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Journal of Histochemistry and Cytochemistry, Vol. 48, 509-522, April 2000, Copyright © 2000, The Histochemical Society, Inc.

ARTICLE

Metabolic Imaging in Multicellular Spheroids of Oncogene-transfected Fibroblasts

Stefan Walentaa, Joerg Doetscha, Wolfgang Mueller–Kliesera, and Leoni A. Kunz–Schugharta,b
a Institute of Physiology and Pathophysiology, University of Mainz, Mainz, Germany
b Institute of Pathology, University of Regensburg, Regensburg, Germany

Correspondence to: Leoni A. Kunz–Schughart, Institute of Pathology, University of Regensburg, 93042 Regensburg, Germany. E-mail: leoni.kunz-schughart@klinik.uni-regensburg.de

Four rat embryo fibroblast (REF) cell lines with defined oncogenic transformation were used to study the relationship between tumorigenic conversion, metabolism, and development of cell death in a 3D spheroid system. Rat1 (spontaneously immortalized) and M1 (myc-transfected) fibroblasts represent early nontumorigenic transformation stages, whereas Rat1-T1 (T24Ha-ras-transfected Rat1) and MR1 (myc/T24Ha-ras-co-transfected REF) cells express a highly tumorigenic phenotype. Localized ATP, glucose, and lactate concentrations in spheroid median sections were determined by imaging bioluminescence. ATP concentrations were low in the nonproliferating Rat1 aggregates despite sufficient oxygen and glucose availability and lack of lactate accumulation. In MR1 spheroids, a 50% decrease in central ATP preceded the development of central necrosis at a spheroid diameter of around 800 µm. In contrast, the histomorphological emergence of cell death at a diameter of around 500 µm in Rat1-T1 spheroids coincided with an initial steep drop in ATP. Concomitantly, reduction in central glucose and increase in lactate before cell death were recorded in MR1 but not in Rat1-T1 spheroids. As shown earlier, myc transfection confers a considerable resistance to hypoxia of MR1 cells in the center of spheroids, which is reflected by their capability to maintain cell integrity and ATP content in a hypoxic environment. The data obtained suggest that small alterations in the genotype of tumor cell lines, such as differences in the immortalization process, lead to substantial differences in morphological structure, metabolism, occurrence of cell death, and tolerance to hypoxia in spheroid culture. (J Histochem Cytochem 48:509–522, 2000)

Key Words: imaging bioluminescence, multicellular tumor spheroids, rat embryo fibroblasts, myc/ras co-transfection, metabolism, ATP, glucose, lactate


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