Molecular Diversity and Physiological Roles of Growth Inhibitors

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Considerable evidence has accumulated indicating that proliferation of animal cells is regulated by a balance between positive and negative growth stimuli. To clarify molecular species and physiological roles of growth inhibitors, each member of this research project has studied cytostatic or cytotoxic proteins present in different sources such as sera and cultured cells. Both cytostatic and cytotoxic factors were purified and characterized from normal rabbit serum. The former was a heat-and acid-labile but dithiothreitol-resistant protein with 56 kDa, which reversibly inhibited the growth of various malignant and nonmalignant cells. The latter existed in a latent form in the serum and was activated by incubating the serum at 37 ^OC for 12 h. Two active forms with 18 kDa and 36 kDa were purified from the incubated serum. Both proteins, which were heat- and acid-labile but dithiothreitol-resistant, exerted a strong cytolytic effect on rodent cells regardless of cell type and malignancy. Other growth inhibitors characterized in this study include mouse neonatal brain-derived carcinostatic factor (NBCF), tumor-degenerating factor (TDF) secreted by human fibroblasts, neuroblast growth inhibitory factor (NGIF) secreted by rat glioblasts, and tumor-regressing factor (TRF) induced by antitumor polysaccharides in the serum of tumor-bearing mice.