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Stomach Cancer in Transgenic Mice Expressing Human Papillomavirus Type 16 Early Region Genes From a Keratin Promoter

Jonathon M. Tinsley

Cancer Research Campaign Laboratories, Department of Cancer Studies, The University of Birmingham Medical School, Birmingham B15 2TJ, U.K.

Certain human papillomaviruses (HPVs) have been implicated as important contributory factors in the development of cervical carcinoma and other epithelial malignancies. In order to investigate the role of papillomavirus early gene expression in epithelial oncogenesis in vivo, we produced transgenic mice expressing HPV-16 early region genes from the promoter of the bovine keratin 6 gene. Spliced transcripts were detected in the tongue, forestomach, glandular stomach, female reproductive tract and tail skin of these mice. This expression was initially asymptomatic. However, at increasing frequency after approx. 100 days, solitary gland within the gastric mucosa became colonized with small dysplastic cells. Later this abnormal cell population spread within the glandular mucosa, invaded the submucosa and outer muscular wall of the stomach, and commonly metastasized to local lymph nodes and the liver. The appearance and staining characteristics of the tumours suggested their classification as malignant carcinoids, originating from the neuroendocrine enterochromaffin-like cells. Expression of HPV mRNAs was increased in the tumours, though it remained comparable to that in forestomach and tongue. The mean age at tumour presentation was 246 days in males and 352 days in females, all transgenic mice in eight independent lines were similarly susceptible. This study confirms the oncogenicity of HPV-16 early region genes, and establishes a model system in which to investigate mechanisms of malignant progression and possible therapeutic strategies for HPV-associated tumours.

Present address: Molecular Genetics Group, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, U.K.

Received 14 September 1993; accepted 26 November 1993.

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