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Cell Hybridization and Cancer J Clin Pathol: first published as 10.1136/jcp.s3-7.1.16 on 1 January 1974. Downloaded from J. clin. Path., 27, Suppl. (Roy. Coll. Path.), 7, 16-18 Cell hybridization and cancer J. F. WATKINS From the Sir William Dunn School ofPathology, Oxford In this paper I want to consider what, if anything, on SV40 virus. When transformed mouse cells of a cell hybridization has contributed to our knowledge line known as SV3T3, which are nonpermissive for of malignant disease in animals, and whether it is virus growth and from which no virus can be possible that the technique would be useful in studies recovered by standard procedures, were fused with on human tumour cells. I shall deal almost ex- African Green Monkey kidney cells, about 5% of clusively with cell fusion produced by Sendai virus the heterokaryons formed produced SV40 virus. If inactivated by ultraviolet light (Watkins, 1971). This the SV3T3 cells were treated with iododeoxyuridine virus, a parainfluenza virus related to mumps and (IUdR) for 24 hours before fusion the proportion of Newcastle disease viruses, attaches to receptors on heterokaryons producing virus rose to over 80 % the cell membrane. If suspensions of two different (Watkins, 1970). This result is interesting in view of kinds of cell are mixed with virus, clumps of cells the subsequent demonstration by Lowy, Rowe, are formed containing both cell types. Within the Teich, and Hartley (1971) that IUdR can induce clumps cytoplasmic bridges form between some of certain transformed cell lines to produce C-type the cells, and this leads to coalescence of their RNA viruses. The action of IUdR as a virus-inducing cytoplasms. If the suspension is allowed to settle on agent should be borne in mind in chemotherapy, to coverslips in culture medium, Giemsa staining since other agents which affect DNA synthesis may copyright. after overnight incubation shows multinucleated possibly have a similar effect. Recently I have cells, many of which have nuclei of both parents, extended these studies to a rabbit line transformed and are therefore called heterokaryons. On continued with SV40 virus. This line differs from SV3T3 in incubation the nuclei in some of the smaller hetero- that about 0 03 % of the cells are producing SV40 karyons enter mitosis synchronously, with the virus spontaneously. Cell fusion studies showed that formation of a mixed metaphase which reconstitutes about 3 % of the heterokaryons produced SV40 into a single nucleus to form a hybrid cell. The virus, but the proportion could not be increased by http://jcp.bmj.com/ hybrid cell may continue to divide to form a hybrid treatment with iododeoxyuridine. In addition, clone, which can be separated from the parental hybridization in situ with heavily labelled RNA cells by various selection procedures. During the complementary to SV40 DNA showed that 2-3 % of development of the clone chromosomes are lost the cells were synthesizing viral DNA. The picture because of such phenomena as non-disjunction and which begins to emerge from these and other studies failure of chromosomes to be incorporated at telo- suggests that SV40 virus may exist in a tumour cell phase. A hybrid clone is therefore genetically line in one of two forms, possibly integrated and heterogeneous, and subclones can readily be non-integrated. If the cell is capable of replicating on September 28, 2021 by guest. Protected selected from it by the application of suitable the viral DNA it will do so when the virus is in the selection pressures. Another important property of non-integrated form, but it will not go on to syn- heterokaryons and hybrid cells is that surface thesize viral capsid protein until other conditions of antigens of both parents are co-dominant, that is, an unknown kind are satisfied. Non-permissiveness are both expressed. may therefore be due to two blocks, in viral DNA Cell fusion has been used in three areas of investi- synthesis and in viral protein synthesis. This model gation of tumour cells: (1) attempts to recover may be relevant to a consideration of the natural virus from virus-transformed cells; (2) genetic history of EB virus of Burkitt's lymphoma. analysis of malignancy; (3) tumour antigens. In contrast to SV40 virus, the related polyoma virus has not been recovered from transformed cells Virus Recovery from Virus-transformed Cells by fusion with permissive cells. Cell fusion is relevant to studies on C-type RNA viruses mainly in situa- The principles of virus recovery, perhaps better tions where the virus has transformed cells of a called 'detection', can be illustrated by experiments species other than its natural host. Svoboda and 16 J Clin Pathol: first published as 10.1136/jcp.s3-7.1.16 on 1 January 1974. Downloaded from Cell hybridization and cancer 17 Dourmashkin (1969), for example, have recovered contribute greatly to the solution of the cancer Rous sarcoma virus from transformed hamster problem. cells by fusing them with chicken fibroblasts. As far as human tumours are concerned genetic It will be obvious that the application of cell analysis has no part to play unless interspecific fusion to the search for a human tumour virus is not hybrids can be made which turn out to be malignant: straightforward. First a cell line permissive for the this would support the view that malignancy is a putative virus must be found; this means that any positive genetic character which may be associated human tumour must be screened against a wide with a specific chromosome. If Harris and Klein are range of cell types. Secondly, even if a permissive right such a hybrid could not exist, even if problems cell line could be found, the virus might behave like of cross-species transplantation immunity were polyoma rather than SV40. If one speculated that a overcome. human tumour were caused by a C-type RNA virus from another species, for example, domestic cats or Tumour Antigens dogs, then, by analogy with Svoboda's studies on Rous virus, it might be worth using cells of the species in question in fusion studies. Finally, in the area of tumour antigens, one example of cell fusion studies must suffice to illustrate the Genetic Analysis of Malignancy kind of analysis which can be attempted. Mouse primary cells are not malignant when first trans- In the early 1960s Barski and Cornefert (1962) formed by SV40 virus, but malignant derivatives carried out some experiments to determine whether can sometimes be obtained on continued growth. a hybrid line between a malignant cell and a non- This non-malignancy is usually attributed to the malignant cell would be malignant or non- presence of SV40 transplantation antigens. How- malignant. They concluded that the hybrid was ever, Wesslen (1970) found that a malignant deriva- malignant. Recently Klein and Harris (see Harris, tive of an SV40 transformed mouse line retained the 1971) and their colleagues re-investigated the SV40-specific transplantation antigen. I have been question, using several different tumours of inbred studying a hybrid population formed between a non- copyright. mice crossed with a line of cells derived from C3H malignant SV40-transformed C3H mouse line and mouse fibroblasts, and concluded that the hybrid Ehrlich ascites tumour. The hybrid population is was not malignant. They found, however, that the over 990 positive for SV40 T (intranuclear) antigen. hybrid would revert to malignancy, and that the The ascites tumours which arose in 14 out of 20 reversion was accompanied by a reduction in the C3H mice two weeks after intraperitoneal injection number of chromosomes which had arisen from the of 106 hybrid cell had lower chromosome counts normal parent. Two interpretations are possible. One than the original culture, and 13 of the 14 tumours http://jcp.bmj.com/ is that reversion to malignancy occurred first, by were over 99% negative for SV40 T antigen. Thus some unknown genetic change, and the consequent there seemed to be strong selection pressure in most rapid growth led to chromosome reduction; the of the mice against cells carrying SV40 virus: tumour other is that one or more chromosomes of the cellswhich hadpresumably lost theSV40genomegrew normal parent carry genes capable of suppressing faster in the peritoneal cavity than cells which had malignancy, and reversion occurs because of retained it. In fact, nearly all of the 106 hybrid cells random loss of certain chromosomes, among which which were injected into each mouse must have been on September 28, 2021 by guest. Protected may be chromosomes carrying suppressor genes. rejected. These results suggest either that the SV40 The second interpretation is supported by their transplantation antigen is so strong for mice that it finding that a hybrid formed between tumour cells can even overcome the malignant potential of and a malignant subclone of the original normal Ehrlich ascites tumour cells, which is at variance parent gave rise to a tumour in which there was with Wesslen's result, or-and this would be little or no reduction in chromosome number in extremely interesting-that SV40 transformed mouse comparison with the population injected; that is, cells are not a priori malignant, and, furthermore, rapid growth, per se, of a hybrid tumour did not the virus in the transformed cells may be linked with lead to gross chromosome loss. Future work with the genes which can apparently suppress the malig- this system requires the demonstration that suppres- nancy of Ehrlich ascites tumour cells. It is hoped sion of malignancy is associated with a particular that future experiments will enable a choice to be chromosome or chromosomes but this is impossible made between these two explanations. in the absence of a method for selecting, in vivo, non- As far as human tumours are concerned it should malignant cells from malignant cells.
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