Summary
Experimental brain tumors were produced in rats by stereotactical implantation of various neoplastic cell lines (RG 2, RGl 2.2, G 13/11, F 98, RN 6, B 104, and E 367). Using autoradiographic, bioluminescence, and fluoroscopic methods, the following regional hemodynamic and metabolic parameters were measured on intact brain sections: blood flow, glucose utilization, pH, and the tissue content of ATP, glucose, and lactate. Tumors exnhibited a considerable diversity of regional blood flow and metabolic activity which did not correlate with the implanted cell line, location, or growth pattern. In solid regions of tumors the most consistent finding was a higher glucose utilization rate, a higher lactate, and a higher pH than in the surrounding brain tissue. Tumor ATP was slightly higher and glucose sightly lower than in the brain. In large spherical tumors a declining gradient of blood flow, glucose, and ATP from the periphery to the central parts was frequently observed, the decline being more pronounced for glucose than for ATP. In regions with high ATP tissue pH was usually higher than in the brain, but it decreased in areas in which ATP was depleted.
The results obtained indicate that tumors are able to control tissue pH despite increased glycolysis and lactate production, as long as the energy state is not impaired. The mechanisms of pH regulation, therefore, have to be considered for establishing therapeutic procedures which intend to lower tumor pH for induction of tissue necrosis.
Similar content being viewed by others
References
Aisenberg AC (1961) The glycolysis and respiration of tumors. Academic Press, New York
Bear MP, Schneider FH (1977) The effect of medium pH on rate of growth, neurite formation and acetylcholinesterase activity in mouse neuroblastoma cells in culture. J Cell Physiol 91:63–68
Blasberg RG, Kobayashi T, Patlak CS, Shinobara M, Miyoaka M, Rice JM, Shapiro WR (1981a) Regional blood flow, capillary permeability, and glucose utilization in two brain tumor models: preliminary observations and pharmacokinetic implications. Cancer Treatment Reports [Suppl 2] 65:3–12
Blasberg R, Molnar P, Groothuis D, Patlak C, Fenstermacher J (1981b) Simultaneous measurements of blood flow and relative glucose utilization in ASV-induced brain tumors. J Cereb Blood Flow Metab [Suppl 1] 1:S68-S69
Calderwood SK, Dickson JA (1980) Effect of hyperglycemia on blood flow, pH, and response to hyperthermia (42°C) of the Yoshida sarcoma in the rat. Cancer Res40:4728–4733
Crane PD, Pardridge WM, Braun LD, Nyerges AM, Oldendorf WH (1981) The interaction of transport and metabolism on brain glucose utilization: A reevaluation of the lumped constant. J Neurochem 36:1601–1604
Csiba L, Paschen W, Hossmann K-A (1983) A topographic quantitative method for measuring brain tissue pH under physiological and pathophysiological conditions. Brain Res 289:334–337
Di Chiro G, Brooks RA, Patronas NJ, Bairamian D, Kornblith PL, Smith BH, Mansi L, Barker J (1984) Issues in the in vivo measurement of glucose metabolism of human central nervous system tumors. Ann Neurol [Suppl] 15:S138-S146
Eagle H (1973) The effect of environmental pH on the growth of normal and malignant cells. J Cell Physiol 82:1–8
Groothuis DR, Molnar P, Blasberg RG (1984) Regional blood flow and blood-to-tissue transport in five brain tumor models. Implications for chemotherapy. Prog Exp Tumor Res 27:132–153
Hossmann K-A, Niebuhr I, Tamura M (1982) Local cerebral blood flow and glucose consumption of rats with experimental gliomas. J Cereb Blood Flow Metab 2, 25–32
Ito M, Lammertsma AA, Wise RJS, Bernardi S, Frackowiak RSJ, Heather JD, McKenzie CG, Thomas DGT, Jones T (1982) Measurement of regional cerebral blood flow and oxygen utilization in patients with cerebral tumours using15O and positron emission tomography: Analytical techniques and preliminary results. Neuroradiology 23:63–74
Jähde E, Rajewsky MF (1982a) Tumor-selective modification of cellular microenvironment in vivo: Effect of glucose infusion on the pH in normal and malignant rat tissues. Cancer Res 42:1505–1512
Jähde E, Rajewsky MF, Baumgärtl H (1982b) pH distributions in transplanted neural tumors and normal tissues of BD-IX rats as measured with pH microelectrodes. Cancer Res 42:1498–1504
Junck L, Blasberg R, Rottenberg DA (1981) Brain and tumor pH in experimental leptomeningcal carcinomatosis. Trans Am Neurol Assoc 106:298–301
Kato A, Diksic M, Yamamoto YL, Feindel W (1985) Quantification of glucose utilization in an experimental brain tumor model by the deoxyglucose method. J Cereb Blood Flow Metab 5:108–114
Kirsch WM, Schulz D, Leitner JW (1967) The effect of prolonged ischemia upon regional energy reserves in the experimental glioblastoma. Cancer Res 27:2212–2220
Ko L, Koestner A, Wechsler W (1980) Morphological characterization of nitrosourea-induced glioma cell lines and clones. Acta Neuropathol (Berl) 51:23–31
Kobatake K, Sako K, Izawa M, Yamamoto YL, Hakim AM (1984) Autoradiographic determination of brain pH following middle cerebral artery occlusion in the rat. Stroke 15:540–547
Kogure K, Alonso OF (1978) A pictorial representation of endogenous brain ATP by a bioluminescent method. Brain Res 154:273–284
Lowry OH, Berger SJ, Chi MM-Y, Carter JG, Blackshaw A, Outlaw W (1977) Diversity of metabolic patterns in human brain tumors. I. High-energy phosphate compounds and basic composition. J Neurochem 29:959–977
Lowry OH, Berger SJ, Carter JG, Chi MM-Y, Manchester JK, Knor J, Pusateri ME (1983) Diversity of metabolic patterns in human brain tumors: Enzymes of energy metabolism and related metabolites and cofactors. J Neurochem 41:994–1010
Mies G, Paschen W, Bodsch W, Hossmann K-A (1983) Regional evaluation of blood flow and metabolism in experimental brain tumor of rats. In: Ishii S, Nagai H, Brock M (eds) Intracranial pressure. V. Proceedings of the Fifth International Symposium on Intracranial Pressure, Tokyo, May 30–June 3, 1982 Springer, Berlin Heidelberg New York Tokyo, pp 429–435
Mies G, Paschen W, Csiba L, Krajewski S, Wechsler W, Hossmann K-A (1985) Comparison of regional tissue pH measured with the umbelliferone and14C-DMO technique in rat brain. J Cereb Blood Flow Metab [Suppl 1] 5:247–248
Nemoto EM, Severinghaus JW (1974) Stereospecific permeability of rat blood-brain barrier to lactic acid. Stroke 5:81–84
Oldendorf WH (1973) Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids. Am J Physiol 224:1450–1453
Overgaard J (1976) Influence of extracellular pH on the viability and morphology of tumour cells exposed to hyperthermia. J Natl Cancer Inst 56:1243–1250
Pappius HM (1980) Mapping of cerebral functional activity with radioactive deoxyglucose: Application in studies of traumatized brain. Adv Neurol 28:271–279
Paschen W, Niebuhr I, Hossmann K-A (1981) A bioluminescence method for the demonstration of regional glucose distribution in brain slices. J Neurochem 36:513–517
Paschen W, Hossmann K-A, Kerckhoff W vd (1983) Regional assessment of energy-producing metabolism following prolonged complete ischemia of cat brain. J Cereb Blood Flow Metab 3:321–329
Paschen W, Mies G, Kloiber O, Hossmann K-A (1985) Regional quantitative determination of glucose in tissue sections: A bioluminescent approach. J Cereb Blood Flow Metab 5: 465–468
Paschen W (1985) Regional quantitative determination of lactate in brain sections. A bioluminescent approach. J Cereb Blood Flow Metab (in press)
Paxton HD (1959) Quantitative histochemistry of brain tumors and analogous normal tissue. Neurology (Minneap) 9: 367–370
Reivich M, Jehle J, Sokoloff L, Kety SS (1969) Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. J Appl Physiol 27:296–300
Reivich M, Jones S, Ginsberg M, Slater R, Greenberg J (1977) Regional hemodynamic and metabolic alterations in focal cerebral ischemia: Studies of diaschisis. Adv Exp Med Biol 94:617–622
Rhodes CG, Wise RJS, Gibbs JM, Frackowiak RSJ, Hatazawa J, Palmer AJ, Thomas DGT, Jones T (1983) In vivo disturbance of oxidative metabolism of glucose in human cerebral gliomas. Ann Neurol 14:614–626
Roos A Baron WF (1981) Intracellular pH. Physiol Rev 61:296–434
Rottenberg DA, Ginos JZ, Kearfott KJ, Junek L, Bigner DD (1984) In vivo measurement of regional brain tissue pH using positron emission tomography. Ann Neurol [Suppl] 15:S98-S102
Sakurada O, Kennedy C, Jehle J, Brown JD, Carbin GL, Sokoloff L (1978) Measurement of local cerebral blood flow with iodo-14C-antipyrine. Am J Physiol 234:H59–H66
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The14C deoxyglucose method for the measurement of local cerebral glucose utilization: Theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28:897–916
Viale GL (1969a) Biochemical patterns in brain tumours. I. Enzymes of the glycolysis. Acta Neurochir 20:263–272
Viale GL (1969b) Biochemical patterns in brain tumours. II. Enzymes of the tricarboxylic acid cycle. Acta Neurochir 20:273–279
von Ardenne M, Reitnauer PG, Rhode K, Westmeyer H (1969) In vivo pH-Messungen in Krebs-Mikrometastasen bei optimierter Übersauerung Z Naturforsch [B] 24:1610–1619
Warburg O (1926) Über den Stoffwechsel der Tumoren. Springer, Berlin
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hossmann, K.A., Mies, G., Paschen, W. et al. Regional metabolism of experimental brain tumors. Acta Neuropathol 69, 139–147 (1986). https://doi.org/10.1007/BF00687050
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00687050