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Glucose Uptake, Lactate Release, Ketone Body Turnover, Metabolic Micromilieu, and pH Distributions in Human Breast Cancer Xenografts in Nude Rats¹

Department of Radiation Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 [F. K., P. V.]; Department of Applied Physiology [S. R., G. B., W. M-K., S. W.] and Department of Physiological Chemistry [K. H. B., K. W.], University of Mainz, D-6500 Mainz, and Department of Animal Experimentation, University Clinics of Frankfurt, D-6000 Frankfurt/M. [H. P. F.], FRG

Glucose uptake, lactate release, ketone body utilization, spatial distribution of glucose, lactate, and ATP concentrations as well as tissue pH distributions were systematically investigated in s.c. and/or "tissue-isolated" human breast cancer xenografts in T-cell-deficient rnu/rnu rats. Large variations in all parameters were detected within and between tumors indicating a very nonuniform substrate turnover. Glucose was taken up by all xenografts. Glucose consumption rates increased with increasing glucose availabilities, implying that the glucose uptake is mainly determined by the efficiency of nutritive tumor blood flow. The average glucose uptake was 0.37 µmol/g/min in medullary and 0.26 µmol/g/min in squamous cell carcinomas of the breast. At wet weights below 5 g, medullary breast cancers consumed more glucose than squamous cell carcinomas (2P < 0.05). Most tumors (97%) released lactate in an amount linearly related to glucose consumption. The lactate production of medullary (0.33 µmol/g/min) and squamous cell (0.31 µmol/g/min) breast cancers was similar. In general, the xenografts utilized ketone bodies. ß-Hydroxybutyrate was consumed by 82% and acetoacetate by 73% of the tumors, the uptake rates being linearly related to the respective availabilities. The mean uptake of ß-hydroxybutyrate was 3.48 nmol/g/min and that of acetoacetate 2.56 nmol/g/min. No significant differences were seen between medullary and squamous cell breast cancers. The ß-hydroxybutyrate/acetoacetate ratio in the tumorvenous blood rose with decreasing tumor blood flow indicating the development of hypoxia at advanced growth stages. Glucose, lactate, and ATP levels were all very heterogeneously distributed in medullary and squamous cell tumors as compared with normal tissue. No relationship was evident between the spatial distribution of concentrations of these three substrates. The xenografts were acidotic compared with pH values in normal subcutis. The mean tissue pH in medullary breast cancers was 6.81 ± 0.25 (SD). Compared with these values, the tissue pH distribution in squamous cell breast cancers was shifted to significantly higher values. The mean pH of the latter tumors was 7.04 ± 0.19 (2P < 0.001). From the experimental data presented there is clear indication that the metabolism of the xenografts investigated was mainly determined by the efficiency of nutritive blood flow, i.e., by substrate availability, and not by the metabolic demand of the cancer cells.

¹ Supported by Grants Va 57/2-4 and Mu 576/2-3 from the Deutsche Forschungsgemeinschaft.

² To whom all requests for reprints should be addressed, at Department of Radiation Medicine, Massachusetts General Hospital, Boston, MA 02114.

Received 6/ 3/88. Revised 8/ 9/88. Accepted 9/ 2/88.