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. 1987 May;113(3):209–215. doi: 10.1007/BF00396375

l-glutamine: a major substrate for tumor cells in vivo?

F Kallinowski 1, S Runkel 1, H P Fortmeyer 2, H Förster 3, P Vaupel 1,✉
PMCID: PMC12248313  PMID: 3584211

Abstract

From 65 human breast cancer xenografts investigated, a net glutamine uptake was found in 13 tumors (mean±SE: 15.7±4.5 nmol/g per min) whereas a net release (22.5±3.3 nmol/g per min) was observed in 40 tumors. In 12 tumors neither a significant net uptake nor a net release was obvious. There is experimental evidence that glutamine is taken up by cancer cells only at arterial concentrations>0.5 mM. Another parameter determining glutamine utilization by tumor cells may be the tissue oxygenation. In hypoxic or anoxic tumor areas, glutamine oxidation is unlikely since oxygen is required for the reoxidation of coenzymes which are reduced in the course of this metabolic pathway. The pronounced net release could be due to proteolysis within the tumors investigated. In ascitic fluid (DS-carcinosarcoma), glutamine accumulated during growth, implicating a reduction in the glutamine consumption rate, proposedly also due to a worsening of the oxygen supply to the suspended tumor cells. Thus, the generally held opinion that l-glutamine is a (if not the) major substrate for the energy metabolism of rapidly growing tumor cells should be reconsidered since evidence for this hypothesis has been derived mainly from in vitro system with abundant oxygen.

Key words: Glutamine, Glutaminolysis, Tumor energy metabolism, Tumor substrate utilization, Tumor oxygenation

References

  1. Busemeyer J, Vaupel P, Thews G (1977) Diffusion coefficients of glucose in tumor tissue. Pfluegers Arch 368:R17 [Google Scholar]
  2. Carrascosa JM, Martinez P, de Castro IN (1984) Nitrogen movement between host and tumor in mice incubated with Ehrlich ascitic tumor cells. Cancer Res 44:3831–3835 [PubMed] [Google Scholar]
  3. Coles NW, Johnstone RM (1962) Glutamine metabolism in Ehrlich ascites carcinoma cells. Biochem J 83:284–291 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Eagle H (1965) The specific amino acid requirements of a human carcinoma cell (strain HeLa) in tissue culture. J Exp Med 102:37–48 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Eagle H, Oyama VI, Levy M, Horton CL, Fleischman R (1956) The growth response of mammalian cells in tissue culture to l-glutamine and l-glutamic acid. J Biol Chem 218:607–616 [PubMed] [Google Scholar]
  6. Eigenbrodt E, Fister P, Reinacher M (1985) New perspectives on carbohydrate metabolism in tumor cells. In: Beitner R (ed) Regulation of carbohydrate metabolism, vol II. CRC Press, Boca Raton, pp 141–179 [Google Scholar]
  7. Gabbert H, Wagner R (1983) Tumorzellproliferation und Tumorvaskularisation experimentell erzeugter Dickdarmkarzinome wähend früher Wachstumsphasen. Mikrozirk Forsch Klin 2:107–113 [Google Scholar]
  8. Gatenby RA, Coia LR, Richter MP, Katz H, Moldofsky PJ, Engstrom P, Brown DQ, Brookland R, Broder GJ (1985) Oxygen tension in human tumors: In vivo mapping using CT-guided probes. Radiology 156:211–214 [DOI] [PubMed] [Google Scholar]
  9. Goodlad GAJ (1964) Protein metabolism and tumor growth. In: Munro HN, Allison JB (eds) Mammalian protein metabolism, vol II. Academic Press, New York London, pp 415–444 [Google Scholar]
  10. Gullino PM, Grantham FH, Courtney AH (1967) Utilization of oxygen by transplanted tumors in vivo. Cancer Res 27:1020–1030 [PubMed] [Google Scholar]
  11. Jewell WR, Krishnan EC, Schloerb PR (1975) Apparent cellular ingress of albumin in Walker 256 tumor and rat muscle. Cancer Res 35:405–408 [PubMed] [Google Scholar]
  12. Knox WE, Linder M, Friedell GH (1970) A series of transplantable rat mammary tumors with graded differentiation, growth rate, and glutaminase content. Cancer Res 30:283–287 [PubMed] [Google Scholar]
  13. Kovacevic Z, Morris H (1972) The role of glutamine in the oxidative metabolism of malignant cells. Cancer Res 32:326–333 [PubMed] [Google Scholar]
  14. Kovacevic Z, McGivan JD (1983) Mitochondrial metabolism of glutamine and glutamate and its physiological significance. Physiol Rev 63:547–605 [DOI] [PubMed] [Google Scholar]
  15. Kvamme E, Svenneby G (1961) The effect of glucose on glutamine utilization by Ehrlich ascites tumor cells. Cancer Res 21:92–98 [PubMed] [Google Scholar]
  16. Lazo PA (1981) Amino acids and glucose utilization by different metabolic pathways in ascites tumour cells. Eur J Biochem 117:19–25 [DOI] [PubMed] [Google Scholar]
  17. Levintow L (1954) The glutamyltransferase activity of normal and neoplastic tissues. J Natl Cancer Inst 15:347–352 [PubMed] [Google Scholar]
  18. Li CKN (1982) The glucose distribution on 9L rat brain multicell tumor spheroids and its effect on cell necrosis. Cancer 50:2066–2073 [DOI] [PubMed] [Google Scholar]
  19. Moreadith RW, Lehninger AL (1984) The pathway of glutamate and glutamine oxidation by tumor cell mitochondria. J Biol Chem 259:6215–6221 [PubMed] [Google Scholar]
  20. Moyer GH, Pitot H (1974) Static and dynamic aspects of amino acid pools in rat liver and Morris hepatomas 9618A and 7800. Cancer Res 34:2642–2653 [PubMed] [Google Scholar]
  21. Mueller-Klieser W, Sutherland RM (1982) Influence of convection in the growth medium on oxygen tensions in multicellular tumor spheroids. Cancer Res 42:237–242 [PubMed] [Google Scholar]
  22. Neumann RE, McCoy TA (1956) Dual requirement of Walker Carcinosarcoma 256 in vitro for asparagine and glutamine. Science 124:124–125 [DOI] [PubMed] [Google Scholar]
  23. Quadbeck R (1981) Stoffwechselwirkungen von einzelnen Aminosäuren bei parenteraler Applikation-zugleich ein Beitrag zur Aminosäure-Toxizität. Inaugural-Dissertation, Justus-Liebig-Universität Giessen
  24. Rabinovitz M, Olson ME, Greenberg DM (1956) Role of glutamine in protein synthesis by the Ehrlich ascites carcinoma. J Biol Chem 222:879–893 [PubMed] [Google Scholar]
  25. Regan DH, Lavietes BB, Regan MG, Denopoulus HB, Morris HP (1973) Glutamate-mediated respiration in tumors. J Natl Cancer Inst 51:1013–1017 [DOI] [PubMed] [Google Scholar]
  26. Reitzer LJ, Wice M, Kennell D (1979) Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 254:2669–2676 [PubMed] [Google Scholar]
  27. Rouser G, Samuels AJ, Heller D, Jelinek B (1962) Free amino acids in the blood of man and animals. III. Chronic lymphatic and acute leukemias. In: Holden JT (ed) Amino acid pools. Elsevier, New York, pp 388–395 [Google Scholar]
  28. Sauer LA, Dauchy RT (1983) Ketone body, glucose, lactic acid, and amino acid utilization by tumors in vivo in fasted rats. Cancer Res 43:3497–3503 [PubMed] [Google Scholar]
  29. Sauer LA, Dauchy RT, Nagel WO, Morris HP (1980) Mitochondrial malic enzymes. J Biol Chem 255:3844–3848 [PubMed] [Google Scholar]
  30. Sauer LA, Stayman III JW, Dauchy RT (1982) Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res 42:4090–4097 [PubMed] [Google Scholar]
  31. Scornik OA (1984) Effects of inhibitors of protein degradation on the rate of protein synthesis in Chinese hamster ovary cells. J Cell Physiol 121:257–262 [DOI] [PubMed] [Google Scholar]
  32. Steinau HU, Bastert G, Eichholz H, Fortmeyer HP, Schmidt-Matthiesen H (1981) Epigastric pouching technique: human xenografts in rnu/rnu rats. In: Bastert GB, Fortmeyer HP, Schmidt-Matthiesen H (eds) Thymusaplastic nude mice and rats in clinical oncology. Fischer, Stutgart New York, pp 531–542 [Google Scholar]
  33. Striebel JP (1985) Aminosäurenaufnahme und-abgabe, neoplastischer Gewebe. 4. Gemeinsame Jahrestagung der Deultschen und Österreichischen Arbeitsgemeinschaften für künstliche Ernährung. Heidelberg [Google Scholar]
  34. Tannock IF, Steele D, Roberts J (1986) Influence of reduced concentration of l-glutamine on growth and viability of cells in monolayer, in spheroids, and in experimental tumors. Br J Cancer 54:733–741 [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Vaupel P (1974) Atemgaswechsel und Glucosestoffwechsel von Implantationstumoren (DS-Carcinosarkom) in vivo. Funktionsanalyse biolog Systeme 1:1–138 [Google Scholar]
  36. Vaupel P (1977) Hypoxia in neoplastic tissue. Microvasc Res 13:399–408 [DOI] [PubMed] [Google Scholar]
  37. Vaupel P (1979) Oxygen supply to malignant tumors. In: Peterson HI (ed) Tumor blood circulation: angiogenesis, vascular morphology and blood flow of experimental and human tumors. CRC Press, Boca Raton, pp 143–168 [Google Scholar]
  38. Vaupel P (1982) Pathophysiologie der Durchblutung maligner Tumoren. Funktionsanalyse biology Systeme 8:155–170 [Google Scholar]
  39. Vaupel P, Hammersen F (eds) (1983) Mikrozirkulation in malignen Tumoren. Karger, Basel München Paris London New York Tokyo Sydney [Google Scholar]
  40. Vaupel P, Kallinowski F (1987) Physiological effects of hyperthermia. Rec. Res Cancer Res 104:71–109 [DOI] [PubMed] [Google Scholar]
  41. Vaupel P, Frinak S, Bicher HI (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41:2008–2013 [PubMed] [Google Scholar]
  42. Zielke HR, Ozand PT, Tidon JT, Sevdalian DA, Cornblath M (1978) Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts. J Cell Physiol 95:41–48 [DOI] [PubMed] [Google Scholar]
  43. Zielke HR, Sumbilla CM, Sevdalian DA, Hawkins RL, Ozand PT (1980) Lactate: a major product of glutamine metabolism by human diploid fibroblasts. J Cell Physiol 104:433–441 [DOI] [PubMed] [Google Scholar]
  44. Zielke HR, Zielke CL, Ozand PT (1984) Glutamine: a major energy source for cultured mammalian cells. Fed Proc 43:121–125 [PubMed] [Google Scholar]

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