Abstract
In this study, we describe new methods for studying cancer cell metabolism with hyperpolarized 13C magnetic resonance spectroscopy (HP 13C MRS) that will enable quantitative studies at low oxygen concentrations. Cultured hepatocellular carcinoma cells were grown on the surfaces of non-porous microcarriers inside an NMR spectrometer. They were perfused radially from a central distributer in a modified NMR tube (bioreactor). The oxygen level of the perfusate was continuously monitored and controlled externally. Hyperpolarized substrates were injected continuously into the perfusate stream with a newly designed system that prevented oxygen and temperature perturbations in the bioreactor. Computational and experimental results demonstrated that cell mass oxygen profiles with radial flow were much more uniform than with conventional axial flow. Further, the metabolism of HP [1-13C]pyruvate was markedly different between the two flow configurations, demonstrating the importance of avoiding large oxygen gradients in cell perfusion experiments.
Highlights
Hepatocellular carcinoma (HCC) is a growing worldwide problem that lacks effective treatments [1]
Oxygen consumption, which is required for oxidative phosphorylation, produces hypoxic regions that play an important role in metastasis [7,8]
The results demonstrate that oxygen gradients can be markedly reduced with radial flow
Summary
Hepatocellular carcinoma (HCC) is a growing worldwide problem that lacks effective treatments [1]. 700,000 new cases are diagnosed each year [2] and the five-year survival rate is less than 15% [3]. HCC tumors are known to be metabolically heterogeneous. Metabolic energy in HCC is derived from both glycolysis and oxidative phosphorylation (in conjunction with the TCA cycle) [5,6]. The relative importance of these two processes in HCC can vary significantly [5]. Oxygen consumption, which is required for oxidative phosphorylation, produces hypoxic regions that play an important role in metastasis [7,8]. Hypoxia is known to interfere with the effectiveness of radiation therapy and chemotherapy [9,10]. Imaging-based methods to identify hypoxic regions of tumors currently do not exist. Such methods could significantly improve patient care [11]
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