Development of a condemned mucosa syndrome and pathogenesis of human papillomavirus-associated upper aerodigestive tract and uterine cervical tumors

Abstract

High-risk human papillomaviruses (HPVs) have been shown to be involved in the pathogenesis of many squamous carcinomas, particularly those of the uterine cervix. A number of random studies have also reported association of high-risk HPV subtypes with cancers of the oral cavity, larynx, hypopharynx, and esophagus. The roles of other molecular factors involved during HPV infection in these tumors still remain unclear. Recent findings from our laboratories have suggested possible mechanisms associated with HPV-mediated carcinogenesis. Both p53 mutation-dependent and mutation-independent pathways may be associated with HPV-mediated carcinogenesis, the former mainly in upper aerodigestive tract tumors (UADT) and the latter in cervical tumors. In cervical tumors, inactivation of the p53 tumor suppressor protein by the E6 gene product of high-risk HPVs and mutation of the p53 gene in UADT is associated with alterations in the apoptotic regulatory bcl-2 and bax genes, leading to downregulation of programmed cell death (PCD) and increased cell proliferation. HPV infection is also associated with increased tissue angiogenesis and activation of telomerase. Altered kinetics of telomere fragments is evident in HPV-infected tissue. We therefore believe that the combined manifestations of all these factors may contribute to development of a "condemned mucosa syndrome" facilitating development UADT and cervical cancers. A distinct step in the pathogenesis of both types of tumors may only be in the mode of p53 inactivation, whereas all other events appear to be strongly correlated to the presence of HPV. The development and validation of such a molecular model has significant clinical priority. It can be used to identify target populations or individuals for intervention, to monitor effects of intervention, and to determine which individuals or groups are at increased risk of developing cancer.