Loss of tumor-suppressive function during chemically induced neoplastic progression of Syrian hamster embryo cells (original) (raw)

1986, Proceedings of the National Academy of Sciences

Cell hybrids between normal, early-passage Syrian hamster embryo cells and a highly tumorigenic, chemically transformed hamster cell line, BP6T, were formed, selected, and analyzed. Tumorigenicity andanchorage-independent growth were suppressed in the hybrid cells compared to the tumorigenic BP6T cells. These two phenotypes segregated coordinately in these cells. To determine at what stage in the neoplastic process this tumor-suppressive function was lost, two chemically induced immortal cell lines were examined at different passages for the ability to suppress the tumorigenic phenotype of BP6T cells following hybridization. Hybrids of BP6T cells with the immortal, nontumorigenic cell lines at early passages were suppressed for tumorigenicity and anchorageindependent growth. This tumor-suppressive ability was reduced in the same cells at later passages and in some cases nearly completely lost, prior to the neoplastic transformation of the immortal cell lines. Subclones of the cell lines were heterogeneous in their ability to suppress tumorigenicity in cell hybrids; some clones retained the tumor-suppressive ability and others lost this function. The susceptibility to neoplastic transformation of these cells following DNA transfection with the viral ras oncogene or BP6T DNA inversely correlated with the tumor-suppressive ability of the cells. These results suggest that chemically induced neoplastic progression of Syrian hamster embryo cells involves at least three steps: (i) induction of immortality, (ii) activation of a transforming oncogene, and (iii) loss of a tumor-suppressive function. The conversion of a normal cell into a malignant cell is recognized as a multistep process (1-3); however, the number of genetic changes involved is not known. A major advance in our understanding was the discovery of oncogenes that are capable of transforming immortal cells as well as normal, primary rodent cells when certain combinations of oncogenes are transfected into the cells (4-7). These experiments indicate that at least two cooperating, apparently dominantly acting, oncogenes are required for neoplastic transformation ofnormal, diploid cells. It has been proposed that one oncogene is involved in the immortalization process and the second in the expression of various transformed phenotypes, such as focus formation or anchorage-independent growth (3, 4, 7). However, certain observations suggest that changes in addition to these two steps are also needed. One of the most compelling lines of evidence comes from experiments involving hybridization of normal and malignant cells. Many, but not all, of these experiments indicate that tumorigenicity is a recessive trait (8-14). A major paradox in cancer biology, therefore, exists: DNA transfection experiments have identified dominantly acting cancer genes (oncogenes), whereas cell hybridization experiments suggest that tumorigenicity is recessive in nature.