It is generally accepted that tumours arise through the accumulation of several changes affecting the control of cell growth. Recent advances in molecular biology have made it possible to define some of these changes in molecular terms and to trace the steps by which certain tumours evolve.

Evolution of tumours and the impact of molecular oncology.

https://www.cell.com/cell/pdf/0092-8674(89)90238-9.pdf

Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene

Genes that can inhibit the expression of the tumorigenic phenotype have been detected by the fusion of normal and malignant cells, the phenotypic reversion of in vitro transformants, the induction of terminal differentiation of malignant cell lineages, the loss of "recessive cancer genes," the discovery of regulatory sequences in the immediate vicinity of certain oncogenes, and the inhibition of tumor growth by normal cell products Such tumor suppressor genes will probably turn out to be as, if not more, diversified as the oncogenes Consideration of both kinds of genes may reveal common or interrelated functional properties

The Approaching Era of the Tumor Suppressor Genes

Both tumorigenic segregant HeLa X human fibroblast hybrids and tumorigenic HeLa (D98/AH-2) cells can be converted to a non-tumorigenic state following introduction of a single copy of a fibroblast t(X;11) chromosome. The translocated chromosome contains approximately 95% of the 11 chromosome and the q26-qter portion of the X chromosome which contains the hypoxanthine guanine phosphoribosyl transferase (HPRT) gene. Introduction of a human X chromosome has no effect on tumorigenic expression. Suppression of tumorigenicity is relieved by selecting cells which have lost the t(X;11) chromosome by growth in medium containing 6-thioguanine (6-TG). Further, reintroduction of the t(X;11) chromosome into tumorigenic 6TGR cells again suppresses tumorigenicity. Thus, the introduction of a single copy of a human chromosome 11 is sufficient to completely suppress the tumorigenic phenotype of HeLa cells and is suggestive of the presence of tumor-suppressor gene(s) on this chromosome.

Introduction of human chromosome 11 via microcell transfer controls tumorigenic expression of HeLa cells.

Sex reversal in the mouse (Mus musculus) is caused by a recurrent nonreciprocal crossover involving the X and an aberrant Y chromosome

Previous experiments with crosses between malignant and diploid mouse cells had shown that the reappearance of malignancy in hybrids in which it was initially suppressed was associated in some cases with the elimination of the chromosomes 4 derived from the diploid parent cell. In others, however, this did not appear to be so. In the present study, we have re-examined the role of the diploid chromosomes 4 in the suppression of malignancy using natural polymorphisms of the centromeric heterochromatin to identify the parental origin of the chromosomes 4 in the hybrid cells. We now find that the diploid chromosomes 4 are indeed involved in the suppression of malignancy in all the tumours that we have examined, which include a carcinoma, a melanoma, a sarcoma and a lymphoma. In all crosses between these malignant tumour cells and diploid fibroblasts, there is selective pressure in vivo against the chromosomes 4 derived from the diploid cell and in favour of the chromosomes 4 derived from the malignant cell. This indicates that the chromosomes 4 in all these tumours are in some way functionally different from the chromosomes 4 of the diploid fibroblast. Reappearance of malignancy in hybrids in which it was initially suppressed may result from a reduction in the number of diploid chromosomes 4, an increase in the number of malignant chromosomes 4, or both. The gene on the diploid chromosome 4 responsible for the suppression of malignancy acts in a dose-dependent manner.

The analysis of malignancy by cell fusion ix.* re-examination and clarification of the cytogenetic problem

If the sex-reversal factor (Sxr) in mice is represented by a segment of the Y chromosome translocated on to an autosome, this segment might be expected to show some evidence of attempted pairing with the normal Y chromosome at the first meiotic division. Our failure to find such evidence in a light microscope study of the silver-stained pachytene spermatocytes from Sxr/4, XY males further supports existing cytological information that the factor is more likely to be represented by an autosomal dominant gene mutation.

M. D. Burtenshaw

Papers

The analysis of malignancy by cell fusion ix.* re-examination and clarification of the cytogenetic problem

Meiosis in Sxr male mice: II. Further absence of cytological evidence for a Y-autosome rearrangement in sex-reversed (Sxr) mice.

Centric fusion polymorphism in Romney Marsh sheep of England