Data from An <i>In vitro</i> Multistep Carcinogenesis Model for Human Cervical Cancer

Abstract

<div>Abstract<p>Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes <i>E6</i> and <i>E7</i> in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of <i>E6</i> and <i>E7</i> genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 <i>E6</i> and <i>E7</i> with or without <i>hTERT</i> into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic Hras<sup>G12V</sup> (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumor-initiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer. [Cancer Res 2008;68(14):5699–705]</p></div>