Human Papillomavirus Early Gene Products and Maintenance of the Transformed State of Cervical Cancer Cells in Vitro

Abstract

There are several lines of evidence from epidemiological as well as from laboratory experimental work linking human papillomaviruses (HPV) to the development of squamous cell cancer of the uterine cervix:

• 1. The association of a sexually transmissible infectious agent is strongly suggested by epidemiological observations (for review, see Doll 1986)

• 2. Cervical intraepithelial neoplasias (CIN), considered as putative precursor lesions of cervical cancer, are regularly associated with HPVs. Recently, the development of this kind of lesion was induced by infection of normal human epithelium in vitro and subsequent grafting into nude mice (Kreider et al. 1985). From such lesions papillomavirus particles can be purified which are efficient in a second round of infection. Thus the Koch’s postulate for a causal relationship of the infectious agent and the disease have been fulfilled.

• 3. HPVs exhibit a transforming potential in vitro. Primary or established rodent cells can be transformed by transfection with the HPV early gene E7 (Bedell et al. 1987; Kanda et al. 1988; L. Laimins, personal communication), and a synergistic effect was observed with the activated human ras oncogene (Matlashewski et al. 1987). In addition, human keratinocytes, which represent the natural target cells for papillomavirus infection, are immortalized by HPV-16 or HPV-18 DNA, respectively (Drst et al. 1987; Pirisi et al. 1987; P. Kaur and J. McDougall, personal communication).