Experimental reproduction of the papilloma-carcinoma complex of the alimentary canal in cattle.

Bovine papillomavirus type 4 (BPV-4) is the aetiological agent of epithelial papillomas of the upper alimentary canal in cattle. These benign tumours can become a focus for transformation to squamous cell carcinomas in animals feeding on bracken fern. Strong epidemiological evidence suggests that the progression to malignancy is due to the interplay between BPV-4 and mutagenic and immunosuppressing chemicals present in the fern. The carcinomas of the upper alimentary canal are often accompanied by adenomas and adenocarcinomas of the lower intestine and bracken-grazing animals are also heavily immunosuppressed. To elucidate the individual roles and the concerted action of the viral and chemical factors involved in tumorigenesis and malignant conversion, we attempted to reproduce experimentally the cancer syndrome observed in the field. Florid persistent papillomatosis of the upper alimentary canal was reproduced in animals infected with BPV-4 and immunosuppressed either by a diet of bracken or by treatment with azathioprine; cancer of the upper alimentary tract or of the lower intestine developed only in animals infected with virus and fed on bracken fern. As in field cases, BPV-4 DNA was detected in papillomas but not in cancers. We conclude that immunosuppression is necessary for persistence and spread of viral papillomas, that the fern mutagens are responsible for neoplastic conversion of papilloma cells, and that continuous expression of viral functions is not required for the maintenance of the malignant state.