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A genetic approach to the role of energy metabolism in the growth of tumor cells: Tumorigenicity of fibroblast mutants deficient either in glycolysis or in respiration

To analyze the role of the cell energy metabolism in the expression of the malignant phenotype, we isolated fibroblast mutants with specific defects either in aerobic glycolysis or in respiration. From the anchorage‐independent and tumorigenic subclone (023) of Chinese hamster lung fibroblasts, we selected two mutants. The first, DS7, is deficient in aerobic glycolysis and glucose transport as a consequence of a block in phosphoglucose isomerase activity. DS7 is strictly dependent upon respiration for cell viability. The second mutant, GSK3, is unable to oxidize glucose as a result of a defect in oxidative metabolism, therefore its energy for growth relies exclusively on aerobic glycolysis. When injected into nude mice, these two mutant cells have kept the capacity to form tumors. For both mutants we observed an increase in the latency of tumor formation and a decreased tumorigenicity only for the respiration defective cells. The tumoral cells analyzed after passaging in vivo have retained the respective phenotypes, glycolysis‐ and respiration‐, of the injected cells. Finally, from the anchorage‐dependent and non‐tumorigenic Fisher rat fibroblast cell line, FR 3T3, we isolated mutants with a 6‐fold derepressed aerobic glycolysis and high glucose transport rate. In spite of this transformed character, these mutants (GSR 16/24) have kept the normal growth characteristics of the parent FR 3T3 (anchorage dependency and non‐tumorigenicity). These results indicate that only one of the two energy metabolisms of the mammalian cell ‐ respiration or aerobic glycolysis ‐ is enough for the expression of the malignant phenotype. Therefore, the high aerobic glycolysis of tumoral cells should be regarded as a non‐essential character of tumoral growth.