Multicellular origin of fibrosarcomas in mice induced by the chemical carcinogen 3-methylcholanthrene.

Abstract

The cellular origin of tumors induced by the chemical carcinogen 3-methylcholanthrene (MCA) was studied in mice with X-chromosome inactivation mosaicism. Because only 1 of the 2 X-chromosomes is active in XX somatic cells, a female heterozygous at the X-linked phosphoglycerate kinase (PGK-1) locus for the usual Pgk-1b gene and the variant Pgk-1a has 2 populations of cells; in the cells of 1 population, Pgk-1b is active and B-type enzyme is synthesized, whereas in cells of the other population, A-type enzyme is produced. Both enzyme types are found in normal tissues from these mosaic mice. A tumor developing from a single cell exhibits only 1 of the 2 PGK enzyme types, whereas a tumor with a multicellular origin expresses both enzymes (i.e., it has a double-enzyme phenotype). Five fibrosarcomas developing at the site of injection of 0.2 or 2.0 mg of MCA were analyzed. From the 5 tumors, 36 of 38 fragments had double-enzyme PGK phenotypes. One piece from each of 2 tumors showed a single-enzyme phenotype. Histological, cell culture and cloning studies indicate that the phenotypes reflect the presence of both types of malignant cells and not an admixture of normal with neoplastic elements in the specimens tested for PGK. These fibrosarcomas apparently have a multicellular origin.