Pathology

  • Thomas H. Haugen, MD, PhD
    Research Laboratory

    Contact Information
    Phone: 319-158-7554, Ext 7554
    VA Health Care System

    Papillomavirus Infection and Carcinogenesis

    Papillomaviruses induce benign epithelial proliferation (e.g., warts) of the skin and mucosa. Individual papilloma-virus types are associated with benign lesions whereas others are found in proliferative lesions with a low or even considerable malignant potential.

    Mucosal human papillomaviruses (HPV) cause cervical cancer and are associated with a subset of head and neck cancers. In the infected cell, productive papillomavirus particles are derived from extrachromosomal viral plasmids. However, in many invasive HPV positive neoplasms, the HPV DNA is partially deleted and integrated into the cell genomic DNA.

    We have identiļ¬ed HPV-16 isolates that can establish persistent replication and "immortalize" primary human foreskin, cervical and tonsillar keratinocytes. Using primary keratinocytes and keratinocyte derived cell lines we have developed assays that allow us study human papilloma virus (HPV)-16 infection leading to persistence of replicating viral plasmid genomes. Our system allows us to dissect the individual viral factors required for this process. Studies are ongoing to determine how the regulation of viral gene expression controls viral replication.

    Primary keratinocytes normally exhibit a limited life span in culture. Introduction of HPV-16 into these cells extends their ability to divide without limit. Many of the derived keratinocyte cultures exhibit no detectable chromosomal alterations and contain 10-40 copies of non-integrated plasmid HPV-16 DNA. Upon extended culture, cell lines may spontaneously arise that overgrow the culture and contain only integrated HPV-16 DNA and variable additional chromosomal abnormalities. These cell lines have many similarities to cells of squamous carcinomas that also contain integrated HPV. Studies are underway to determine the role these genetic alterations play in altered cell growth and other acquired phenotypes in these cell lines. These cell lines provide a useful model system for the study of papillomavirus induced carcinogenesis.