Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens. (28th March 2020) - Böttinger, Paula
Abstract: Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma- in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E + ), mutant Kras (m Kras ) (K + ) and/or loss of Pten (P −/− ), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P +/+ mice, E6/E7 alone (P +/+ E + K − ) failed to cause premalignant changes, while m Kras alone (P +/+ E − K + ) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P +/+ mice needed both E6/E7 and m Kras expression. Longitudinal endoscopies of P +/+ E + K + mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P −/− E + K + genotype led to precipitous cancer development within a few weeks and E6/E7 -independent cancer development occurred in the P −/− E − K + genotype. In the P −/− E + K − genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis. Abstract : HPV16 E6/E7 -dependent carcinogenesis initiated by intravaginal instillation of adenoCre virus causes focal premalignant lesions that progress to cancer in the absence of exogenous estrogen and chemical carcinogens and that are detectable and individually tracked by longitudinal endoscopies.