratio fit methods.


RESULTS
Consistent results from the three methods showed that the highly metastatic tumors exhibited a smaller apparent forward rate constant (k(+) = 0.060 ± 0.004 s(-1)) than the relatively indolent tumors (k(+) = 0.097 ± 0.013 s(-1)). The ratio fit generated the greatest statistical significance for the difference (P = .02). No significant difference in the reverse rate constant was found between the two tumor lines.


CONCLUSIONS
The result indicates that the less metastatic breast tumors may produce more lactate than the highly metastatic ones from the injected (13)C-pyruvate and supports the notion 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.
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104; Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA.
He N
HN
Xu
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104.
Stephen
S
Kadlececk
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104.
Harrilla
H
Profka
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104.
Jerry D
JD
Glickson
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104.
Rahim
R
Rizi
Department of Radiology, University of Pennsylvania, 423 Guardian Dr. Blockley B6, Philadelphia, PA 10104; Britton Chance Laboratory of Redox Imaging, Johnson Research Foundation, University of Pennsylvania, Philadelphia, PA. Electronic address: linli@mail.med.upenn.edu.
Lin Z
LZ
Li
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D019289:Pyruvic Acid / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D015203:Reproducibility of Results; D012307:Risk Factors; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D019344:Lactic Acid; D019289:Pyruvic Acid
NMR; Pyruvate; Warburg effect; ratio fit; two-site exchange model