Metabolic Imaging: A Link between Lactate Dehydrogenase A, Lactate, and Tumor Phenotype

TLDR

The 67NR and 4T1 murine breast cancer cell lines, derived from a single mammary tumor, exhibit distinct growth and metabolic phenotypes. The study compared LDH‑A expression and lactate production in the isogenic 67NR and 4T1 murine breast cancer cell lines and tumors. The authors measured LDH‑A expression, lactate, glucose utilization, and oxygen consumption in cells and evaluated the correlation between tumor lactate (via MRSI) and glucose uptake (via FDG‑PET) in orthotopic tumors from these lines. They found that 4T1 cells and tumors express higher LDH‑A and produce tenfold more lactate than 67NR, with high lactate correlating with intense hypoxia; lactate‑MRSI showed a broader dynamic range than FDG‑PET and may better assess aggressive breast tumors. Published in Clinical Cancer Research, 17(19):6250–61; ©2011 AACR.

Abstract

Abstract Purpose: We compared the metabolic profiles and the association between LDH-A expression and lactate production in two isogenic murine breast cancer cell lines and tumors (67NR and 4T1). These cell lines were derived from a single mammary tumor and have different growth and metabolic phenotypes. Experimental Design: LDH-A expression, lactate concentration, glucose utilization, and oxygen consumption were measured in cells, and the potential relationship between tumor lactate levels [measured by magnetic resonance spectroscopic imaging (MRSI)] and tumor glucose utilization [measured by [18F]2-deoxy-2-fluoro-d-glucose positron emission tomography ([18F]FDG-PET)] was assessed in orthotopic breast tumors derived from these cell lines. Results: We show a substantial difference in LDH-A expression between 67NR and 4T1 cells under normoxia and hypoxia. We also show that small orthotopic 4T1 tumors generate 10-fold more lactate than corresponding 67NR tumors. The high lactate levels in small primary 4T1 tumors are associated with intense pimonidazole staining (a hypoxia indicator). Less-intense hypoxia staining was observed in the larger 67NR tumors and is consistent with the gradual increase and plateau of lactate concentration in enlarging 67NR tumors. Conclusions: Lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure with which to evaluate the aggressive and metastatic potential of primary breast tumors. Clin Cancer Res; 17(19); 6250–61. ©2011 AACR.