The in vivo malignant transformation of mouse fibroblasts in the presence of human tumour xenografts

Abstract

Summary During the routine serial passage of over 30 human tumour xenografts in athymic (nu. nu.) mice over a period of 6 years the induction of murine fibrosarcomas at the site of transplantation has been observed on three occasions. In two cases it has been possible to follow the development of these tumours over successive transplant generations. These sarcomas had growth rates, tumour karyotypes and isoenzyme patterns which clearly distinguished them from the original human xenografts.Human tumour xenografts are now an established model for tumour biology and therapy studies (Steel et al., 1983). Although a number of different types of immunodeficient animals have been used as hosts for the transplant tumours (Castro, 1972;Steel et al., 1978;Rygaard & Povlsen, 1969;Lozzio et al., 1976;Festing et al., 1978) the athymic nude mouse mutant (nu. nu.) is now the most popular. A number of workers have demonstrated that the tumours tend to retain the morphology of the original explant in successive transplants in spite of the rodent stromal and vascular components of these tumours (Sharkey et al., 1978;Povlsen et al., 1982;Sebesteny et al., 1979).Athymic mice can exhibit a high incidence of malignant lymphomas (Custer et al., 1973) and it has been suggested that this is associated with chronic antigenic stimulation . The occurrence of lymphomas has also been directly linked to the transplantation of human tumours (Gautsch et al., 1980). The apparent induction of malignant lymphoma by human xenografts could conceivably become a problem in the routine passage of human tumours in mice as each transplant generation carries the risk of propagating the induced lymphoma as well as, or instead of, the human tumour under investigation (Figure 1).Types of 'spontaneous' tumour other than malignant lymphoma are rare in athymic mice (Sharkey et al., 1982). Houghton and Taylor (1978) from that which was expected. Although they also reported that this tumour had a different histological pattern from the original tumour no details were given. Beattie et al. (1982) reported the occurrence of two cases of murine sarcoma induction during the course of serial passage of 50 human tumour xenografts in anthymic mice over a period of 5 years. Our own experience with over 30 human xenografts over a 6 year period, some of which have been through more than 30 passages in athymic mice, has revealed the occurrence of 3 cases of murine sarcoma induction. This paper follows the development of 2 of these sarcomas over successive passages. Materials and methods AnimalsAthymic nude mice (nu. nu.) on a random TO background were bred and maintained in flexible film plastic isolators to minimise disease from infectious agents. Heterozygous litter mates (nu. +.) were used to test the transformed tumours for their ability to grow in immunocompetent animals. TumoursExplants from patients at the Royal Marsden Hospital were implanted as small (1-2mm3) fragments, subcutaneously into the right flank of 12-week old mice. Serial passage was carried out when th...

Activation of murine 'T' lymphomas in the presence of a human myeloma cell line, RPMI-8226, in vivo

“…Although there was no evidence for metastatic spread in the experiments reported herein this may have been due to the rapid growth of the primary tumours which necessitated the termination of experiments before the tumours ulcerated. Our findings concerning the rapid growth of these tumours are in agreement with those of Sparrow et al (1986) who pointed out that since human tumour xenografts grow relatively slowly, rapid tumour growth and skin ulceration should alert the investigator of possible malignant transformation of endogenous murine cells. The incidence of 'T' lymphomas in our system (5/6) is much higher than that reported by other workers.…”

“…The incidence of 'T' lymphomas in our system (5/6) is much higher than that reported by other workers. Sparrow et al (1986) reported 3 murine fibrosarcomas which arose over a 6 year period from 30 human xenografts. In this respect the RPMI-8226 cell line appears more effective in initiating the production of endogenous virus which results in lynmphoma production than they are of becoming established as a xenograft.…”

Human tumor xenografts as model for drug testing

“…Occasionally, the induction of murine tumors following human tumor transplantation has been observed [61,120]. These s.c. tumors were invasive, penetrating both the muscularis and the epidermis [120].…”

Malignant transformation of host stromal fibroblasts derived from the bone marrow traced in a dual-color fluorescence xenograft tumor model

“…These stromal cells are considered normal and never undergo malignant transformation (2,(25)(26)(27). However, the malignant transformation of the tumor stromal cells, particularly CAFs and their origin, MSCs, in vitro and in vivo has been previously reported (28)(29)(30)(31)(32)(33)(34). Therefore, this remains a controversial topic that requires further investigation.…”