Virchows Archiv B

, 63:351 | Cite as

Expression of glucose transporter isoforms (GLUT1, GLUT2) and activities of hexokinase, pyruvate kinase, and malic enzyme in preneoplastic and neoplastic rat renal basophilic cell lesions

  • Young Soo Ahn
  • Heide Zerban
  • Peter Bannasch


Sequential changes in the expression of two glucose transporter isoforms (GLUT1, GLUT2), and in the activities of hexokinase, pyruvate kinase and malic enzyme during the development of rat renal basophilic cell tumors were studied using histochemical techniques. Early basophilic cell tubules are similar to proximal convoluted tubules (PCT) in their overall histochemical pattern, particularly in the expression of glucose transporters, suggesting that basophilic cell tubules and tumors derived from them arise from PCT. In comparison with PCT, basophilic cell tubules show slightly increased activities of all the enzymes studied. In basophilic cell tumors, markedly elevated hexokinase and pyruvate kinase activities are accompanied by a considerable reduction in the expression of GLUT2. GLUT1 expression is not found in basophilic cell tubules or PCT. Small basophilic cell tumors also do not express GLUT1, but GLUT1 is regularly expressed in several cell layers surrounding necrotic areas within large basophilic cell tumors. Our results indicate that increased glycolytic activity and reduced GLUT2 expression take place during the development of renal basophilic cell tumors.

Key words

Renal cell tumor Proximal tubule Glucose transporters Hexokinase Metabolic aberrations 


  1. Ahn YS, Zerban H, Grobholz R, Bannasch P (1992) Sequential changes in glycogen content, expression of glucose transporters and enzymic patterns during development of clear/acidophilic cell tumors in rat kidney. Carcinogenesis 13:2329–2334PubMedCrossRefGoogle Scholar
  2. Bannasch P, Zerban H (1990) Animal models and renal carcinogenesis. In: Eble JN (ed) Tumor and tumor-like conditions of the kidneys and ureters. Churchill Livingstone, New York, pp 1–34Google Scholar
  3. Bannasch P, Krech R, Zerban H (1980) Morphogenese und Mikromorphologie epithelialer Nierentumoren bei Nitrosomorpholinvergifteten Ratten. IV. Tubuläre Läsionen und basophile Tumoren. J Cancer Res Clin Oncol 98:243–265PubMedCrossRefGoogle Scholar
  4. Bannasch P, Hacker HJ, Tsuda H, Zerban H (1986) Aberrant regulation of carbohydrate metabolism and metamorphosis during renal carcinogenesis. Adv Enzyme Regul 25:279–296PubMedCrossRefGoogle Scholar
  5. Bannasch P, Klimek F, Mayer D, Hacker HJ, Dettler T, Zerban H (1991) Metabolic aberrations and metamorphosis during chemical carcinogenesis. In: Columbano A, Feo F, Pascale R, Pani P (eds) Chemical carcinogenesis 2. Plenum, New York, pp 189–201Google Scholar
  6. Beemer FA, Vlug AMC, Rijksen G, Hamburg A, Staal GEJ (1982) Characterization of some glycolytic enzymes from human retina and retinoblastoma. Cancer Res 42:4228–4232PubMedGoogle Scholar
  7. Beemer FA, Vlug AMC, Rousseau-Merck MF, Van Veelen CWM, Rijksen G, Staal GEJ (1984) Glycolytic enzymes from human neuroectodermal tumors of childhood. Eur J Cancer Clin Oncol 20:253–259PubMedCrossRefGoogle Scholar
  8. Birnbaum MJ, Haspel HC, Rosen OM (1987) Transformation of rat fibroblasts by FSV rapidly increases glucose transporter gene transcription. Science 235:1495–1498PubMedCrossRefGoogle Scholar
  9. Brummer C, Rabes HM (1992) Morphology and proliferation kinetics of early tumor stages induced by dimethylnitrosamine in rat kidneys. Virchows Arch [B] 62:133–142Google Scholar
  10. Burk D, Woods M, Hunter J (1967) On the significance of glycolysis for cancer growth, with special reference to Morris rat hepatomas. J Natl Cancer Inst 38:839–863PubMedGoogle Scholar
  11. Criss WE (1969) A new pyruvate kinase isozyme in hepatomas. Biochem Biophys Res Commun 35:901–905PubMedCrossRefGoogle Scholar
  12. Elbers JRJ, Van Unnik JAM, Rijksen G, Van Oirschot BA, Roholl PJM, Oosting J, Staal GEJ (1991) Pyruvate kinase activity and isozyme composition in normal fibrous tissue and fibroblastic proliferations. Cancer 67:2552–2559PubMedCrossRefGoogle Scholar
  13. Farina FA, Shatton JB, Morris HP, Weinhouse S (1974) Isozymes of pyruvate kinase in liver and hepatomas of the rat. Cancer Res 34:1439–1446PubMedGoogle Scholar
  14. Fischer G, Holzrichter S, Reinacher M, Heinrichs M, Dembowski J, Eigenbrodt E (1989) Immunohistochemical demonstration of Land M2-pyruvate kinase in renal cell carcinomas and their metastases. Verh Dtsch Ges Pathol 73:422–427PubMedGoogle Scholar
  15. Flier JS, Mueckler MM, Usher P, Lodish HF (1987) Elevated levels of glucose transport and transporter messenger RNA are induced byras orsrc oncogenes. Science 235:1492–1495PubMedCrossRefGoogle Scholar
  16. Gould GW, Bell GI (1990) Facilitative glucose transporters: an expanding family. Trends Biochem Sci 15:18–23PubMedCrossRefGoogle Scholar
  17. Hacker HJ, Moore MA, Mayer D, Bannasch P (1982) Correlative histochemistry of some enzymes of carbohydrate metabolism in preneoplastic and neoplastic lesions in the rat liver. Carcinogenesis 3:1265–1272PubMedCrossRefGoogle Scholar
  18. Hacker HJ, Grobholz R, Klimek F (1991 a) Enzyme histochemistry and biochemical microanalysis of preneoplastic lesions. Progr Histochem Cytochem 23:62–71Google Scholar
  19. Hacker HJ, Thorens B, Grobholz R (1991 b) Expression of facilitative glucose transporter in rat liver and choroid plexus. Histochemistry 96:435–439PubMedCrossRefGoogle Scholar
  20. Hard GC (1990) Tumours of the kidney, renal pelvis and ureter. In: Turusov VS, Mohr U (eds) Pathology of tumours in laboratory animals, vol I. Tumours of the rat. Oxford University Press, New York, pp 301–324Google Scholar
  21. Hard GC, Butler WH (1971) Morphogenesis of epithelial neoplasms induced in the rat kidney by dimethylnitrosamine. Cancer Res 31:1496–1505PubMedGoogle Scholar
  22. Heatfield BM, Hinton DE, Trump BF (1976) Adenocarcinomas of the kidney. II. Enzyme histochemistry of renal adenocarcinomas induced in rat by N-(4′-fluoro-4-biphenyl) acetamide. J Natl Cancer Inst 57:795–808PubMedGoogle Scholar
  23. Hennipman A, Van Oirschot BA, Smits J, Rijksen G, Staal GEJ (1988) Heterogeneity of glycolytic enzyme activity and isozyme composition of pyruvate kinase in breast cancer. Tumor Biol 9:178–189Google Scholar
  24. Ito N (1973) Experimental studies on tumors of the urinary system of rats induced by chemical carcinogens. Acta Pathol Jpn 23:87–109PubMedGoogle Scholar
  25. Jasmin G, Riopelle JL (1968) Renal adenomas induced by dimethylnitrosamine. Enzyme histochemistry in the rat. Arch Pathol 85:298–305PubMedGoogle Scholar
  26. Kahn BB (1992) Facilitative glucose transporters: regulatory mechanism and dysregulation in diabetes. J Clin Invest 89:1367–1374PubMedCrossRefGoogle Scholar
  27. Kahn BB, Flier JS (1990) Regulation of glucose-transporter gene expression in vitro and in vivo. Diabetes Care 13:548–564PubMedCrossRefGoogle Scholar
  28. Klimek F, Bannasch P (1990) Biochemical microanalysis of pyru-357 vate kinase activity in preneoplastic and neoplastic liver lesions induced in rats by N-nitrosomorpholine. Carcinogenesis 11:1377–1380PubMedCrossRefGoogle Scholar
  29. Klimek F, Moore MA, Schneider E, Bannasch P (1988) Histochemical and microbiochemical demonstration of reduced pyruvate kinase activity in thioacetamide-induced neoplastic nodules of rat liver. Histochemistry 90:37–42PubMedCrossRefGoogle Scholar
  30. Kugler P (1990) Microphotometric determination of enzymes in brain sections. I. Hexokinase. Histochemistry 93:295–298PubMedGoogle Scholar
  31. Lojda Z, Gossrau R, Schiebler TH (1979) Enzyme histochemistry. Springer, Berlin Heidelberg New YorkGoogle Scholar
  32. Lopez-Alcaron L, Ruiz P, Gosalvez M (1981) Quantitative determination of the degree of differentiation of mammary tumors by pyruvate kinase analysis. Cancer Res 41:2019–2020Google Scholar
  33. Mao P, Molnar JJ (1967) The fine structure and histochemistry of lead induced renal tumors in rats. Am J Pathol 50:571–603PubMedGoogle Scholar
  34. Moreadith RW, Lehninger AL (1984) Purification, kinetic behavior, and regulation of NAD(P)+ malic enzyme of tumor mitochondria. J Biol Chem 259:6222–6227PubMedGoogle Scholar
  35. Mueckler M (1990) Family of glucose-transporter genes: implication for glucose homeostasis and diabetes. Diabetes 39:6–11PubMedCrossRefGoogle Scholar
  36. Nagel WO, Dauchy RT, Sauer LA (1980) Mitochondrial malic enzymes: an association between NAD(P)+-dependent malic enzyme and cell renewal in Sprague-Dawley rat tissues. J Biol Chem 255:3849–3864PubMedGoogle Scholar
  37. Ohmori T, Hiasa Y, Murata Y, Williams G (1982) Gamma glutamyl transpeptidase activity in carcinogen-induced epithelial lesions of rat kidney. Gann 73:543–548PubMedGoogle Scholar
  38. Pedersen PL (1978) Tumor mitochondria and the bioenergetics of cancer cells. Prog Exp Tumor Res 22:190–274PubMedGoogle Scholar
  39. Romano AH, Colby C (1973) SV 40 virus transformation of mouse 3T3 cells does not specifically enhance sugar transport. Science 179:1238–1240PubMedCrossRefGoogle Scholar
  40. Ross BD, Guder WG (1982) Heterogeneity and compartmentation in the kidney. In: Sies H (ed) Metabolic compartmentation. Academic Press, New York, pp 363–409Google Scholar
  41. Sauer LA, Dauchy RT (1978) Identification and properties of the nicotinamide adenine dinucleotide (phosphate)+-dependent malic enzyme in mouse ascites tumor mitochondria. Cancer Res 38:1751–1756PubMedGoogle Scholar
  42. Sauer LA, Dauchy RT, Nagel WO, Morris HP (1980) Mitochondrial malic enzymes: mitochondrial NAD(P)+-dependent malic enzyme activity and malate-dependent pyruvate formation are progression-linked in Morris hepatomas. J Biol Chem 255:3844–3848PubMedGoogle Scholar
  43. Singh VN, Singh M, August JT, Horecker BL (1974) Alterations in glucose metabolism in chick-embryo cells transformed by Rous sarcoma virus: intracellular levels of glycolytic intermediates. Proc Natl Acad Sci USA 71:4129–4132PubMedCrossRefGoogle Scholar
  44. Su TS, Tsai TF, Chi CW, Han SH, Chou CK (1990) Elevation of facilitated glucose-transporter messenger RNA in human hepatocellular carcinoma. Hepatology 11:118–122PubMedCrossRefGoogle Scholar
  45. Taylor CB, Morris HP, Weber G (1969) A comparison of the properties of pyruvate kinase from hepatoma 3924A, normal liver and muscle. Life Sci 8:635–644PubMedCrossRefGoogle Scholar
  46. Thorens B, Lodish HF, Brown D (1990a) Differential localization of two glucose transporter isoforms in rat kidney. Am J Physiol 259:C286-C294PubMedGoogle Scholar
  47. Thorens B, Flier JS, Lodish HF, Kahn BB (1990b) Differential regulation of two glucose transporters in rat liver by fasting and refeeding and by diabetes and insulin treatment. Diabetes 39:712–719PubMedCrossRefGoogle Scholar
  48. Tsuda H, Hacker HJ, Katayama H, Masui T, Ito N, Bannasch P (1986) Correlative histochemical studies on preneoplastic and neoplastic lesions in the kidney of rats treated with nitrosamines. Virchows Arch [B] 51:385–404CrossRefGoogle Scholar
  49. Van Veelen CWM, Verbiest H, Vlug AMC, Rijksen G, Staal GEJ (1978) Isoenzymes of pyruvate kinase from human brain, meningeomas and malignant gliomas. Cancer Res 38:4681–4687PubMedGoogle Scholar
  50. Verhagen JN, Van der Heijden MCM, De Jongvan Dijken J, Rijksen G, Der Rinderen PJ, Van Unnik JAM, Staal GEJ (1985) Pyruvate kinase in normal thyroid tissue and thyroid neoplasms. Cancer 55:142–148PubMedCrossRefGoogle Scholar
  51. Wirthenson G, Guder WG (1986) Renal substrate metabolism. Physiol Rev 66:469–497Google Scholar
  52. Zak FG, Holzner JH, Singer EJ, Popper H (1960) Renal and pulmonary tumors in rats fed dimethylnitrosamine. Cancer Res 20:96–99PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Young Soo Ahn
    • 1
  • Heide Zerban
    • 1
  • Peter Bannasch
    • 1
  1. 1.Abteilung für CytopathologieDeutsches KrebsforschungszentrumHeidelbergGermany

Personalised recommendations