Abstract
Objective. Currently, we lack a theoretical explanation for why squamous cell cervical cancer develops predominantly in specific sites (i.e., along the squamocolumnar junction). We therefore implanted human cervical tissues containing the transformation zone in severe combined immunodeficiency (SCID) mice and studied morphology, steroid effects, gene expression, and human papillomavirus (HPV) factors.Methods. Normal and dysplastic human cervical tissues (3 × 2 mm) were placed subcutaneously in SCID-beige mice and later assessed by in situ hybridization for HPV 16/18 DNA and by immunohistochemistry for expression of CD31, keratin, proliferating-cell nuclear antigen, HPV 16 E6, p53, and Notch-1 (a binary cell fate determination protein). Some normal tissues were implanted with either a 90-day release 1.7-mg 17β-estradiol pellet or a 5-mg tamoxifen pellet; others were infected prior to implantation with human recombinant adenovirus 5 vector containing a human cytomegalovirus promoter-driven β-galactosidase gene and later assessed by X-gal staining.Results. Murine and human vessels formed anastomoses by 3 weeks. For at least 11 weeks, normal tissue retained the transformation zone and normal cell-type-specific keratin expression and exhibited normal proliferation; Notch-1 was present only in the basal cell layer. Dysplastic tissues exhibited koilocytosis, increased levels of cellular proliferation, and aberrant keratin, p53, and Notch-1 expression; HPV 16/18 DNA and HPV 16 E6 protein were detected for at least 6 weeks. Squamous metaplasia of normal cervical epithelium resulted from estrogen exposure, and a predominant columnar differentiation pattern was associated with tamoxifen administration. Through stable adenovirus infection, β-galactosidase was expressed for at least 6 weeks.Conclusions. This small manipulatable xenograft model maintains normal and dysplastic human cervical epithelium through neovascularization. Neoplastic tissue retains HPV 16/18 DNA and a premalignant phenotype, including elevated levels of cellular proliferation and aberrant keratin, p53, and Notch-1 expression. These attributes constitute essential features of a biologic model through which one may study HPV-mediated human disease and may be superior to cell culture and transgenic murine systems. Furthermore, this may serve as a model for gene therapy. Finally, we suggest that the normal cervical epithelium is maintained through putative interactions between the Notch locus and cell cycle growth regulators such as p53 and pRb. Neoplastic cervical epithelium may arise through disruption of this pathway. This theory may be testable in our animal model.
Highlights
The ability to study the molecular and physiologic mechanisms which underly the development of cervical neoplasia is frustrated by the lack of an intact and manipulatable biologic model
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Summary
The ability to study the molecular and physiologic mechanisms which underly the development of cervical neoplasia is frustrated by the lack of an intact and manipulatable biologic model. Such a model is required to develop and test the various hypotheses which have been advanced to explain cervical carcinogenesis. Mutation of p53 has been associated with the disruption of apoptosis and stimulation of angiogenesis in a variety of human malignancies, including cervical carcinoma. Because the vast majority of cervical cancers contain integrated human papillomavirus (HPV) 16 or 18 DNA, the ability to assess viral factors would be a prerequisite for any model [1,2,3]. The protein products of the HPV 16/18 oncogenes E6 and E7 have been shown to cause inactivation and degradation of p53 and pRb, respectively, and may be involved in reprogramming the host immune system so that HPV infection is unrecognized
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