Die Anämie bei malignen Tumorerkrankungen

Cellular uptake of ⁶⁷Ga-labelled transferrin by the tumor tissue was studied in rats with tumors of different malignancy and different tumor mass using the slowly growing Morris hepatoma 5123C, the moderately growing Novikoff hepatoma and the very fast and aggressive Yoshida hepatoma AH130. The cellular accumulation of ⁶⁷Ga-transferrin was found to correlate with the proliferation activity of the tumor. The ⁶⁷Ga-transferrin concentration in the very fast growing Yoshida hepatoma was 4.8 times higher than the concentration in the slowly growing Morris hepatoma. The uptake of ⁶⁷Ga-transferrin by the tumors resulted in a faster disappearance of circulating ⁶⁷Ga-transferrin from the blood. The rate of disappearance correlated with the proliferation activity and the spread of the tumors. Using tumors of identical size the elimination of ⁶⁷Ga-transferrin from the blood was much faster in the rats with Yoshida hepatoma than in those with the slowly growing Morris hepatoma. On the other hand, using tumors of different tumor size it could be demonstrated that the rate of disappearance of ⁶⁷Ga-transferrin from the blood correlated directly with tumor mass. It is concluded that cellular incorporation of transferrin within the tumor cells results in a loss of circulating transferrin, which correlates with tumor mass and proliferation of tumor. This mechanism is supposed to be the cause for the hypotransferrinemia seen in patients with malignant tumors.

Zusammenfassung

Es wird am Modell des langsam wachsenden Morris-Hepatoms 5123C, des mäßig schnell wachsenden Novikoff-Hepatoms und des sehr schnell und aggressiv wachsenden Yoshida- Hepatoms AH130 die Aufnahme von ⁶⁷Ga-markiertem Transferrin in das Tumorgewebe untersucht. Es zeigt sich dabei mit zunehmender Proliferationsaktivität der Tumoren eine ansteigende ⁶⁷Ga-Transferrinaufnahme proGramm Tumorfeuchtgewicht. Diese Aufnahme von ⁶⁷Ga-Transferrin ins Tumorgewebe geht mit einem Verlust von zirkulierendem ⁶⁷Ga- Transferrin aus dem Blut einher. Die Elimination von zirkulierendem ⁶⁷Ga- Transferrin hängt einerseits von der Tumormasse, andererseits von der Proliferationsrate der Tumoren ab. So zeigte sich bei gleicher Tumorgröße der verschiedenen Tumormodelle, daß die Elimination von ⁶⁷Ga-Transferrin aus dem Blut bei Tieren mit dem sehr schnell wachsenden Yoshida-Hepatom sehr viel schneller erfolgte als bei dem weniger schnell wachsenden Novikoff-Hepatom und dem langsam wachsenden Morris-Hepatom. Andererseits zeigte sich bei histologisch gleichem Tumortyp mit zunehmender Tumorgröße eine zunehmend schnelle Elimination von ⁶⁷Ga- Transferrin aus dem Blut. Aus diesen Befunden wird geschlossen, daß die zelluläre Anreicherung von Transferrin im Tumorgewebe und, damit verbunden, die Verluste von Transferrin aus dem zirkulierenden Blut die Ursache für die bei malignen Tumorerkrankungen bekannte Hypotransferrinämie darstellt.

• LITERATUR

• 1 Allison A C. The role of lysosomes in pathology. Proc Royal Soc Med 1966; 59: 867-71.
• 2 Aulbert E, Disselhoff W, Sörje H, Schulz E, Gerieke D. Lysosomal accumulation of ⁶⁷Ga-transferrin in malignant tumors in relation to their growth rate. Europ J Cancer 1980; 16: 1217-932.
• 3 Aulbert E. Die ⁶⁷Ga-Szintigraphie - Ein Spiegelbild der zellulären Transferrinaufnahme schnell proliferierender Gewebe. Prax Klin Pneumol 1985; 39: 638-40.
• 4 Aulbert E. Transferrinmangelanämic bei malignen Tumorerkrankungen. Stuttgart: Thieme; 1986
• 5 Aulbert E. Die Anämie bei malignen Tumorerkrankungen. II. Tumorbedingte Verluste von Transferrin als Ursache für die Entwicklung einer Anämie am Modell der Ratte. Nucl-Med. 1989 28. (im Druck)
• 6 Bichel P, Hansen H H. The incorporation of ⁶⁷Ga in normal and malignant cells and its dependence on growth rate. Br J Radiol 1972; 45: 182-4.
• 7 Ciechanover A, Schwartz A I, Dantry-Varsat A, Lodish H F. Kinetics of internalization and recycling of transferrin and the transferrin receptor in a human hepatoma cell line. J Biol Chem 1983; 258: 9681-9.
• 8 Ekblom P, Thesleff I, Saxen L, Miettinen A, Timpl R. Transferrin as a fetal growth factor: acquisition of responsiveness related to embryonic induction. Proc Natl Acad Sci (USA) 1983; 80: 2651-5.
• 9 Farrer P A, Saha G B. Studies of the mechanism of ⁶⁷Ga uptake by normal and malignant tissue and cell systems. J Nucl Med 1973; 14: 625-6.
• 10 Faulk W P, Hsi B L, Stevens P J. Transferrin and transferrin receptors in carcinoma of the breast. Lancet 1980; ii 390-2.
• 11 Foster M, Fell L, Pockington T. et al. Electron spin resonance as a useful technique in the management of Hodgkin’s disease. Clin Radiol 1977; 28: 15-22.
• 12 Galbraith R M, Werner P, Arnaud P, Galbraith G M P. Transferrin binding to peripheral blood lymphoctes activated by phytohemagglutinin involves a specific receptor. J Clin Invest 1980; 66: 1135-43.
• 13 Haigler H T, McKanna J A, Cohen S. Rapid stimulation of pinocytosis in human carcinoma ce11s A-431 by epidermal growth factor. J Cell Biol 1979; 83: 82-90.
• 14 Hamilton T A, Wada H G, Sussman H H. Identification of transferrin receptors on the surface of human cultured cells. Proc Natl Acad Sci (USA) 1979; 76: 6406-10.
• 15 Hammcrslcy PA, Cauchi M N, Taylor D H. Uptake of ⁶⁷Ga in the regenerating rat liver and its relationship to lysosomal enzyme activity. Cancer Res 1975; 35: 1154-8.
• 16 Hopkins C R. Intracellular routing of transferrin and transferrin receptors in epidermoid carcinoma A 431 cells. Cell 1983; 35: 321-30.
• 17 Hopkins C R, Trowbridge I S. Internalization and processing of transferrin and the transferrin receptor in human carcinoma A 431 cells. J Cell Biol 1983; 97: 508-21.
• 18 Karin M, Mintz B. Receptor mediated endocytosis of transferrin in developmentally totipotent mouse teratocarcinoma stem cells. J Biol Chem 1981; 256: 3245-52.
• 19 Klausner R D, Renswonde J V, Ashwell G. et al. Receptor-mediated endocytosis of transferrin in K 562 cells. J Biol Chem 1983; 258: 4715-24.
• 20 Klausner R D, Harford J, van Renswonde J. Rapid internalization of the transferrin receptor K 562 cells is triggered by ligand binding or treatment with a phorbol ester. Proc Natl Acad Sci (USA) 1984; 81: 3005-9.
• 21 Lamb J E, Ray F, Ward J H, Kushner J P, Kaplan J. Internalization and subcellular localization of transferrin and transferrin receptors in HeLa cells. J Biol Chem 1983; 258: 8751-8.
• 22 Larrick J W, Cresswell P. Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J Supramol Struct 1979; 11: 579-86.
• 23 Larrick J W, Logue G. Transferrin receptors on leukaemic cells. Lancet 1980; ii 862-3.
• 24 May W S, Jacobs S, Cuatrecasas P. Association of phrobol ester-induced hyperphosphorylation and reversible regulation of transferrin membrane receptors in HL60 cells. Proc Natl Acad Sci (USA) 1984; 81: 2016-20.
• 25 Nash A G, Cance D R, McCready V R, Griffiths J D. Uptake of Gallium-67 in colonic and rectal tumours. Br Med J 1972; 03: 508-10.
• 26 Neckers L M, Cossman J. Transferrin receptor induction in mitogen-stimulated human T lymphocytes is required for DNA synthesis and cell division and is regulated by interleukin 2. Proc Natl Acad Sci (USA) 1983; 80: 3494-8.
• 27 Nunez M T, Glass J, Fischer S. et al. Transferrin receptors in developing murine erythroid cells. Br J Haematol 1977; 36: 519-26.
• 28 Pan B T, Blostein R, Johnstone R M. Loss of the transferrin receptor during the maturation of sheep reticulocytes in vitro. Biochem J 1983; 210: 37-47.
• 29 Phillips J I, Azari P. Zinc transferrin. Enhancement of nucleic acid synthesis in phytohemagglutinin-stimulated human lymphocytes. Cell Immunol 1974; 10: 31-7.
• 30 Phillips J I. Uptake of transferrin-bound zinc by human lymphocytes. Cell Immunol 1978; 35: 318-29.
• 31 Salomin D S. Correlation of receptors for growth factors on mouse embryonal carcinoma cells with growth in serum-free hormone-supplemented medium. Exp Cell Res 1980; 128: 311-21.
• 32 Shindelman J E, Ortmeyer A D, Sussman H H. Demonstration of the transferrin receptor in human breast cancer tissue. Potential marker for identifying dividing cells. Int J Cancer 1981; 27: 329-34.
• 33 Sutherland R, Delia D, Schneider C. et al. Ubiquitous cell-surface glycoprotein on tumor cells is proliferation-associated receptor for transferrin. Proc Natl Acad Sci (USA) 1981; 78: 4515-9.
• 34 Tormey D C, Imrie R C, Müller G C. Identification of transferrin as a lymphocyte growth promotor in human scrum. Exp Cell Res 1972; 74: 163-9.
• 35 Tormey D C, Müller G C. Biological effects of transferrin on human lymphocytes in vitro. Exp Cell Res 1972; 74: 220-6.
• 36 Trowbridge I S, Omary M B. Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc Natl Acad Sci (USA) 1981; 78: 3039-43.
• 37 Trowbridge I S, Lopes F. Monoclonal antibody to transferrin receptors blocks transferrin binding and inhibits human cell growth in vitro. Proc Natl Acad Sci (USA) 1982; 79: 1175-9.
• 38 Vogt A, Mishell R J, Dutton R W. Stimulation of DNA-synthesis in cultures of mouse spleen cell suspensions by bovine transferrin. Exp Cell Res 1969; 54: 195-200.
• 39 Vorbrodt A, Meo P, Rovera G. Regulation of acid phosphatase activity in human pro- myelocytic leukemic cells induced to differentate in culture. J Cell Biol 1979; 83: 300-7.
• 40 Yeh C G, Papamichael M, Faulk W P. Loss of transferrin receptors following induced differentiation of HL-60 promyelocytic leukemic cells. Exp Cell Res 1982; 138: 429-33.