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

Abstract

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 glands within the gastric mucosa became colonized with small dysplastic ceils. 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.

Human keratin 14 driven HPV 16 E6/E7 transgenic mice exhibit hyperkeratinosis

“…These findings suggest that HPV16 E6/E7 expression can induce aberrant epithelial hyperplasia and epidermal differentiation within the suprabasal compartment of epidermis. These findings were similar to that of other transgenic mouse models (Searle et al, 1994).…”

“…Recently, numbers of transgenic mice carrying HPV16 E6/E7 gene has been established, however, these HPV16 E6/E7 transgenic mice did not exhibit any tissue specificity for the induction of tumorigenesis (Arbeit et al, 1993;Greenhalgh et al, 1994;Sasagawa et al, 1994;Searle et al, 1994).…”

Impact of transforming viruses on cellular mutagenesis, genome stability, and cellular transformation

“…Interestingly, in contrast to Tax-or HBxtransformed cells, E6-, E7-, or E6/E7-transformed cells rarely produce tumors when transplanted into nude mice [Kaur and McDougall, 1988;Pirisi et al, 1988;Woodworth et al, 1988]. However, numerous versions of E6, E7, and E6/E7 transgenic mice develop either benign tumors or cancers [Kondoh et al, 1991;Arbeit et al, 1993Arbeit et al, , 1994Griep et al, 1993;Lambert et al, 1993;Searle et al, 1994;Comerford et al, 1995;Herber et al, 1996;Song et al, 1999]. The frequency and type of malignancy seems to depend largely on the promoter used to drive expression of the viral oncogene(s).…”

Corneal Epithelium-specific Mouse Keratin K12 Promoter

“…Keratin promoters have been used extensively to drive expression of transgenes in transgenic animals because of the tissue-specific expression characteristic of many of these genes (Alexander et al, 1995 ;Bailleul et al, 1990 ;Cheng et al, 1992 ;Davis et al, 1993 ;Davis et al, 1996 ;Jonas, Snape and Sargent, 1989 ;McNab et al, 1990 ;Rodriguez et al, 1997 ;Searie et al, 1994 ;Sutton et al, 1991 ;Wang et al, 1997 ;Werner et al, 1994 ;Williams and Kupper, 1994). Expression of keratin K12 is restricted to the corneal epithelium, even though keratin K3 may be undetectable in mouse cornea (Chaloin-Dufau et al, 1993).…”