Morphological transformation in vivo of human uterine cervix with papillomavirus from condylomata acuminata

Abstract

Carcinoma of the human uterine cervix has been associated with several infectious agents including papillomavirus. Papillomavirus group-specific antigen (GSA) and viral particles have been demonstrated in human condylomata acuminata (CA) and flat warts of the uterine cervix. Cell alterations consisting of nuclear enlargement, hyperchromasia, irregularity, binucleation and cytoplasmic clearing (koilocytosis) are often interpreted as mild to moderate dysplasia. Present evidence that human papillomavirus (HPV) is responsible for the development of these lesions relies on the association of GSA and virus particles in the affected tissue, fulfilling the first two of Koch's postulates. Direct proof of an aetiological relationship, however, requires induction of the CA change in normal, human uterine cervix after exposure to papillomavirus. Infecting human subjects with HPV is ethically unacceptable and no satisfactory alternative systems have been defined. Also, human cell cultures do not support growth or transformation by HPV. Here we report the first demonstration of the morphological transformation of human tissues with a human papillomavirus under controlled, experimental conditions. 'Transformation' is used here in its literal sense to refer to a heritable morphological alteration in the appearance of the cells. The use of this term does not indicate that the changes described are neoplastic, but they are identical to the dysplastic changes found in biopsies of uterine cervical CA. Our results demonstrate the direct involvement of CA virus in dysplastic change of human cervical tissue and indicate that the experimental system described may be useful in elucidating the contribution of human papillomaviruses to the pathogenesis of human cervical cancer.

Development and Assessment of a General Theory of Cervical Carcinogenesis Utilizing a Severe Combined Immunodeficiency Murine–Human Xenograft Model

“…In 1985, Kreider and co-workers reported a xenograft model for the study of human papillomavirus infections [11]. Human uterine cervix fragments were infected with a lysate prepared from condylomata acuminata and placed under the renal capsule of nude (i.e., athymic) mice.…”

“…As it is at the transformation zone where neoplasia develops, its absence from the keratinocyte models is problematic. In reports where cervical tissue had been successfully implanted below the renal capsule of mice, the implants were devoid of columnar epithelium and not well differentiated [11]. Because proliferation is not synonymous with differentiation, we proposed a small animal model which contained the human cervical transformation zone and ascertained the viability and morphologies of the implants at several points in time.…”

Use of human papillomavirus type 11 virions in an ELISA to detect specific antibodies in humans with condylomata acuminata

“…Fragments of human neonatal foreskins were infected with an HPV-11 viral suspension and placed under the renal capsule of nu/nu athymic mice according to the protocol described by Kreider et al (1985Kreider et al ( , 1987. The resulting tumours were collected several months later, pooled, and HPV-11 virions were purified by a series of high-speed and caesium chloride centrifugations, according to the protocol described by Favre et al (1975), but omitting trypsin treatment and the final sucrose gradient centrifugation.…”

“…The paucity of virions in most warts, including condylomata acuminata, and the inability to grow papillomaviruses in vitro, have limited the availability of suitable native antigens. The description by Kreider et al (1985Kreider et al ( , 1987 of the athymic mouse HPV-11-infected human xenograft model has now provided investigators with a method for the production of HPV-11 viral particles. Using these particles in an ELISA, we detected specific antibodies in sera of patients with documented condylomata acuminata.…”

Differentiation of xenografted human fetal lung parenchyma

“…Various xenograft models have been used extensively in cancer research to study mechanisms of carcinogenesis and the effects of different pharmacological agents on human tumor growth (Giovanella and Fogh, 1985;Malkinson, 2001), as well as in studies of transmission of infection in various tissues by pathogens (Howett et al, 1997;Howett et al, 1990;Howett et al, 1999;Kish et al, 2001;Kreider et al, 1985). With respect to lung embryogenesis, immunocompromised mice have been used to study whole organ lung development in mice (Schwarz et al, 2000;Vu et al, 2003), as well as lower (Groscurth and Tondury, 1982;Peault et al, 1994) and upper airway development in humans (Delplanque et al, 2000;Deutsch, 1997;Engelhardt et al, 1993;Filali et al, 2002;Pilewski et al, 1994;Puchelle and Peault, 2000).…”