Facilitation of nodal metastasis from a non-immunogenic murine carcinoma by previous whole-body irradiation of tumour recipients

Abstract

Summary.-Of 193 CBA mice kept under prolonged observation after excision of small intradermal transplants of a non-immunogenic tumour (CBA Carcinoma NT), 27 (14%) presented with local recurrence, 19 (10%) with regional lymphnodal metastasis (RNM) and 72 (37o%), with pulmonary metastasis + other systemic metastases.When mice were exposed to sublethal whole-body irradiation (WBI) before tumour transplantation, the incidence of RNM rose to -80% and the latent period was reduced fronm 60 days to -40 days after tumour transplantation. This enhancement of RNM by WBI was undiminished when the interval between WBI and tumour transplantation was increased from 1 to 90 days. An explanation for this effect in terms of immunosuppression by the WBI is unlikely for the following reasons: the tumour was non-immunogenic by standard quantitative tests; the effect persisted long after the expected time for recovery of immune reactivity; and i.v. injection of normal marrow and lymphoid cells after WBI failed to reduce the effect. That the effect was systemic was proved by failure of local pre-irradiation of the tumour bed or regional node to enhance RNM. The effect was not observed when WBI was given 4 days after excision of tumours. These and other experiments failed to indicate the mechanism of the effect of WBI, but its long persistence suggests that it may relate to stored lethal radiation damage in migrating cells of slow turnover tissues.IT HAS been commonly reported over the past decades that preliminary wholebody irradiation (WBI) of rodents enhances the growth of transplanted tumours and/or metastases from them. In the great majority of reports, the information was obtained from tumours which were frankly immunogenic in the hosts, and it is reasonable to conclude, as most authors do, that the enhancement was attributable to suppression of immunity by the WBI. Indeed, the demonstration of enhancement by WBI has now come to be regarded as evidence that a tumour is immunogenic. In the case of enhancement of metastasis by preliminary local irradiation, the site most commonly studied has been the lung. It has been shown that local pre-irradiation of the lung increases the yield of tumour nodules in the lung following i.v. injection of tumour cells (Milas and Withers, 1970; Withers and Milas, 1973;Brown, 1973). Because these authors found no greater enhancement after WBI than after local irradiation, they were inclined to dismiss immunosuppression as contributing to their findings.We report here a powerful and longlasting enhancing effect of pre-WBI on the incidence of regional nodal metastases from intradermal (i.d.) implants of a syngeneic carcinoma for which there is no evidence of immunogenicity. Local pre-irradiation of the tumour bed or regional node did not enhance nodal metastasis. Thus, the phenomenon we are to describe is clearly distinct both from enhancement by immunosuppression and from enhancement by local pre-irradiation independent of immunosuppression. We also describe a number of experiments

Critical Review of Preclinical Approaches to Evaluate the Potential of Immunosuppressive Drugs to Influence Human Neoplasia

“…125 As IR is a complete carcinogen and the end points measure tumor incidence, this assay provides a global measure of carcinogenesis, and it is unlikely that the standard assay will provide insight into the mechanisms by which an immunotoxicant has affected carcinogenesis. Moreover, because IR itself is immunosuppressive and can enhance tumor growth and metastasis, 126 understanding the effects of an immunotoxicant could be problematic. That being said, special studies at the molecular level and studies of IR carcinogenesis in knockout mice or transgenic mice may shed light on the mechanism/mechanisms by which an immunotoxicants affects IR carcinogenesis.…”

Failure of preoperative C. parvum vaccine to modify secondary disease following excision of two non-immunogenic murine carcinomas

“…We have previously published data for the sites and times of manifestation of secondary disease in mice which had had intradermal transplants of this tumour excised (Hewitt, 1976;Hewitt and Blake, 1977a).…”

“…Fewer of the vaccinated than of the unvaccinated mice survived without disease to the end of the period of observation, but this difference is not significant. Additionally, we have compared the incidences and latent periods of the 3 forms of presentation of secondary disease in the vaccinated mice with the corresponding pooled values for 193 unvaccinated, operated mice observed in previous metastasis studies of this tumour (Hewitt and Blake, 1977a Table II, in the same form as for the similar experiment with the CBA carcinoma. It is seen that there is no significant difference in the incidence or mean time of presentation of the various categories of secondary disease, in the mean number of metastases per mouse, or in the survival rate at the end of the observation period.…”