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Characterization of a Variant-producing Tumor Cell Line from a Heterogeneous Strain BALB/cfC₃H Mouse Mammary Tumor¹

Departments of Immunology [J. C. H., G. H. H.] and Tumor Biology [W. S.], Michigan Cancer Foundation, Detroit, Michigan 48201; Department of Medicine [A. M. R.], Roger Williams General Hospital and Brown University, Providence, Rhode Island 02912; and Department of Pathology [S. F.], Center of the Health Sciences, University of California, Los Angeles, California 90024

We have described previously the isolation and characterization of markedly different subpopulations of tumor cells from a single spontaneous strain BALB/cfC₃H mouse mammary tumor (Cancer Res., 38: 3174–3181, 3758–3763, 1978). One of these subpopulations, 68H, contained morphological variants in vitro following one passage in vivo. Six 68H variants were cloned in soft agar, resulting in two epithelioid (E1 to E2) and four fusiform (F1 to F4) variants, as determined by in vitro morphology. These variants displayed a range in tumorigenicity in syngeneic hosts; i.e., when 10⁶ cells were injected s.c., clone F2 had a tumor incidence of 100% and a latency period of 2 weeks whereas clone E2 had a tumor incidence of 40% and a latency period of 10 weeks. The tumors produced by the variants were of several distinct patterns: glandular; sarcomatous; and angiomatous. The type of histological pattern was independent of the in vitro morphology of the variant lines. The variants also displayed a spectrum of in vitro characteristics; i.e., the plating efficiency of clone E2 was 100%, the doubling time was 19 hr, and the saturation density was 3.7 x 10⁵ cells/sq cm whereas the plating efficiency of clone F4 was 56%, the doubling time was 29 hr, and the saturation density was 6.2 x 10⁵ cells/sq cm. Expression of mammary tumor virus-associated cell surface antigens ranged from 50% (E1 and F4) to almost 100% (F2) of the cells being positive by membrane immunofluorescence. Karyotypically, the variants were quite diverse. In contrast to fusiform variants, which remained stable when passaged, epithelioid clones produced further morphological variants. Thirteen fusiform and epithelioid variants were subcloned from the epithelioid clone E2. Eight of these subclones were distinct, although certain marker chromosomes indicated a common lineage. Thus, 68H is a candidate mammary tumor stem cell line and along with its epithelioid derivatives provides a model system with which to study the origin, development, and expression of tumor heterogeneity.

¹ This work was supported by USPHS Grants CA-27419 and CA-13943 from the NIH, Institutional Grant IN45R to Brown University from the American Cancer Society, and a bequest from the E. Walter Albachten Fund.

² To whom requests for reprints should be addressed, at Department of Immunology, Michigan Cancer Foundation, 110 E. Warren Ave., Detroit, Mich. 48201.

Received 7/11/80. Accepted 1/ 9/81.