Abstract 1003: A link between lactate dehydrogenase A, lactate and tumor phenotype identified by imaging

Abstract

Abstract Metabolic changes in primary tumors have a significant impact on tumor progression and on the development of the metastatic phenotype. In cancer patients, serum total lactate dehydrogenase (LDH) levels are often increased, and the gene for LDH-A protein, is frequently upregulated in tumors (Koukourakis, Giatromanolaki et al. 2003). These features have been linked to poor prognosis, and a greater metastatic potential has been reported in patients with high LDH serum levels. Since LDH-A protein is required for the maintenance and progression of many tumors (Fantin, St-Pierre et al. 2006), it is also becoming a potential target for cancer therapy (Le, Cooper et al. 2010; Seth, Grant et al. 2011). We investigated the relationship between LDH-A expression and lactate production in two isogenic breast cancer lines (67NR and 4T1) (Serganova, Rizwan et al. 2011). These two cell lines were derived from a single mammary tumor that developed spontaneously in a BALB/c mouse. Each subclone was shown to have different phenotypic properties (Aslakson and Miller 1992). 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. 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 ten-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. We show that lactate-MRSI has a greater dynamic range than [18F]FDG-PET and may be a more sensitive measure to evaluate the aggressive and metastatic potential of primary breast tumors. We hypothesized that tumor lactate levels monitored by MRSI will reflect LDH-A enzymatic activity and tumor phenotype. We also suggest that lactate-MRSI is a more sensitive measure than [18F]FDG-PET, and could be used in the clinic to evaluate the aggressive potential of primary breast tumors. Aslakson, C. J. and F. R. Miller (1992). Cancer Res 52(6): 1399-1405. Fantin, V. R., J. St-Pierre, et al. (2006). Cancer Cell 9(6): 425-434. Koukourakis, M. I., A. Giatromanolaki, et al. (2003). Br J Cancer 89(5): 877-885.Le, A., C. R. Cooper, et al. (2010). Proc Natl Acad Sci U S A 107(5): 2037-2042. Serganova, I., A. Rizwan, et al. (2011). Clin Cancer Res 17(19): 6250-6261. Seth, P., A. Grant, et al. (2011). Neoplasia 13(1): 60-71. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1003. doi:1538-7445.AM2012-1003