Abstract
This study uses dynamic hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to estimate differences in glycolytic metabolism between highly metastatic (4T1, n = 7) and metastatically dormant (4T07, n = 7) murine breast cancer models. The apparent conversion rate of pyruvate-to-lactate (kPL) and lactate-to-pyruvate area-under-the-curve ratio (AUCL/P) were estimated from the metabolite images and compared with biochemical metabolic measures and immunohistochemistry (IHC). A non-significant trend of increasing kPL (p = 0.17) and AUCL/P (p = 0.11) from 4T07 to 4T1 tumors was observed. No significant differences in tumor IHC lactate dehydrogenase-A (LDHA), monocarboxylate transporter-1 (MCT1), cluster of differentiation 31 (CD31), and hypoxia inducible factor-α (HIF-1α), tumor lactate-dehydrogenase (LDH) activity, or blood lactate or glucose levels were found between the two tumor lines. However, AUCL/P was significantly correlated with tumor LDH activity (ρspearman = 0.621, p = 0.027) and blood glucose levels (ρspearman = −0.474, p = 0.042). kPL displayed a similar, non-significant trend for LDH activity (ρspearman = 0.480, p = 0.114) and blood glucose levels (ρspearman = −0.414, p = 0.088). Neither kPL nor AUCL/P were significantly correlated with blood lactate levels or tumor LDHA or MCT1. The significant positive correlation between AUCL/P and tumor LDH activity indicates the potential of AUCL/P as a biomarker of glycolytic metabolism in breast cancer models. However, the lack of a significant difference between in vivo tumor metabolism for the two models suggest similar pyruvate-to-lactate conversion despite differing metastatic potential.
Highlights
Breast cancer is the most common cancer diagnosis in women worldwide
These results suggest that tumor lactate production may be an important biomarker for breast cancer aggressiveness and propensity to metastasize
We investigate the use of hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (MRSI) to differentiate between murine breast tumor xenografts of highly metastatic and metastatically dormant cells
Summary
Breast cancer is the most common cancer diagnosis in women worldwide. This disease is responsible for the second most cancer-related deaths for women in developed countries and the most cancer-related deaths for women in developing countries [1]. While committing pyruvate to oxidative phosphorylation constitutes a more efficient means of energy metabolism, in cancer the lactate-dehydrogenase (LDH)-mediated conversion of pyruvate to lactate is hypothesized to enable production of glycolytic intermediates useful for building the macromolecules required for cell proliferation. Tumor lactate levels have been significantly positively correlated with the development of distant metastasis despite there being different lactate levels in tumors of the same grade and stage [5]. These results suggest that tumor lactate production may be an important biomarker for breast cancer aggressiveness and propensity to metastasize
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